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FDA expands remdesivir use for all COVID-19 hospitalized patients
An EUA of remdesivir issued in May allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who need oxygen therapy or mechanical ventilation.
“Today, based on the Agency’s ongoing review of the EUA, including its review of the totality of scientific information now available, the FDA has determined that it is reasonable to believe Veklury may be effective for the treatment of suspected or laboratory-confirmed COVID-19 in all hospitalized adult and pediatric patients,” the FDA news release about the expanded EUA said. “The Agency’s review has also concluded that the known and potential benefits of Veklury outweigh the known and potential risks for these uses.”
‘Further evaluation’ needed
The EUA expansion is partially based on the results of a randomized, open-label trial that Gilead Sciences, remdesivir’s manufacturer, conducted at multiple sites.
The trial showed that a 5-day course of remdesivir was associated with statistically significant improvement among patients hospitalized with moderate COVID-19 in comparison with those receiving standard care. However, patients who were randomly assigned to a receive longer, 10-day remdesivir course had not improved significantly 11 days after treatment started, compared with those who received standard care.
Results with remdesivir in this trial and in two previously reported randomized trials varied, “raising the question of whether the discrepancies are artifacts of study design choices, including patient populations, or whether the drug is less efficacious than hoped,” wrote Erin K. McCreary, PharmD, and Derek C. Angus, MD, MPH, with the University of Pittsburgh School of Medicine, in an editorial that accompanied publication of the trials in JAMA.
Angus previously expressed concern that expanding remdesivir’s EUA could “interrupt or thwart efforts to execute the needed RCTs [randomized controlled trials].
“We think there really needs to be further evaluation of remdesivir in large-scale RCTs adequately powered to understand in which patients, at which dose, given at which point in the course of illness leads to what concrete and tangible improvement in clinical outcomes,” he told Medscape Medical News.
“At this point, remdesivir definitely holds promise, but given the cost to produce and distribute the drug, it seems crucial to know with more certainty how best to use it,” Angus said.
The EUA expansion is also partially based on results from a randomized, double-blind, placebo-controlled clinical trial that the National Institutes of Allergy and Infectious Diseases conducted. In that trial, there was a statistically significant reduction in median recovery time and higher odds of clinical improvement after 2 weeks for hospitalized patients who received remdesivir.
For hospitalized patients with mild to moderate disease, the results were consistent with the overall study results but were not statistically significant.
This article first appeared on Medscape.com.
An EUA of remdesivir issued in May allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who need oxygen therapy or mechanical ventilation.
“Today, based on the Agency’s ongoing review of the EUA, including its review of the totality of scientific information now available, the FDA has determined that it is reasonable to believe Veklury may be effective for the treatment of suspected or laboratory-confirmed COVID-19 in all hospitalized adult and pediatric patients,” the FDA news release about the expanded EUA said. “The Agency’s review has also concluded that the known and potential benefits of Veklury outweigh the known and potential risks for these uses.”
‘Further evaluation’ needed
The EUA expansion is partially based on the results of a randomized, open-label trial that Gilead Sciences, remdesivir’s manufacturer, conducted at multiple sites.
The trial showed that a 5-day course of remdesivir was associated with statistically significant improvement among patients hospitalized with moderate COVID-19 in comparison with those receiving standard care. However, patients who were randomly assigned to a receive longer, 10-day remdesivir course had not improved significantly 11 days after treatment started, compared with those who received standard care.
Results with remdesivir in this trial and in two previously reported randomized trials varied, “raising the question of whether the discrepancies are artifacts of study design choices, including patient populations, or whether the drug is less efficacious than hoped,” wrote Erin K. McCreary, PharmD, and Derek C. Angus, MD, MPH, with the University of Pittsburgh School of Medicine, in an editorial that accompanied publication of the trials in JAMA.
Angus previously expressed concern that expanding remdesivir’s EUA could “interrupt or thwart efforts to execute the needed RCTs [randomized controlled trials].
“We think there really needs to be further evaluation of remdesivir in large-scale RCTs adequately powered to understand in which patients, at which dose, given at which point in the course of illness leads to what concrete and tangible improvement in clinical outcomes,” he told Medscape Medical News.
“At this point, remdesivir definitely holds promise, but given the cost to produce and distribute the drug, it seems crucial to know with more certainty how best to use it,” Angus said.
The EUA expansion is also partially based on results from a randomized, double-blind, placebo-controlled clinical trial that the National Institutes of Allergy and Infectious Diseases conducted. In that trial, there was a statistically significant reduction in median recovery time and higher odds of clinical improvement after 2 weeks for hospitalized patients who received remdesivir.
For hospitalized patients with mild to moderate disease, the results were consistent with the overall study results but were not statistically significant.
This article first appeared on Medscape.com.
An EUA of remdesivir issued in May allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who need oxygen therapy or mechanical ventilation.
“Today, based on the Agency’s ongoing review of the EUA, including its review of the totality of scientific information now available, the FDA has determined that it is reasonable to believe Veklury may be effective for the treatment of suspected or laboratory-confirmed COVID-19 in all hospitalized adult and pediatric patients,” the FDA news release about the expanded EUA said. “The Agency’s review has also concluded that the known and potential benefits of Veklury outweigh the known and potential risks for these uses.”
‘Further evaluation’ needed
The EUA expansion is partially based on the results of a randomized, open-label trial that Gilead Sciences, remdesivir’s manufacturer, conducted at multiple sites.
The trial showed that a 5-day course of remdesivir was associated with statistically significant improvement among patients hospitalized with moderate COVID-19 in comparison with those receiving standard care. However, patients who were randomly assigned to a receive longer, 10-day remdesivir course had not improved significantly 11 days after treatment started, compared with those who received standard care.
Results with remdesivir in this trial and in two previously reported randomized trials varied, “raising the question of whether the discrepancies are artifacts of study design choices, including patient populations, or whether the drug is less efficacious than hoped,” wrote Erin K. McCreary, PharmD, and Derek C. Angus, MD, MPH, with the University of Pittsburgh School of Medicine, in an editorial that accompanied publication of the trials in JAMA.
Angus previously expressed concern that expanding remdesivir’s EUA could “interrupt or thwart efforts to execute the needed RCTs [randomized controlled trials].
“We think there really needs to be further evaluation of remdesivir in large-scale RCTs adequately powered to understand in which patients, at which dose, given at which point in the course of illness leads to what concrete and tangible improvement in clinical outcomes,” he told Medscape Medical News.
“At this point, remdesivir definitely holds promise, but given the cost to produce and distribute the drug, it seems crucial to know with more certainty how best to use it,” Angus said.
The EUA expansion is also partially based on results from a randomized, double-blind, placebo-controlled clinical trial that the National Institutes of Allergy and Infectious Diseases conducted. In that trial, there was a statistically significant reduction in median recovery time and higher odds of clinical improvement after 2 weeks for hospitalized patients who received remdesivir.
For hospitalized patients with mild to moderate disease, the results were consistent with the overall study results but were not statistically significant.
This article first appeared on Medscape.com.
Immunotherapy should not be withheld because of sex, age, or PS
The improvement in survival in many cancer types that is seen with immune checkpoint inhibitors (ICIs), when compared to control therapies, is not affected by the patient’s sex, age, or Eastern Cooperative Oncology Group (ECOG) performance status (PS), according to a new meta-analysis.
Therefore, treatment with these immunotherapies should not be withheld on the basis of these factors, the authors concluded.
Asked whether there have been such instances of withholding ICIs, lead author Yucai Wang, MD, PhD, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News: “We did this study solely based on scientific questions we had and not because we were seeing any bias at the moment in the use of ICIs.
“And we saw that the survival benefits were very similar across all of the categories [we analyzed], with a survival benefit of about 20% from immunotherapy across the board, which is clinically meaningful,” he added.
The study was published online August 7 in JAMA Network Open.
“The comparable survival advantage between patients of different sex, age, and ECOG PS may encourage more patients to receive ICI treatment regardless of cancer types, lines of therapy, agents of immunotherapy, and intervention therapies,” the authors commented.
Wang noted that there have been conflicting reports in the literature suggesting that male patients may benefit more from immunotherapy than female patients and that older patients may benefit more from the same treatment than younger patients.
However, there are also suggestions in the literature that women experience a stronger immune response than men and that, with aging, the immune system generally undergoes immunosenescence.
In addition, the PS of oncology patients has been implicated in how well patients respond to immunotherapy.
Wang noted that the findings of past studies have contradicted each other.
Findings of the Meta-Analysis
The meta-analysis included 37 randomized clinical trials that involved a total of 23,760 patients with a variety of advanced cancers. “Most of the trials were phase 3 (n = 34) and conduced for subsequent lines of therapy (n = 22),” the authors explained.
The most common cancers treated with an ICI were non–small cell lung cancer and melanoma.
Pooled overall survival (OS) hazard ratios (HRs) were calculated on the basis of sex, age (younger than 65 years and 65 years and older), and an ECOG PS of 0 and 1 or higher.
Responses were stratified on the basis of cancer type, line of therapy, the ICI used, and the immunotherapy strategy used in the ICI arm.
Most of the drugs evaluated were PD-1 and PD-L1 inhibitors. The specific drugs assessed included ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab.
A total of 32 trials that involved more than 20,000 patients reported HRs for death according to the patients’ sex. Thirty-four trials that involved more than 21,000 patients reported HRs for death according to patients’ age, and 30 trials that involved more than 19,000 patients reported HRs for death according to patients’ ECOG PS.
No significant differences in OS benefit were seen by cancer type, line of therapy, agent of immunotherapy, or intervention strategy, the investigators pointed out.
There were also no differences in survival benefit associated with immunotherapy vs control therapies for patients with an ECOG PS of 0 and an ECOG PS of 1 or greater. The OS benefit was 0.81 for those with an ECOG PS of 0 and 0.79 for those with an ECOG PS of 1 or greater.
Wang has disclosed no relevant financial relationships.
This article first appeared on Medscape.com .
The improvement in survival in many cancer types that is seen with immune checkpoint inhibitors (ICIs), when compared to control therapies, is not affected by the patient’s sex, age, or Eastern Cooperative Oncology Group (ECOG) performance status (PS), according to a new meta-analysis.
Therefore, treatment with these immunotherapies should not be withheld on the basis of these factors, the authors concluded.
Asked whether there have been such instances of withholding ICIs, lead author Yucai Wang, MD, PhD, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News: “We did this study solely based on scientific questions we had and not because we were seeing any bias at the moment in the use of ICIs.
“And we saw that the survival benefits were very similar across all of the categories [we analyzed], with a survival benefit of about 20% from immunotherapy across the board, which is clinically meaningful,” he added.
The study was published online August 7 in JAMA Network Open.
“The comparable survival advantage between patients of different sex, age, and ECOG PS may encourage more patients to receive ICI treatment regardless of cancer types, lines of therapy, agents of immunotherapy, and intervention therapies,” the authors commented.
Wang noted that there have been conflicting reports in the literature suggesting that male patients may benefit more from immunotherapy than female patients and that older patients may benefit more from the same treatment than younger patients.
However, there are also suggestions in the literature that women experience a stronger immune response than men and that, with aging, the immune system generally undergoes immunosenescence.
In addition, the PS of oncology patients has been implicated in how well patients respond to immunotherapy.
Wang noted that the findings of past studies have contradicted each other.
Findings of the Meta-Analysis
The meta-analysis included 37 randomized clinical trials that involved a total of 23,760 patients with a variety of advanced cancers. “Most of the trials were phase 3 (n = 34) and conduced for subsequent lines of therapy (n = 22),” the authors explained.
The most common cancers treated with an ICI were non–small cell lung cancer and melanoma.
Pooled overall survival (OS) hazard ratios (HRs) were calculated on the basis of sex, age (younger than 65 years and 65 years and older), and an ECOG PS of 0 and 1 or higher.
Responses were stratified on the basis of cancer type, line of therapy, the ICI used, and the immunotherapy strategy used in the ICI arm.
Most of the drugs evaluated were PD-1 and PD-L1 inhibitors. The specific drugs assessed included ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab.
A total of 32 trials that involved more than 20,000 patients reported HRs for death according to the patients’ sex. Thirty-four trials that involved more than 21,000 patients reported HRs for death according to patients’ age, and 30 trials that involved more than 19,000 patients reported HRs for death according to patients’ ECOG PS.
No significant differences in OS benefit were seen by cancer type, line of therapy, agent of immunotherapy, or intervention strategy, the investigators pointed out.
There were also no differences in survival benefit associated with immunotherapy vs control therapies for patients with an ECOG PS of 0 and an ECOG PS of 1 or greater. The OS benefit was 0.81 for those with an ECOG PS of 0 and 0.79 for those with an ECOG PS of 1 or greater.
Wang has disclosed no relevant financial relationships.
This article first appeared on Medscape.com .
The improvement in survival in many cancer types that is seen with immune checkpoint inhibitors (ICIs), when compared to control therapies, is not affected by the patient’s sex, age, or Eastern Cooperative Oncology Group (ECOG) performance status (PS), according to a new meta-analysis.
Therefore, treatment with these immunotherapies should not be withheld on the basis of these factors, the authors concluded.
Asked whether there have been such instances of withholding ICIs, lead author Yucai Wang, MD, PhD, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News: “We did this study solely based on scientific questions we had and not because we were seeing any bias at the moment in the use of ICIs.
“And we saw that the survival benefits were very similar across all of the categories [we analyzed], with a survival benefit of about 20% from immunotherapy across the board, which is clinically meaningful,” he added.
The study was published online August 7 in JAMA Network Open.
“The comparable survival advantage between patients of different sex, age, and ECOG PS may encourage more patients to receive ICI treatment regardless of cancer types, lines of therapy, agents of immunotherapy, and intervention therapies,” the authors commented.
Wang noted that there have been conflicting reports in the literature suggesting that male patients may benefit more from immunotherapy than female patients and that older patients may benefit more from the same treatment than younger patients.
However, there are also suggestions in the literature that women experience a stronger immune response than men and that, with aging, the immune system generally undergoes immunosenescence.
In addition, the PS of oncology patients has been implicated in how well patients respond to immunotherapy.
Wang noted that the findings of past studies have contradicted each other.
Findings of the Meta-Analysis
The meta-analysis included 37 randomized clinical trials that involved a total of 23,760 patients with a variety of advanced cancers. “Most of the trials were phase 3 (n = 34) and conduced for subsequent lines of therapy (n = 22),” the authors explained.
The most common cancers treated with an ICI were non–small cell lung cancer and melanoma.
Pooled overall survival (OS) hazard ratios (HRs) were calculated on the basis of sex, age (younger than 65 years and 65 years and older), and an ECOG PS of 0 and 1 or higher.
Responses were stratified on the basis of cancer type, line of therapy, the ICI used, and the immunotherapy strategy used in the ICI arm.
Most of the drugs evaluated were PD-1 and PD-L1 inhibitors. The specific drugs assessed included ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab.
A total of 32 trials that involved more than 20,000 patients reported HRs for death according to the patients’ sex. Thirty-four trials that involved more than 21,000 patients reported HRs for death according to patients’ age, and 30 trials that involved more than 19,000 patients reported HRs for death according to patients’ ECOG PS.
No significant differences in OS benefit were seen by cancer type, line of therapy, agent of immunotherapy, or intervention strategy, the investigators pointed out.
There were also no differences in survival benefit associated with immunotherapy vs control therapies for patients with an ECOG PS of 0 and an ECOG PS of 1 or greater. The OS benefit was 0.81 for those with an ECOG PS of 0 and 0.79 for those with an ECOG PS of 1 or greater.
Wang has disclosed no relevant financial relationships.
This article first appeared on Medscape.com .
Aspirin may accelerate cancer progression in older adults
Aspirin may accelerate the progression of advanced cancers and lead to an earlier death as a result, new data from the ASPREE study suggest.
The results showed that patients 65 years and older who started taking daily low-dose aspirin had a 19% higher chance of being diagnosed with metastatic cancer, a 22% higher chance of being diagnosed with a stage 4 tumor, and a 31% increased risk of death from stage 4 cancer, when compared with patients who took a placebo.
John J. McNeil, MBBS, PhD, of Monash University in Melbourne, Australia, and colleagues detailed these findings in the Journal of the National Cancer Institute.
“If confirmed, the clinical implications of these findings could be important for the use of aspirin in an older population,” the authors wrote.
When results of the ASPREE study were first reported in 2018, they “raised important concerns,” Ernest Hawk, MD, and Karen Colbert Maresso wrote in an editorial related to the current publication.
“Unlike ARRIVE, ASCEND, and nearly all prior primary prevention CVD [cardiovascular disease] trials of aspirin, ASPREE surprisingly demonstrated increased all-cause mortality in the aspirin group, which appeared to be driven largely by an increase in cancer-related deaths,” wrote the editorialists, who are both from the University of Texas MD Anderson Cancer Center in Houston.
Even though the ASPREE investigators have now taken a deeper dive into their data, the findings “neither explain nor alleviate the concerns raised by the initial ASPREE report,” the editorialists noted.
ASPREE design and results
ASPREE is a multicenter, double-blind trial of 19,114 older adults living in Australia (n = 16,703) or the United States (n = 2,411). Most patients were 70 years or older at baseline. However, the U.S. group also included patients 65 years and older who were racial/ethnic minorities (n = 564).
Patients were randomized to receive 100 mg of enteric-coated aspirin daily (n = 9,525) or matching placebo (n = 9,589) from March 2010 through December 2014.
At inclusion, all participants were free from cardiovascular disease, dementia, or physical disability. A previous history of cancer was not used to exclude participants, and 19.1% of patients had cancer at randomization. Most patients (89%) had not used aspirin regularly before entering the trial.
At a median follow-up of 4.7 years, there were 981 incident cancer events in the aspirin-treated group and 952 in the placebo-treated group, with an overall incident cancer rate of 10.1%.
Of the 1,933 patients with newly diagnosed cancer, 65.7% had a localized cancer, 18.8% had a new metastatic cancer, 5.8% had metastatic disease from an existing cancer, and 9.7% had a new hematologic or lymphatic cancer.
A quarter of cancer patients (n = 495) died as a result of their malignancy, with 52 dying from a cancer they already had at randomization.
Aspirin was not associated with the risk of first incident cancer diagnosis or incident localized cancer diagnosis. The hazard ratios were 1.04 for all incident cancers (95% confidence interval, 0.95-1.14) and 0.99 for incident localized cancers (95% CI, 0.89-1.11).
However, aspirin was associated with an increased risk of metastatic cancer and cancer presenting at stage 4. The HR for metastatic cancer was 1.19 (95% CI, 1.00-1.43), and the HR for newly diagnosed stage 4 cancer was 1.22 (95% CI, 1.02-1.45).
Furthermore, “an increased progression to death was observed amongst those randomized to aspirin, regardless of whether the initial cancer presentation had been localized or metastatic,” the investigators wrote.
The HRs for death were 1.35 for all cancers (95% CI, 1.13-1.61), 1.47 for localized cancers (95% CI, 1.07-2.02), and 1.30 for metastatic cancers (95% CI, 1.03-1.63).
“Deaths were particularly high among those on aspirin who were diagnosed with advanced solid cancers,” study author Andrew Chan, MD, of Massachusetts General Hospital in Boston, said in a press statement.
Indeed, HRs for death in patients with solid tumors presenting at stage 3 and 4 were a respective 2.11 (95% CI, 1.03-4.33) and 1.31 (95% CI, 1.04-1.64). This suggests a possible adverse effect of aspirin on the growth of cancers once they have already developed in older adults, Dr. Chan said.
Where does that leave aspirin for cancer prevention?
“Although these results suggest that we should be cautious about starting aspirin therapy in otherwise healthy older adults, this does not mean that individuals who are already taking aspirin – particularly if they began taking it at a younger age – should stop their aspirin regimen,” Dr. Chan said.
There are decades of data supporting the use of daily aspirin to prevent multiple cancer types, particularly colorectal cancer, in individuals under the age of 70 years. In a recent meta-analysis, for example, regular aspirin use was linked to a 27% reduced risk for colorectal cancer, a 33% reduced risk for squamous cell esophageal cancer, a 39% decreased risk for adenocarcinoma of the esophagus and gastric cardia, a 36% decreased risk for stomach cancer, a 38% decreased risk for hepatobiliary tract cancer, and a 22% decreased risk for pancreatic cancer.
While these figures are mostly based on observational and case-control studies, it “reaffirms the fact that, overall, when you look at all of the ages, that there is still a benefit of aspirin for cancer,” John Cuzick, PhD, of Queen Mary University of London (England), said in an interview.
In fact, the meta-analysis goes as far as suggesting that perhaps the dose of aspirin being used is too low, with the authors noting that there was a 35% risk reduction in colorectal cancer with a dose of 325 mg daily. That’s a new finding, Dr. Cuzick said.
He noted that the ASPREE study largely consists of patients 70 years of age or older, and the authors “draw some conclusions which we can’t ignore about potential safety.”
One of the safety concerns is the increased risk for gastrointestinal bleeding, which is why Dr. Cuzick and colleagues previously recommended caution in the use of aspirin to prevent cancer in elderly patients. The group published a study in 2015 that suggested a benefit of taking aspirin daily for 5-10 years in patients aged 50-65 years, but the risk/benefit ratio was unclear for patients 70 years and older.
The ASPREE data now add to those uncertainties and suggest “there may be some side effects that we do not understand,” Dr. Cuzick said.
“I’m still optimistic that aspirin is going to be important for cancer prevention, but probably focusing on ages 50-70,” he added. “[The ASPREE data] reinforce the caution that we have to take in terms of trying to understand what the side effects are and what’s going on at these older ages.”
Dr. Cuzick is currently leading the AsCaP Project, an international effort to better understand why aspirin might work in preventing some cancer types but not others. AsCaP is supported by Cancer Research UK and also includes Dr. Chan among the researchers attempting to find out which patients may benefit the most from aspirin and which may be at greater risk of adverse effects.
The ASPREE trial was funded by grants from the National Institute on Aging, the National Cancer Institute, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Several ASPREE investigators disclosed financial relationships with Bayer Pharma. The editorialists had no conflicts of interest. Dr. Cuzick has been an advisory board member for Bayer in the past.
SOURCE: McNeil J et al. J Natl Cancer Inst. 2020 Aug 11. doi: 10.1093/jnci/djaa114.
Aspirin may accelerate the progression of advanced cancers and lead to an earlier death as a result, new data from the ASPREE study suggest.
The results showed that patients 65 years and older who started taking daily low-dose aspirin had a 19% higher chance of being diagnosed with metastatic cancer, a 22% higher chance of being diagnosed with a stage 4 tumor, and a 31% increased risk of death from stage 4 cancer, when compared with patients who took a placebo.
John J. McNeil, MBBS, PhD, of Monash University in Melbourne, Australia, and colleagues detailed these findings in the Journal of the National Cancer Institute.
“If confirmed, the clinical implications of these findings could be important for the use of aspirin in an older population,” the authors wrote.
When results of the ASPREE study were first reported in 2018, they “raised important concerns,” Ernest Hawk, MD, and Karen Colbert Maresso wrote in an editorial related to the current publication.
“Unlike ARRIVE, ASCEND, and nearly all prior primary prevention CVD [cardiovascular disease] trials of aspirin, ASPREE surprisingly demonstrated increased all-cause mortality in the aspirin group, which appeared to be driven largely by an increase in cancer-related deaths,” wrote the editorialists, who are both from the University of Texas MD Anderson Cancer Center in Houston.
Even though the ASPREE investigators have now taken a deeper dive into their data, the findings “neither explain nor alleviate the concerns raised by the initial ASPREE report,” the editorialists noted.
ASPREE design and results
ASPREE is a multicenter, double-blind trial of 19,114 older adults living in Australia (n = 16,703) or the United States (n = 2,411). Most patients were 70 years or older at baseline. However, the U.S. group also included patients 65 years and older who were racial/ethnic minorities (n = 564).
Patients were randomized to receive 100 mg of enteric-coated aspirin daily (n = 9,525) or matching placebo (n = 9,589) from March 2010 through December 2014.
At inclusion, all participants were free from cardiovascular disease, dementia, or physical disability. A previous history of cancer was not used to exclude participants, and 19.1% of patients had cancer at randomization. Most patients (89%) had not used aspirin regularly before entering the trial.
At a median follow-up of 4.7 years, there were 981 incident cancer events in the aspirin-treated group and 952 in the placebo-treated group, with an overall incident cancer rate of 10.1%.
Of the 1,933 patients with newly diagnosed cancer, 65.7% had a localized cancer, 18.8% had a new metastatic cancer, 5.8% had metastatic disease from an existing cancer, and 9.7% had a new hematologic or lymphatic cancer.
A quarter of cancer patients (n = 495) died as a result of their malignancy, with 52 dying from a cancer they already had at randomization.
Aspirin was not associated with the risk of first incident cancer diagnosis or incident localized cancer diagnosis. The hazard ratios were 1.04 for all incident cancers (95% confidence interval, 0.95-1.14) and 0.99 for incident localized cancers (95% CI, 0.89-1.11).
However, aspirin was associated with an increased risk of metastatic cancer and cancer presenting at stage 4. The HR for metastatic cancer was 1.19 (95% CI, 1.00-1.43), and the HR for newly diagnosed stage 4 cancer was 1.22 (95% CI, 1.02-1.45).
Furthermore, “an increased progression to death was observed amongst those randomized to aspirin, regardless of whether the initial cancer presentation had been localized or metastatic,” the investigators wrote.
The HRs for death were 1.35 for all cancers (95% CI, 1.13-1.61), 1.47 for localized cancers (95% CI, 1.07-2.02), and 1.30 for metastatic cancers (95% CI, 1.03-1.63).
“Deaths were particularly high among those on aspirin who were diagnosed with advanced solid cancers,” study author Andrew Chan, MD, of Massachusetts General Hospital in Boston, said in a press statement.
Indeed, HRs for death in patients with solid tumors presenting at stage 3 and 4 were a respective 2.11 (95% CI, 1.03-4.33) and 1.31 (95% CI, 1.04-1.64). This suggests a possible adverse effect of aspirin on the growth of cancers once they have already developed in older adults, Dr. Chan said.
Where does that leave aspirin for cancer prevention?
“Although these results suggest that we should be cautious about starting aspirin therapy in otherwise healthy older adults, this does not mean that individuals who are already taking aspirin – particularly if they began taking it at a younger age – should stop their aspirin regimen,” Dr. Chan said.
There are decades of data supporting the use of daily aspirin to prevent multiple cancer types, particularly colorectal cancer, in individuals under the age of 70 years. In a recent meta-analysis, for example, regular aspirin use was linked to a 27% reduced risk for colorectal cancer, a 33% reduced risk for squamous cell esophageal cancer, a 39% decreased risk for adenocarcinoma of the esophagus and gastric cardia, a 36% decreased risk for stomach cancer, a 38% decreased risk for hepatobiliary tract cancer, and a 22% decreased risk for pancreatic cancer.
While these figures are mostly based on observational and case-control studies, it “reaffirms the fact that, overall, when you look at all of the ages, that there is still a benefit of aspirin for cancer,” John Cuzick, PhD, of Queen Mary University of London (England), said in an interview.
In fact, the meta-analysis goes as far as suggesting that perhaps the dose of aspirin being used is too low, with the authors noting that there was a 35% risk reduction in colorectal cancer with a dose of 325 mg daily. That’s a new finding, Dr. Cuzick said.
He noted that the ASPREE study largely consists of patients 70 years of age or older, and the authors “draw some conclusions which we can’t ignore about potential safety.”
One of the safety concerns is the increased risk for gastrointestinal bleeding, which is why Dr. Cuzick and colleagues previously recommended caution in the use of aspirin to prevent cancer in elderly patients. The group published a study in 2015 that suggested a benefit of taking aspirin daily for 5-10 years in patients aged 50-65 years, but the risk/benefit ratio was unclear for patients 70 years and older.
The ASPREE data now add to those uncertainties and suggest “there may be some side effects that we do not understand,” Dr. Cuzick said.
“I’m still optimistic that aspirin is going to be important for cancer prevention, but probably focusing on ages 50-70,” he added. “[The ASPREE data] reinforce the caution that we have to take in terms of trying to understand what the side effects are and what’s going on at these older ages.”
Dr. Cuzick is currently leading the AsCaP Project, an international effort to better understand why aspirin might work in preventing some cancer types but not others. AsCaP is supported by Cancer Research UK and also includes Dr. Chan among the researchers attempting to find out which patients may benefit the most from aspirin and which may be at greater risk of adverse effects.
The ASPREE trial was funded by grants from the National Institute on Aging, the National Cancer Institute, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Several ASPREE investigators disclosed financial relationships with Bayer Pharma. The editorialists had no conflicts of interest. Dr. Cuzick has been an advisory board member for Bayer in the past.
SOURCE: McNeil J et al. J Natl Cancer Inst. 2020 Aug 11. doi: 10.1093/jnci/djaa114.
Aspirin may accelerate the progression of advanced cancers and lead to an earlier death as a result, new data from the ASPREE study suggest.
The results showed that patients 65 years and older who started taking daily low-dose aspirin had a 19% higher chance of being diagnosed with metastatic cancer, a 22% higher chance of being diagnosed with a stage 4 tumor, and a 31% increased risk of death from stage 4 cancer, when compared with patients who took a placebo.
John J. McNeil, MBBS, PhD, of Monash University in Melbourne, Australia, and colleagues detailed these findings in the Journal of the National Cancer Institute.
“If confirmed, the clinical implications of these findings could be important for the use of aspirin in an older population,” the authors wrote.
When results of the ASPREE study were first reported in 2018, they “raised important concerns,” Ernest Hawk, MD, and Karen Colbert Maresso wrote in an editorial related to the current publication.
“Unlike ARRIVE, ASCEND, and nearly all prior primary prevention CVD [cardiovascular disease] trials of aspirin, ASPREE surprisingly demonstrated increased all-cause mortality in the aspirin group, which appeared to be driven largely by an increase in cancer-related deaths,” wrote the editorialists, who are both from the University of Texas MD Anderson Cancer Center in Houston.
Even though the ASPREE investigators have now taken a deeper dive into their data, the findings “neither explain nor alleviate the concerns raised by the initial ASPREE report,” the editorialists noted.
ASPREE design and results
ASPREE is a multicenter, double-blind trial of 19,114 older adults living in Australia (n = 16,703) or the United States (n = 2,411). Most patients were 70 years or older at baseline. However, the U.S. group also included patients 65 years and older who were racial/ethnic minorities (n = 564).
Patients were randomized to receive 100 mg of enteric-coated aspirin daily (n = 9,525) or matching placebo (n = 9,589) from March 2010 through December 2014.
At inclusion, all participants were free from cardiovascular disease, dementia, or physical disability. A previous history of cancer was not used to exclude participants, and 19.1% of patients had cancer at randomization. Most patients (89%) had not used aspirin regularly before entering the trial.
At a median follow-up of 4.7 years, there were 981 incident cancer events in the aspirin-treated group and 952 in the placebo-treated group, with an overall incident cancer rate of 10.1%.
Of the 1,933 patients with newly diagnosed cancer, 65.7% had a localized cancer, 18.8% had a new metastatic cancer, 5.8% had metastatic disease from an existing cancer, and 9.7% had a new hematologic or lymphatic cancer.
A quarter of cancer patients (n = 495) died as a result of their malignancy, with 52 dying from a cancer they already had at randomization.
Aspirin was not associated with the risk of first incident cancer diagnosis or incident localized cancer diagnosis. The hazard ratios were 1.04 for all incident cancers (95% confidence interval, 0.95-1.14) and 0.99 for incident localized cancers (95% CI, 0.89-1.11).
However, aspirin was associated with an increased risk of metastatic cancer and cancer presenting at stage 4. The HR for metastatic cancer was 1.19 (95% CI, 1.00-1.43), and the HR for newly diagnosed stage 4 cancer was 1.22 (95% CI, 1.02-1.45).
Furthermore, “an increased progression to death was observed amongst those randomized to aspirin, regardless of whether the initial cancer presentation had been localized or metastatic,” the investigators wrote.
The HRs for death were 1.35 for all cancers (95% CI, 1.13-1.61), 1.47 for localized cancers (95% CI, 1.07-2.02), and 1.30 for metastatic cancers (95% CI, 1.03-1.63).
“Deaths were particularly high among those on aspirin who were diagnosed with advanced solid cancers,” study author Andrew Chan, MD, of Massachusetts General Hospital in Boston, said in a press statement.
Indeed, HRs for death in patients with solid tumors presenting at stage 3 and 4 were a respective 2.11 (95% CI, 1.03-4.33) and 1.31 (95% CI, 1.04-1.64). This suggests a possible adverse effect of aspirin on the growth of cancers once they have already developed in older adults, Dr. Chan said.
Where does that leave aspirin for cancer prevention?
“Although these results suggest that we should be cautious about starting aspirin therapy in otherwise healthy older adults, this does not mean that individuals who are already taking aspirin – particularly if they began taking it at a younger age – should stop their aspirin regimen,” Dr. Chan said.
There are decades of data supporting the use of daily aspirin to prevent multiple cancer types, particularly colorectal cancer, in individuals under the age of 70 years. In a recent meta-analysis, for example, regular aspirin use was linked to a 27% reduced risk for colorectal cancer, a 33% reduced risk for squamous cell esophageal cancer, a 39% decreased risk for adenocarcinoma of the esophagus and gastric cardia, a 36% decreased risk for stomach cancer, a 38% decreased risk for hepatobiliary tract cancer, and a 22% decreased risk for pancreatic cancer.
While these figures are mostly based on observational and case-control studies, it “reaffirms the fact that, overall, when you look at all of the ages, that there is still a benefit of aspirin for cancer,” John Cuzick, PhD, of Queen Mary University of London (England), said in an interview.
In fact, the meta-analysis goes as far as suggesting that perhaps the dose of aspirin being used is too low, with the authors noting that there was a 35% risk reduction in colorectal cancer with a dose of 325 mg daily. That’s a new finding, Dr. Cuzick said.
He noted that the ASPREE study largely consists of patients 70 years of age or older, and the authors “draw some conclusions which we can’t ignore about potential safety.”
One of the safety concerns is the increased risk for gastrointestinal bleeding, which is why Dr. Cuzick and colleagues previously recommended caution in the use of aspirin to prevent cancer in elderly patients. The group published a study in 2015 that suggested a benefit of taking aspirin daily for 5-10 years in patients aged 50-65 years, but the risk/benefit ratio was unclear for patients 70 years and older.
The ASPREE data now add to those uncertainties and suggest “there may be some side effects that we do not understand,” Dr. Cuzick said.
“I’m still optimistic that aspirin is going to be important for cancer prevention, but probably focusing on ages 50-70,” he added. “[The ASPREE data] reinforce the caution that we have to take in terms of trying to understand what the side effects are and what’s going on at these older ages.”
Dr. Cuzick is currently leading the AsCaP Project, an international effort to better understand why aspirin might work in preventing some cancer types but not others. AsCaP is supported by Cancer Research UK and also includes Dr. Chan among the researchers attempting to find out which patients may benefit the most from aspirin and which may be at greater risk of adverse effects.
The ASPREE trial was funded by grants from the National Institute on Aging, the National Cancer Institute, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Several ASPREE investigators disclosed financial relationships with Bayer Pharma. The editorialists had no conflicts of interest. Dr. Cuzick has been an advisory board member for Bayer in the past.
SOURCE: McNeil J et al. J Natl Cancer Inst. 2020 Aug 11. doi: 10.1093/jnci/djaa114.
FROM JOURNAL OF THE NATIONAL CANCER INSTITUTE
Nine antihypertensive drugs associated with reduced risk of depression
The risk of depression is elevated in patients with cardiovascular diseases, but several specific antihypertensive therapies are associated with a reduced risk, and none appear to increase the risk, according to a population-based study that evaluated 10 years of data in nearly 4 million subjects.
“As the first study on individual antihypertensives and risk of depression, we found a decreased risk of depression with nine drugs,” reported a collaborative group of investigators from multiple institutions in Denmark where the study was undertaken.
In a study period spanning from 2005 to 2015, risk of a diagnosis of depression was evaluated in patients taking any of 41 antihypertensive therapies in four major categories. These were identified as angiotensin agents (ACE inhibitors or angiotensin II receptor blockers), calcium antagonists, beta-blockers, and diuretics.
Within these groups, agents associated with a reduced risk of depression were: two angiotensin agents, enalapril and ramipril; three calcium antagonists, amlodipine, verapamil, and verapamil combinations; and four beta-blockers, propranolol, atenolol, bisoprolol, and carvedilol. The remaining drugs in these classes and diuretics were not associated with a reduced risk of depression. However, no antihypertensive agent was linked to an increased risk of depression.
All people living in Denmark are assigned a unique personal identification number that permits health information to be tracked across multiple registers. In this study, information was linked for several registries, including the Danish Medical Register on Vital Statistics, the Medicinal Product Statistics, and the Danish Psychiatric Central Register.
Data from a total of 3.75 million patients exposed to antihypertensive therapy during the study period were evaluated. Roughly 1 million of them were exposed to angiotensin drugs and slightly more than a million were exposed to diuretics. For calcium antagonists or beta-blockers, the numbers were approximately 835,000 and 775,000, respectively.
After adjustment for such factors as concomitant somatic diagnoses, sex, age, and employment status, the hazard ratios for depression among drugs associated with protection identified a risk reduction of 10%-25% in most cases when those who had been given 6-10 prescriptions or more than 10 prescriptions were compared with those who received 2 or fewer.
At the level of 10 or more prescriptions, for example, the risk reductions were 17% for ramipril (HR, 0.83; 95% CI, 0.78-0.89), 8% for enalapril (HR, 0.92; 95% CI, 0.88-0.96), 18% for amlodipine (HR, 0.82; 95% CI, 0.79-0.86), 15% for verapamil (HR, 0.85; 95% CI, 0.79-0.83), 28% for propranolol (HR, 0.72; 95% CI, 0.67-0.77), 20% for atenolol (HR, 0.80; 95% CI, 0.74-0.86), 25% for bisoprolol (HR, 0.75; 95% CI, 0.67-0.84), and 16% for carvedilol (HR, 0.84; 95% CI, 0.75-0.95).
For verapamil combinations, the risk reduction was 67% (HR, 0.33; 95% CI, 0.17-0.63), but the investigators cautioned that only 130 individuals were exposed to verapamil combinations, limiting the reliability of this analysis.
Interpreting the findings
A study hypothesis, the observed protective effect against depression, was expected for angiotensin drugs and calcium-channel blockers, but not for beta-blockers, according to the investigators.
“The renin-angiotensin systems is one of the pathways known to modulate inflammation in the central nervous system and seems involved in the regulation of the stress response. Angiotensin agents may also exert anti-inflammatory effects,” the investigators explained. “Dysregulation of intracellular calcium is evident in depression, including receptor-regulated calcium signaling.”
In contrast, beta-blockers have been associated with increased risk of depression in some but not all studies, according to the investigators. They maintained that some clinicians avoid these agents in patients with a history of mood disorders.
In attempting to account for the variability within drug classes regarding protection and lack of protection against depression, the investigators speculated that differences in pharmacologic properties, such as relative lipophilicity or anti-inflammatory effect, might be important.
Despite the large amount of data, William B. White, MD, professor emeritus at the Calhoun Cardiology Center, University of Connecticut, Farmington, is not convinced.
“In observational studies, even those with very large samples sizes, bias and confounding are hard to extricate with controls and propensity-score matching,” Dr. White said. From his perspective, the protective effects of some but not all drugs within a class “give one the impression that the findings are likely random.”
A member of the editorial board of the journal in which this study appeared, Dr. White said he was not involved in the review of the manuscript. Ultimately, he believed that the results are difficult to interpret.
“For example, there is no plausible rationale for why 2 of the 16 ACE inhibitors or angiotensin II receptor blockers or 4 of the 15 beta-blockers or 3 of the 10 calcium-channel blockers would reduce depression while the others in the class would have no effect,” he said.
Despite the investigators’ conclusion that these data should drive drug choice for patients at risk of depression, “I would say the results of this analysis would not lead me to alter clinical practice,” Dr. White added.
According to the principal investigator of the study, Lars Vedel Kessing, MD, DSc, professor of psychiatry at the University of Copenhagen, many variables affect choice of antihypertensive drug. However, the depression risk is elevated in patients with cardiovascular or cerebrovascular disease and hypertension.
When risk of a mood disorder is a concern, use of one of the nine drugs associated with protection from depression should be considered, “especially in patients at increased risk of developing depression, including patients with prior depression or anxiety and patients with a family history of depression,” he and his coinvestigators concluded.
However, Dr. Kessing said in an interview that the data do not help with individual treatment choices. “We do not compare different antihypertensives against each other due to the risk of confounding by indications, so, no, it is not reasonable to consider relative risk among specific agents.”
The authors reported no potential conflicts of interest involving this topic.
SOURCE: Kessing LV et al. Hypertension. 2020 Aug 24. doi: 10.1161/HYPERTENSIONAHA.120.15605.
The risk of depression is elevated in patients with cardiovascular diseases, but several specific antihypertensive therapies are associated with a reduced risk, and none appear to increase the risk, according to a population-based study that evaluated 10 years of data in nearly 4 million subjects.
“As the first study on individual antihypertensives and risk of depression, we found a decreased risk of depression with nine drugs,” reported a collaborative group of investigators from multiple institutions in Denmark where the study was undertaken.
In a study period spanning from 2005 to 2015, risk of a diagnosis of depression was evaluated in patients taking any of 41 antihypertensive therapies in four major categories. These were identified as angiotensin agents (ACE inhibitors or angiotensin II receptor blockers), calcium antagonists, beta-blockers, and diuretics.
Within these groups, agents associated with a reduced risk of depression were: two angiotensin agents, enalapril and ramipril; three calcium antagonists, amlodipine, verapamil, and verapamil combinations; and four beta-blockers, propranolol, atenolol, bisoprolol, and carvedilol. The remaining drugs in these classes and diuretics were not associated with a reduced risk of depression. However, no antihypertensive agent was linked to an increased risk of depression.
All people living in Denmark are assigned a unique personal identification number that permits health information to be tracked across multiple registers. In this study, information was linked for several registries, including the Danish Medical Register on Vital Statistics, the Medicinal Product Statistics, and the Danish Psychiatric Central Register.
Data from a total of 3.75 million patients exposed to antihypertensive therapy during the study period were evaluated. Roughly 1 million of them were exposed to angiotensin drugs and slightly more than a million were exposed to diuretics. For calcium antagonists or beta-blockers, the numbers were approximately 835,000 and 775,000, respectively.
After adjustment for such factors as concomitant somatic diagnoses, sex, age, and employment status, the hazard ratios for depression among drugs associated with protection identified a risk reduction of 10%-25% in most cases when those who had been given 6-10 prescriptions or more than 10 prescriptions were compared with those who received 2 or fewer.
At the level of 10 or more prescriptions, for example, the risk reductions were 17% for ramipril (HR, 0.83; 95% CI, 0.78-0.89), 8% for enalapril (HR, 0.92; 95% CI, 0.88-0.96), 18% for amlodipine (HR, 0.82; 95% CI, 0.79-0.86), 15% for verapamil (HR, 0.85; 95% CI, 0.79-0.83), 28% for propranolol (HR, 0.72; 95% CI, 0.67-0.77), 20% for atenolol (HR, 0.80; 95% CI, 0.74-0.86), 25% for bisoprolol (HR, 0.75; 95% CI, 0.67-0.84), and 16% for carvedilol (HR, 0.84; 95% CI, 0.75-0.95).
For verapamil combinations, the risk reduction was 67% (HR, 0.33; 95% CI, 0.17-0.63), but the investigators cautioned that only 130 individuals were exposed to verapamil combinations, limiting the reliability of this analysis.
Interpreting the findings
A study hypothesis, the observed protective effect against depression, was expected for angiotensin drugs and calcium-channel blockers, but not for beta-blockers, according to the investigators.
“The renin-angiotensin systems is one of the pathways known to modulate inflammation in the central nervous system and seems involved in the regulation of the stress response. Angiotensin agents may also exert anti-inflammatory effects,” the investigators explained. “Dysregulation of intracellular calcium is evident in depression, including receptor-regulated calcium signaling.”
In contrast, beta-blockers have been associated with increased risk of depression in some but not all studies, according to the investigators. They maintained that some clinicians avoid these agents in patients with a history of mood disorders.
In attempting to account for the variability within drug classes regarding protection and lack of protection against depression, the investigators speculated that differences in pharmacologic properties, such as relative lipophilicity or anti-inflammatory effect, might be important.
Despite the large amount of data, William B. White, MD, professor emeritus at the Calhoun Cardiology Center, University of Connecticut, Farmington, is not convinced.
“In observational studies, even those with very large samples sizes, bias and confounding are hard to extricate with controls and propensity-score matching,” Dr. White said. From his perspective, the protective effects of some but not all drugs within a class “give one the impression that the findings are likely random.”
A member of the editorial board of the journal in which this study appeared, Dr. White said he was not involved in the review of the manuscript. Ultimately, he believed that the results are difficult to interpret.
“For example, there is no plausible rationale for why 2 of the 16 ACE inhibitors or angiotensin II receptor blockers or 4 of the 15 beta-blockers or 3 of the 10 calcium-channel blockers would reduce depression while the others in the class would have no effect,” he said.
Despite the investigators’ conclusion that these data should drive drug choice for patients at risk of depression, “I would say the results of this analysis would not lead me to alter clinical practice,” Dr. White added.
According to the principal investigator of the study, Lars Vedel Kessing, MD, DSc, professor of psychiatry at the University of Copenhagen, many variables affect choice of antihypertensive drug. However, the depression risk is elevated in patients with cardiovascular or cerebrovascular disease and hypertension.
When risk of a mood disorder is a concern, use of one of the nine drugs associated with protection from depression should be considered, “especially in patients at increased risk of developing depression, including patients with prior depression or anxiety and patients with a family history of depression,” he and his coinvestigators concluded.
However, Dr. Kessing said in an interview that the data do not help with individual treatment choices. “We do not compare different antihypertensives against each other due to the risk of confounding by indications, so, no, it is not reasonable to consider relative risk among specific agents.”
The authors reported no potential conflicts of interest involving this topic.
SOURCE: Kessing LV et al. Hypertension. 2020 Aug 24. doi: 10.1161/HYPERTENSIONAHA.120.15605.
The risk of depression is elevated in patients with cardiovascular diseases, but several specific antihypertensive therapies are associated with a reduced risk, and none appear to increase the risk, according to a population-based study that evaluated 10 years of data in nearly 4 million subjects.
“As the first study on individual antihypertensives and risk of depression, we found a decreased risk of depression with nine drugs,” reported a collaborative group of investigators from multiple institutions in Denmark where the study was undertaken.
In a study period spanning from 2005 to 2015, risk of a diagnosis of depression was evaluated in patients taking any of 41 antihypertensive therapies in four major categories. These were identified as angiotensin agents (ACE inhibitors or angiotensin II receptor blockers), calcium antagonists, beta-blockers, and diuretics.
Within these groups, agents associated with a reduced risk of depression were: two angiotensin agents, enalapril and ramipril; three calcium antagonists, amlodipine, verapamil, and verapamil combinations; and four beta-blockers, propranolol, atenolol, bisoprolol, and carvedilol. The remaining drugs in these classes and diuretics were not associated with a reduced risk of depression. However, no antihypertensive agent was linked to an increased risk of depression.
All people living in Denmark are assigned a unique personal identification number that permits health information to be tracked across multiple registers. In this study, information was linked for several registries, including the Danish Medical Register on Vital Statistics, the Medicinal Product Statistics, and the Danish Psychiatric Central Register.
Data from a total of 3.75 million patients exposed to antihypertensive therapy during the study period were evaluated. Roughly 1 million of them were exposed to angiotensin drugs and slightly more than a million were exposed to diuretics. For calcium antagonists or beta-blockers, the numbers were approximately 835,000 and 775,000, respectively.
After adjustment for such factors as concomitant somatic diagnoses, sex, age, and employment status, the hazard ratios for depression among drugs associated with protection identified a risk reduction of 10%-25% in most cases when those who had been given 6-10 prescriptions or more than 10 prescriptions were compared with those who received 2 or fewer.
At the level of 10 or more prescriptions, for example, the risk reductions were 17% for ramipril (HR, 0.83; 95% CI, 0.78-0.89), 8% for enalapril (HR, 0.92; 95% CI, 0.88-0.96), 18% for amlodipine (HR, 0.82; 95% CI, 0.79-0.86), 15% for verapamil (HR, 0.85; 95% CI, 0.79-0.83), 28% for propranolol (HR, 0.72; 95% CI, 0.67-0.77), 20% for atenolol (HR, 0.80; 95% CI, 0.74-0.86), 25% for bisoprolol (HR, 0.75; 95% CI, 0.67-0.84), and 16% for carvedilol (HR, 0.84; 95% CI, 0.75-0.95).
For verapamil combinations, the risk reduction was 67% (HR, 0.33; 95% CI, 0.17-0.63), but the investigators cautioned that only 130 individuals were exposed to verapamil combinations, limiting the reliability of this analysis.
Interpreting the findings
A study hypothesis, the observed protective effect against depression, was expected for angiotensin drugs and calcium-channel blockers, but not for beta-blockers, according to the investigators.
“The renin-angiotensin systems is one of the pathways known to modulate inflammation in the central nervous system and seems involved in the regulation of the stress response. Angiotensin agents may also exert anti-inflammatory effects,” the investigators explained. “Dysregulation of intracellular calcium is evident in depression, including receptor-regulated calcium signaling.”
In contrast, beta-blockers have been associated with increased risk of depression in some but not all studies, according to the investigators. They maintained that some clinicians avoid these agents in patients with a history of mood disorders.
In attempting to account for the variability within drug classes regarding protection and lack of protection against depression, the investigators speculated that differences in pharmacologic properties, such as relative lipophilicity or anti-inflammatory effect, might be important.
Despite the large amount of data, William B. White, MD, professor emeritus at the Calhoun Cardiology Center, University of Connecticut, Farmington, is not convinced.
“In observational studies, even those with very large samples sizes, bias and confounding are hard to extricate with controls and propensity-score matching,” Dr. White said. From his perspective, the protective effects of some but not all drugs within a class “give one the impression that the findings are likely random.”
A member of the editorial board of the journal in which this study appeared, Dr. White said he was not involved in the review of the manuscript. Ultimately, he believed that the results are difficult to interpret.
“For example, there is no plausible rationale for why 2 of the 16 ACE inhibitors or angiotensin II receptor blockers or 4 of the 15 beta-blockers or 3 of the 10 calcium-channel blockers would reduce depression while the others in the class would have no effect,” he said.
Despite the investigators’ conclusion that these data should drive drug choice for patients at risk of depression, “I would say the results of this analysis would not lead me to alter clinical practice,” Dr. White added.
According to the principal investigator of the study, Lars Vedel Kessing, MD, DSc, professor of psychiatry at the University of Copenhagen, many variables affect choice of antihypertensive drug. However, the depression risk is elevated in patients with cardiovascular or cerebrovascular disease and hypertension.
When risk of a mood disorder is a concern, use of one of the nine drugs associated with protection from depression should be considered, “especially in patients at increased risk of developing depression, including patients with prior depression or anxiety and patients with a family history of depression,” he and his coinvestigators concluded.
However, Dr. Kessing said in an interview that the data do not help with individual treatment choices. “We do not compare different antihypertensives against each other due to the risk of confounding by indications, so, no, it is not reasonable to consider relative risk among specific agents.”
The authors reported no potential conflicts of interest involving this topic.
SOURCE: Kessing LV et al. Hypertension. 2020 Aug 24. doi: 10.1161/HYPERTENSIONAHA.120.15605.
FROM HYPERTENSION
FDA pulls amputation boxed warning off canagliflozin label
The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.
As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.
The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.
In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.
In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.
“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.
The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”
The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”
The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.
Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.
As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.
The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.
In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.
In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.
“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.
The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”
The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”
The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.
Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.
As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.
The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.
In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.
In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.
“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.
The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”
The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”
The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.
Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
A version of this article originally appeared on Medscape.com.
FDA approves clinical trials for cannabinoid drug designed to reduce COVID-19 lung inflammation
The US Food and Drug Administration has approved phase one clinical trials for a synthetic cannabinoid drug designed to treat acute respiratory distress syndrome (ARDS), a life-threatening lung condition which may occur in severe cases of the novel coronavirus, Forbes reported.
ARDS can be triggered by over-creation of cytokines, proteins which tell the body to produce more inflammation, Forbes said.
The drug going to clinical trials, ARDS-003, would “dampen the cytokine release” and prevent development of ARDS, Tetra Bio-Pharma company CEO and chief regulatory officer Guy Chamberland, MD, said in a news release.
Consequences of ARDS include scarring of the lungs and organ injury caused by the decrease in blood to the tissue, the release said.
“The FDA repeatedly stated that they want clinical trials for COVID-19 to begin as soon as possible, as long as they meet regulatory requirements,” the news release said. “The medical community is in urgent need of drugs that can reduce the strength and duration of the severe inflammation. It is anticipated that this type of new drug would favorably impact health care and possibly reduce the negative health outcomes post infection.”
ARDS-003 works by binding to CB2 receptors, one of two main receptors in the endocannabinoid system which modulate inflammation and cytokine activity, Forbes said. CB2 receptors don’t bring on a psychoactive high.
Phase one clinical trials would begin enrolling participants in December to determine if the drug is safe, Chamberland said, according to Forbes.
If phase one is successful, phase two would test the drug on a larger group in the second quarter of 2021 to assess safety and tolerability for people who have COVID-19.
If phase two is successful, the company may seek emergency authorization through the FDA, Chamberland said. Phase three would start at the end of 2021.
Tetra Bio-Pharma says it has already contracted with Dalton Pharma Services to manufacture the active pharmaceutical ingredient (API), HU-308, and the finished drug product ARDS-003.
This article first appeared on Medscape.com.
The US Food and Drug Administration has approved phase one clinical trials for a synthetic cannabinoid drug designed to treat acute respiratory distress syndrome (ARDS), a life-threatening lung condition which may occur in severe cases of the novel coronavirus, Forbes reported.
ARDS can be triggered by over-creation of cytokines, proteins which tell the body to produce more inflammation, Forbes said.
The drug going to clinical trials, ARDS-003, would “dampen the cytokine release” and prevent development of ARDS, Tetra Bio-Pharma company CEO and chief regulatory officer Guy Chamberland, MD, said in a news release.
Consequences of ARDS include scarring of the lungs and organ injury caused by the decrease in blood to the tissue, the release said.
“The FDA repeatedly stated that they want clinical trials for COVID-19 to begin as soon as possible, as long as they meet regulatory requirements,” the news release said. “The medical community is in urgent need of drugs that can reduce the strength and duration of the severe inflammation. It is anticipated that this type of new drug would favorably impact health care and possibly reduce the negative health outcomes post infection.”
ARDS-003 works by binding to CB2 receptors, one of two main receptors in the endocannabinoid system which modulate inflammation and cytokine activity, Forbes said. CB2 receptors don’t bring on a psychoactive high.
Phase one clinical trials would begin enrolling participants in December to determine if the drug is safe, Chamberland said, according to Forbes.
If phase one is successful, phase two would test the drug on a larger group in the second quarter of 2021 to assess safety and tolerability for people who have COVID-19.
If phase two is successful, the company may seek emergency authorization through the FDA, Chamberland said. Phase three would start at the end of 2021.
Tetra Bio-Pharma says it has already contracted with Dalton Pharma Services to manufacture the active pharmaceutical ingredient (API), HU-308, and the finished drug product ARDS-003.
This article first appeared on Medscape.com.
The US Food and Drug Administration has approved phase one clinical trials for a synthetic cannabinoid drug designed to treat acute respiratory distress syndrome (ARDS), a life-threatening lung condition which may occur in severe cases of the novel coronavirus, Forbes reported.
ARDS can be triggered by over-creation of cytokines, proteins which tell the body to produce more inflammation, Forbes said.
The drug going to clinical trials, ARDS-003, would “dampen the cytokine release” and prevent development of ARDS, Tetra Bio-Pharma company CEO and chief regulatory officer Guy Chamberland, MD, said in a news release.
Consequences of ARDS include scarring of the lungs and organ injury caused by the decrease in blood to the tissue, the release said.
“The FDA repeatedly stated that they want clinical trials for COVID-19 to begin as soon as possible, as long as they meet regulatory requirements,” the news release said. “The medical community is in urgent need of drugs that can reduce the strength and duration of the severe inflammation. It is anticipated that this type of new drug would favorably impact health care and possibly reduce the negative health outcomes post infection.”
ARDS-003 works by binding to CB2 receptors, one of two main receptors in the endocannabinoid system which modulate inflammation and cytokine activity, Forbes said. CB2 receptors don’t bring on a psychoactive high.
Phase one clinical trials would begin enrolling participants in December to determine if the drug is safe, Chamberland said, according to Forbes.
If phase one is successful, phase two would test the drug on a larger group in the second quarter of 2021 to assess safety and tolerability for people who have COVID-19.
If phase two is successful, the company may seek emergency authorization through the FDA, Chamberland said. Phase three would start at the end of 2021.
Tetra Bio-Pharma says it has already contracted with Dalton Pharma Services to manufacture the active pharmaceutical ingredient (API), HU-308, and the finished drug product ARDS-003.
This article first appeared on Medscape.com.
FDA authorizes convalescent plasma for COVID-19
Convalescent plasma contains antibodies from the blood of recovered COVID-19 patients, which can be used to treat people with severe infections. Convalescent plasma has been used to treat patients for other infectious diseases. The authorization allows the plasma to be distributed in the United States and administered by health care providers.
“COVID-19 convalescent plasma is safe and shows promising efficacy,” Stephen Hahn, MD, commissioner of the FDA, said during a press briefing with President Donald Trump.
In April, the FDA approved a program to test convalescent plasma in COVID-19 patients at the Mayo Clinic, followed by other institutions. More than 90,000 patients have enrolled in the program, and 70,000 have received the treatment, Dr. Hahn said.
The data indicate that the plasma can reduce mortality in patients by 35%, particularly if patients are treated within 3 days of being diagnosed. Those who have benefited the most were under age 80 and not on artificial respiration, Alex Azar, the secretary for the Department of Health & Human Services, said during the briefing.
“We dream, in drug development, of something like a 35% mortality reduction,” he said.
But top scientists pushed back against the announcement.
Eric Topol, MD, director of the Scripps Research Translational Institute, professor of molecular medicine, and executive vice president of Scripps Research, said the data the FDA are relying on did not come from the rigorous randomized, double-blind placebo trials that best determine if a treatment is successful.
Still, convalescent plasma is “one more tool added to the arsenal” of combating COVID-19, Mr. Azar said. The FDA will continue to study convalescent plasma as a COVID-19 treatment, Dr. Hahn added.
“We’re waiting for more data. We’re going to continue to gather data,” Dr. Hahn said during the briefing, but the current results meet FDA criteria for issuing an emergency use authorization.
Convalescent plasma “may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients,” according to the FDA announcement. Potential side effects include allergic reactions, transfusion-transmitted infections, and transfusion-associated lung injury.
“We’ve seen a great deal of demand for this from doctors around the country,” Dr. Hahn said during the briefing. “The EUA … allows us to continue that and meet that demand.”
Dr. Topol, however, said it appears Trump and the FDA are playing politics with science.
“There’s no evidence to support any survival benefit,” Dr. Topol said on Twitter. “Two days ago [the] FDA’s website stated there was no evidence for an EUA.”
The American Red Cross and other blood centers put out a national call for blood donors in July, especially for patients who have recovered from COVID-19. Mr. Azar and Dr. Hahn emphasized the need for blood donors during the press briefing.
“If you donate plasma, you could save a life,” Mr. Azar said.
The study has not been peer reviewed and did not include a placebo group for comparison, STAT reported.
Last week several health officials warned that the scientific data were too weak to warrant an emergency authorization, the New York Times reported.
A version of this originally appeared on WebMD.com.
Convalescent plasma contains antibodies from the blood of recovered COVID-19 patients, which can be used to treat people with severe infections. Convalescent plasma has been used to treat patients for other infectious diseases. The authorization allows the plasma to be distributed in the United States and administered by health care providers.
“COVID-19 convalescent plasma is safe and shows promising efficacy,” Stephen Hahn, MD, commissioner of the FDA, said during a press briefing with President Donald Trump.
In April, the FDA approved a program to test convalescent plasma in COVID-19 patients at the Mayo Clinic, followed by other institutions. More than 90,000 patients have enrolled in the program, and 70,000 have received the treatment, Dr. Hahn said.
The data indicate that the plasma can reduce mortality in patients by 35%, particularly if patients are treated within 3 days of being diagnosed. Those who have benefited the most were under age 80 and not on artificial respiration, Alex Azar, the secretary for the Department of Health & Human Services, said during the briefing.
“We dream, in drug development, of something like a 35% mortality reduction,” he said.
But top scientists pushed back against the announcement.
Eric Topol, MD, director of the Scripps Research Translational Institute, professor of molecular medicine, and executive vice president of Scripps Research, said the data the FDA are relying on did not come from the rigorous randomized, double-blind placebo trials that best determine if a treatment is successful.
Still, convalescent plasma is “one more tool added to the arsenal” of combating COVID-19, Mr. Azar said. The FDA will continue to study convalescent plasma as a COVID-19 treatment, Dr. Hahn added.
“We’re waiting for more data. We’re going to continue to gather data,” Dr. Hahn said during the briefing, but the current results meet FDA criteria for issuing an emergency use authorization.
Convalescent plasma “may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients,” according to the FDA announcement. Potential side effects include allergic reactions, transfusion-transmitted infections, and transfusion-associated lung injury.
“We’ve seen a great deal of demand for this from doctors around the country,” Dr. Hahn said during the briefing. “The EUA … allows us to continue that and meet that demand.”
Dr. Topol, however, said it appears Trump and the FDA are playing politics with science.
“There’s no evidence to support any survival benefit,” Dr. Topol said on Twitter. “Two days ago [the] FDA’s website stated there was no evidence for an EUA.”
The American Red Cross and other blood centers put out a national call for blood donors in July, especially for patients who have recovered from COVID-19. Mr. Azar and Dr. Hahn emphasized the need for blood donors during the press briefing.
“If you donate plasma, you could save a life,” Mr. Azar said.
The study has not been peer reviewed and did not include a placebo group for comparison, STAT reported.
Last week several health officials warned that the scientific data were too weak to warrant an emergency authorization, the New York Times reported.
A version of this originally appeared on WebMD.com.
Convalescent plasma contains antibodies from the blood of recovered COVID-19 patients, which can be used to treat people with severe infections. Convalescent plasma has been used to treat patients for other infectious diseases. The authorization allows the plasma to be distributed in the United States and administered by health care providers.
“COVID-19 convalescent plasma is safe and shows promising efficacy,” Stephen Hahn, MD, commissioner of the FDA, said during a press briefing with President Donald Trump.
In April, the FDA approved a program to test convalescent plasma in COVID-19 patients at the Mayo Clinic, followed by other institutions. More than 90,000 patients have enrolled in the program, and 70,000 have received the treatment, Dr. Hahn said.
The data indicate that the plasma can reduce mortality in patients by 35%, particularly if patients are treated within 3 days of being diagnosed. Those who have benefited the most were under age 80 and not on artificial respiration, Alex Azar, the secretary for the Department of Health & Human Services, said during the briefing.
“We dream, in drug development, of something like a 35% mortality reduction,” he said.
But top scientists pushed back against the announcement.
Eric Topol, MD, director of the Scripps Research Translational Institute, professor of molecular medicine, and executive vice president of Scripps Research, said the data the FDA are relying on did not come from the rigorous randomized, double-blind placebo trials that best determine if a treatment is successful.
Still, convalescent plasma is “one more tool added to the arsenal” of combating COVID-19, Mr. Azar said. The FDA will continue to study convalescent plasma as a COVID-19 treatment, Dr. Hahn added.
“We’re waiting for more data. We’re going to continue to gather data,” Dr. Hahn said during the briefing, but the current results meet FDA criteria for issuing an emergency use authorization.
Convalescent plasma “may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients,” according to the FDA announcement. Potential side effects include allergic reactions, transfusion-transmitted infections, and transfusion-associated lung injury.
“We’ve seen a great deal of demand for this from doctors around the country,” Dr. Hahn said during the briefing. “The EUA … allows us to continue that and meet that demand.”
Dr. Topol, however, said it appears Trump and the FDA are playing politics with science.
“There’s no evidence to support any survival benefit,” Dr. Topol said on Twitter. “Two days ago [the] FDA’s website stated there was no evidence for an EUA.”
The American Red Cross and other blood centers put out a national call for blood donors in July, especially for patients who have recovered from COVID-19. Mr. Azar and Dr. Hahn emphasized the need for blood donors during the press briefing.
“If you donate plasma, you could save a life,” Mr. Azar said.
The study has not been peer reviewed and did not include a placebo group for comparison, STAT reported.
Last week several health officials warned that the scientific data were too weak to warrant an emergency authorization, the New York Times reported.
A version of this originally appeared on WebMD.com.
Pan-Pseudothrombocytopenia in COVID-19: A Harbinger for Lethal Arterial Thrombosis?
In late 2019 a new pandemic started in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarities with the virus responsible for the SARS outbreak of 2003. The disease manifestations are named coronavirus disease 2019 (COVID-19).1
Pseudothrombocytopenia, or platelet clumping, visualized on the peripheral blood smear, is a common cause for artificial thrombocytopenia laboratory reporting and is frequently attributed to laboratory artifact. In this case presentation, a critically ill patient with COVID-19 developed pan-pseudothrombocytopenia (ethylenediaminetetraacetic acid [EDTA], sodium citrate, and heparin tubes) just prior to his death from a ST-segment elevation myocardial infarction (STEMI) in the setting of therapeutic anticoagulation during a prolonged hospitalization. This case raises the possibility that pseudothrombocytopenia in the setting of COVID-19 critical illness may represent an ominous feature of COVID-19-associated coagulopathy (CAC). Furthermore, it prompts the question whether pseudothrombocytopenia in this setting is representative of increased platelet aggregation activity in vivo.
Case Presentation
A 50-year-old African American man who was diagnosed with COVID-19 3 days prior to admission presented to the emergency department of the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, with worsening dyspnea and fever. His primary chronic medical problems included obesity (body mass index, 33), type 2 diabetes mellitus (hemoglobin A1c 2 months prior of 6.6%), migraine headaches, and obstructive sleep apnea. Shortly after presentation, his respiratory status declined, requiring intubation. He was admitted to the medical intensive care unit for further management.
Notable findings at admission included > 20 mcg/mL FEU D-dimer (normal range, 0-0.56 mcg/mL FEU), 20.4 mg/dL C-reactive protein (normal range, < 1 mg/dL), 30 mm/h erythrocyte sedimentation rate (normal range, 0-25 mm/h), and 3.56 ng/mL procalcitonin (normal range, 0.05-1.99 ng/mL). Patient’s hemoglobin and platelet counts were normal. Empiric antimicrobial therapy was initiated with ceftriaxone (2 g IV daily) and doxycycline (100 mg IV twice daily) due to concern of superimposed infection in the setting of an elevated procalcitonin.
A heparin infusion was initiated (5,000 U IV bolus followed by continuous infusion with goal partial thromboplastin time [PTT] of 1.5x the upper limit of normal) on admission to treat CAC. Renal function worsened requiring intermittent renal replacement therapy on day 3. His lactate dehydrogenase was elevated to 1,188 U/L (normal range: 100-240 U/L) and ferritin was elevated to 2,603 ng/mL (normal range: 25-350 ng/mL) (Table). Initial neuromuscular blockade and prone positioning maneuvers were instituted to optimize oxygenation based on the latest literature for respiratory distress in the COVID-19 management.2
Intermittent norepinephrine infusion (5 mcg/min with a 2 mcg/min titration every 5 minutes as needed to maintain mean arterial pressure of > 65 mm Hg) was required for hemodynamic support throughout the patient’s course. Several therapies for COVID-19 were considered and were a reflection of the rapidly evolving literature during the care of patients with this disease. The patient originally received hydroxychloroquine (200 mg by mouth twice daily) in accordance with the US Department of Veterans Affairs (VA) institutional protocol between day 2 and day 4; however, hydroxychloroquine was stopped due to concerns of QTc prolongation. The patient also received 1 unit of convalescent plasma on day 6 after being enrolled in the expanded access program.3 The patient was not a candidate for remdesivir due to his unstable renal function and need for vasopressors. Finally, interleukin-6 inhibitors also were considered; however, the risk of superimposed infection precluded its use.
On day 7 antimicrobial therapy was transitioned to linezolid (600 mg IV twice daily) due to the persistence of fever and a portable chest radiograph revealing diffuse infiltrates throughout the bilateral lungs, worse compared with prior radiograph on day 5, suggesting a worsening of pneumonia. On day 12, the patient was transitioned to cefepime (1 gram IV daily) to broaden antimicrobial coverage and was continued thereafter. Blood cultures were negative throughout his hospitalization.
Given his worsening clinical scenario there was a question about whether or not the patient was still shedding virus for prognostic and therapeutic implications. Therefore, his SARS-CoV-2 test by polymerase chain reaction nasopharyngeal was positive again on day 18. On day 20, the patient developed leukocytosis, his fever persisted, and a portable chest radiograph revealed extensive bilateral pulmonary opacities with focal worsening in left lower base. Due to this constellation of findings, a vancomycin IV (1,500 mg once) was started for empirical treatment of hospital-acquired pneumonia. Sputum samples obtained on day 20 revealed Staphylococcus aureus on subsequent days.
From a hematologic perspective, on day 9 due to challenges to maintain a therapeutic level of anticoagulation with heparin infusion thought to be related to antithrombin deficiency, anticoagulation was changed to argatroban infusion (0.5 mcg/kg/min targeting a PTT of 70-105 seconds) for ongoing management of CAC. Although D-dimer was > 20 mcg/mL FEU on admission and on days 4 and 5, D-dimer trended down to 12.5 mcg/mL FEU on day 16.
Throughout the patient’s hospital stay, no significant bleeding was seen. Hemoglobin was 15.2 g/dL on admission, but anemia developed with a nadir of 6.5 g/dL, warranting transfusion of red blood cells on day 22. Platelet count was 165,000 per microliter on admission and remained within normal limits until platelet clumping was noted on day 15 laboratory collection.
Hematology was consulted on day 20 to obtain an accurate platelet count. A peripheral blood smear from a sodium citrate containing tube was remarkable for prominent platelet clumping, particularly at the periphery of the slide (Figure 1). Platelet clumping was reproduced in samples containing EDTA and heparin. Other features of the peripheral blood smear included the presence of echinocytes with rare schistocytes. To investigate for presence of disseminated intravascular coagulation on day 22, fibrinogen was found to be mildly elevated at 538 mg/dL (normal range: 243-517 mg/dL) and a D-dimer value of 11.96 mcg/mL FEU.
On day 22, the patient’s ventilator requirements escalated to requiring 100% FiO2 and 10 cm H20 of positive end-expiratory pressure with mean arterial pressures in the 50 to 60 mm Hg range. Within 30 minutes an electrocardiogram (EKG) obtained revealed a STEMI (Figure 2). Troponin was measured at 0.65 ng/mL (normal range: 0.02-0.06 ng/mL). Just after an EKG was performed, the patient developed a ventricular fibrillation arrest and was unable to obtain return of spontaneous circulation. The patient was pronounced dead. The family declined an autopsy.
Discussion
Pseudothrombocytopenia, or platelet clumping (agglutination), is estimated to be present in up to 2% of hospitalized patients.4 Pseudothrombocytopenia was found to be the root cause of thrombocytopenia hematology consultations in up to 4% of hospitalized patients.5 The etiology is commonly ascribed to EDTA inducing a conformational change in the GpIIb-IIIa platelet complex, rendering it susceptible to binding of autoantibodies, which cause subsequent platelet agglutination.6 In most cases (83%), the use of a non-EDTA anticoagulant, such as sodium citrate, resolves the platelet agglutination and allows for accurate platelet count reporting.4 Pseudothrombocytopenia in most cases is considered an in vitro finding without clinical relevance.7 However, in this patient’s case, his pan-pseudothrombocytopenia was temporally associated with an arterial occlusive event (STEMI) leading to his demise despite therapeutic anticoagulation in the setting of CAC. This temporal association raises the possibility that pseudothrombocytopenia seen on the peripheral blood smear is an accurate representation of in vivo activity.
Pseudothrombocytopenia has been associated with sepsis from bacterial and viral causes as well as autoimmune and medication effect.4,8-10 Li and colleagues reported transient EDTA-dependent pseudothrombocytopenia in a patient with COVID-19 infection; however, platelet clumping resolved with use of a citrate tube, and the EDTA-dependent pseudothrombocytopenia phenomenon resolved with patient recovery.11 The frequency of COVID-19-related pseudothrombocytopenia is currently unknown.
Although the understanding of COVID-19-associated CAC continues to evolve, it seems that initial reports support the idea that hemostatic dysfunction tends to more thrombosis than to bleeding.12 Rather than overt disseminated intravascular coagulation with reduced fibrinogen and bleeding, CAC is more closely associated with blood clotting, as demonstrated by autopsy studies revealing microvascular thrombosis in the lungs.13 The D-dimer test has been identified as the most useful biomarker by the International Society of Thrombosis and Hemostasis to screen for CAC and stratify patients who warrant admission or closer monitoring.12 Other identified features of CAC include prolonged prothrombin time and thrombocytopenia.12
There have been varying clinical approaches to CAC management. A retrospective review found that prophylactic heparin doses were associated with improved mortality in those with elevated D-dimer > 3.0 mg/L.14 There continues to be a diversity of varying clinical approaches with many medical centers advocating for an intensified prophylactic twice daily low molecular-weight heparin compared with others advocating for full therapeutic dose anticoagulation for patients with elevated D-dimer.15 This patient was treated aggressively with full-dose anticoagulation, and despite his having a down-trend in D-dimer, he suffered a lethal arterial thrombosis in the form of a STEMI.
Varatharajah and Rajah
Conclusions
This patient’s case highlights the presence of pan-pseudothrombocytopenia despite the use of a sodium citrate and heparin containing tube in a COVID-19 infection with multiorgan dysfunction. This developed 1 week prior to the patient suffering a STEMI despite therapeutic anticoagulation. Although the exact nature of CAC remains to be worked out, it is possible that platelet agglutination/clumping seen on the peripheral blood smear is representative of in vivo activity and serves as a harbinger for worsening thrombosis. The frequency of such phenomenon and efficacy of further interventions has yet to be explored.
1. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(COVID-2019)-and-the-virus-that-causes-it. Accessed July 15, 2020.
2. Ghelichkhani P, Esmaeili M. Prone position in management of COVID-19 patients; a commentary. Arch Acad Emerg Med. 2020;8(1):e48. Published 2020 April 11.
3. National Library of Medicine, Clinicaltrials.gov. Expanded access to convalescent plasma for the treatment of patients with COVID-19. NCT04338360. https://clinicaltrials.gov/ct2/show/nct04338360. Update April 20, 2020. Accessed July 15, 2020.
4. Tan GC, Stalling M, Dennis G, Nunez M, Kahwash SB. Pseudothrombocytopenia due to platelet clumping: a case report and brief review of the literature. Case Rep Hematol. 2016;2016:3036476. doi:10.1155/2016/3036476
5. Boxer M, Biuso TJ. Etiologies of thrombocytopenia in the community hospital: the experience of 1 hematologist. Am J Med. 2020;133(5):e183-e186. doi:10.1016/j.amjmed.2019.10.027
6. Fiorin F, Steffan A, Pradella P, Bizzaro N, Potenza R, De Angelis V. IgG platelet antibodies in EDTA-dependent pseudothrombocytopenia bind to platelet membrane glycoprotein IIb. Am J Clin Pathol. 1998;110(2):178-183. doi:10.1093/ajcp/110.2.178
7. Nagler M, Keller P, Siegrist S, Alberio L. A case of EDTA-Dependent pseudothrombocytopenia: simple recognition of an underdiagnosed and misleading phenomenon. BMC Clin Pathol. 2014;14:19. doi:10.1186/1472-6890-14-19
8. Mori M, Kudo H, Yoshitake S, Ito K, Shinguu C, Noguchi T. Transient EDTA-dependent pseudothrombocytopenia in a patient with sepsis. Intensive Care Med. 2000;26(2):218-220. doi:10.1007/s001340050050.
9. Choe W-H, Cho Y-U, Chae J-D, Kim S-H. 2013. Pseudothrombocytopenia or platelet clumping as a possible cause of low platelet count in patients with viral infection: a case series from single institution focusing on hepatitis A virus infection. Int J Lab Hematol. 2013;35(1):70-76. doi:10.1111/j.1751-553x.2012.01466.
10. Hsieh AT, Chao TY, Chen YC. Pseudothrombocytopenia associated with infectious mononucleosis. Arch Pathol Lab Med. 2003;127(1):e17-e18. doi:10.1043/0003-9985(2003)1272.0.CO;2
11. Li H, Wang B, Ning L, Luo Y, Xiang S. Transient appearance of EDTA dependent pseudothrombocytopenia in a patient with 2019 novel coronavirus pneumonia [published online ahead of print, 2020 May 5]. Platelets. 2020;1-2. doi:10.1080/09537104.2020.1760231
12. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/jth.14810
13. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1-13. doi:10.1016/j.trsl.2020.04.007
14. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. doi:10.1111/jth.14817
15. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;125(23):2033-2040. doi.org/10.1182/blood.2020006000.
16. Varatharajah N, Rajah S. Microthrombotic complications of COVID-19 are likely due to embolism of circulating endothelial derived ultralarge von Willebrand factor (eULVWF) Decorated-Platelet Strings. Fed Pract. 2020;37(6):258-259. doi:10.12788/fp.0001
17. Bernardo A, Ball C, Nolasco L, Choi H, Moake JL, Dong JF. Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost. 2005;3(3):562-570. doi:10.1111/j.1538-7836.2005.01122.x
In late 2019 a new pandemic started in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarities with the virus responsible for the SARS outbreak of 2003. The disease manifestations are named coronavirus disease 2019 (COVID-19).1
Pseudothrombocytopenia, or platelet clumping, visualized on the peripheral blood smear, is a common cause for artificial thrombocytopenia laboratory reporting and is frequently attributed to laboratory artifact. In this case presentation, a critically ill patient with COVID-19 developed pan-pseudothrombocytopenia (ethylenediaminetetraacetic acid [EDTA], sodium citrate, and heparin tubes) just prior to his death from a ST-segment elevation myocardial infarction (STEMI) in the setting of therapeutic anticoagulation during a prolonged hospitalization. This case raises the possibility that pseudothrombocytopenia in the setting of COVID-19 critical illness may represent an ominous feature of COVID-19-associated coagulopathy (CAC). Furthermore, it prompts the question whether pseudothrombocytopenia in this setting is representative of increased platelet aggregation activity in vivo.
Case Presentation
A 50-year-old African American man who was diagnosed with COVID-19 3 days prior to admission presented to the emergency department of the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, with worsening dyspnea and fever. His primary chronic medical problems included obesity (body mass index, 33), type 2 diabetes mellitus (hemoglobin A1c 2 months prior of 6.6%), migraine headaches, and obstructive sleep apnea. Shortly after presentation, his respiratory status declined, requiring intubation. He was admitted to the medical intensive care unit for further management.
Notable findings at admission included > 20 mcg/mL FEU D-dimer (normal range, 0-0.56 mcg/mL FEU), 20.4 mg/dL C-reactive protein (normal range, < 1 mg/dL), 30 mm/h erythrocyte sedimentation rate (normal range, 0-25 mm/h), and 3.56 ng/mL procalcitonin (normal range, 0.05-1.99 ng/mL). Patient’s hemoglobin and platelet counts were normal. Empiric antimicrobial therapy was initiated with ceftriaxone (2 g IV daily) and doxycycline (100 mg IV twice daily) due to concern of superimposed infection in the setting of an elevated procalcitonin.
A heparin infusion was initiated (5,000 U IV bolus followed by continuous infusion with goal partial thromboplastin time [PTT] of 1.5x the upper limit of normal) on admission to treat CAC. Renal function worsened requiring intermittent renal replacement therapy on day 3. His lactate dehydrogenase was elevated to 1,188 U/L (normal range: 100-240 U/L) and ferritin was elevated to 2,603 ng/mL (normal range: 25-350 ng/mL) (Table). Initial neuromuscular blockade and prone positioning maneuvers were instituted to optimize oxygenation based on the latest literature for respiratory distress in the COVID-19 management.2
Intermittent norepinephrine infusion (5 mcg/min with a 2 mcg/min titration every 5 minutes as needed to maintain mean arterial pressure of > 65 mm Hg) was required for hemodynamic support throughout the patient’s course. Several therapies for COVID-19 were considered and were a reflection of the rapidly evolving literature during the care of patients with this disease. The patient originally received hydroxychloroquine (200 mg by mouth twice daily) in accordance with the US Department of Veterans Affairs (VA) institutional protocol between day 2 and day 4; however, hydroxychloroquine was stopped due to concerns of QTc prolongation. The patient also received 1 unit of convalescent plasma on day 6 after being enrolled in the expanded access program.3 The patient was not a candidate for remdesivir due to his unstable renal function and need for vasopressors. Finally, interleukin-6 inhibitors also were considered; however, the risk of superimposed infection precluded its use.
On day 7 antimicrobial therapy was transitioned to linezolid (600 mg IV twice daily) due to the persistence of fever and a portable chest radiograph revealing diffuse infiltrates throughout the bilateral lungs, worse compared with prior radiograph on day 5, suggesting a worsening of pneumonia. On day 12, the patient was transitioned to cefepime (1 gram IV daily) to broaden antimicrobial coverage and was continued thereafter. Blood cultures were negative throughout his hospitalization.
Given his worsening clinical scenario there was a question about whether or not the patient was still shedding virus for prognostic and therapeutic implications. Therefore, his SARS-CoV-2 test by polymerase chain reaction nasopharyngeal was positive again on day 18. On day 20, the patient developed leukocytosis, his fever persisted, and a portable chest radiograph revealed extensive bilateral pulmonary opacities with focal worsening in left lower base. Due to this constellation of findings, a vancomycin IV (1,500 mg once) was started for empirical treatment of hospital-acquired pneumonia. Sputum samples obtained on day 20 revealed Staphylococcus aureus on subsequent days.
From a hematologic perspective, on day 9 due to challenges to maintain a therapeutic level of anticoagulation with heparin infusion thought to be related to antithrombin deficiency, anticoagulation was changed to argatroban infusion (0.5 mcg/kg/min targeting a PTT of 70-105 seconds) for ongoing management of CAC. Although D-dimer was > 20 mcg/mL FEU on admission and on days 4 and 5, D-dimer trended down to 12.5 mcg/mL FEU on day 16.
Throughout the patient’s hospital stay, no significant bleeding was seen. Hemoglobin was 15.2 g/dL on admission, but anemia developed with a nadir of 6.5 g/dL, warranting transfusion of red blood cells on day 22. Platelet count was 165,000 per microliter on admission and remained within normal limits until platelet clumping was noted on day 15 laboratory collection.
Hematology was consulted on day 20 to obtain an accurate platelet count. A peripheral blood smear from a sodium citrate containing tube was remarkable for prominent platelet clumping, particularly at the periphery of the slide (Figure 1). Platelet clumping was reproduced in samples containing EDTA and heparin. Other features of the peripheral blood smear included the presence of echinocytes with rare schistocytes. To investigate for presence of disseminated intravascular coagulation on day 22, fibrinogen was found to be mildly elevated at 538 mg/dL (normal range: 243-517 mg/dL) and a D-dimer value of 11.96 mcg/mL FEU.
On day 22, the patient’s ventilator requirements escalated to requiring 100% FiO2 and 10 cm H20 of positive end-expiratory pressure with mean arterial pressures in the 50 to 60 mm Hg range. Within 30 minutes an electrocardiogram (EKG) obtained revealed a STEMI (Figure 2). Troponin was measured at 0.65 ng/mL (normal range: 0.02-0.06 ng/mL). Just after an EKG was performed, the patient developed a ventricular fibrillation arrest and was unable to obtain return of spontaneous circulation. The patient was pronounced dead. The family declined an autopsy.
Discussion
Pseudothrombocytopenia, or platelet clumping (agglutination), is estimated to be present in up to 2% of hospitalized patients.4 Pseudothrombocytopenia was found to be the root cause of thrombocytopenia hematology consultations in up to 4% of hospitalized patients.5 The etiology is commonly ascribed to EDTA inducing a conformational change in the GpIIb-IIIa platelet complex, rendering it susceptible to binding of autoantibodies, which cause subsequent platelet agglutination.6 In most cases (83%), the use of a non-EDTA anticoagulant, such as sodium citrate, resolves the platelet agglutination and allows for accurate platelet count reporting.4 Pseudothrombocytopenia in most cases is considered an in vitro finding without clinical relevance.7 However, in this patient’s case, his pan-pseudothrombocytopenia was temporally associated with an arterial occlusive event (STEMI) leading to his demise despite therapeutic anticoagulation in the setting of CAC. This temporal association raises the possibility that pseudothrombocytopenia seen on the peripheral blood smear is an accurate representation of in vivo activity.
Pseudothrombocytopenia has been associated with sepsis from bacterial and viral causes as well as autoimmune and medication effect.4,8-10 Li and colleagues reported transient EDTA-dependent pseudothrombocytopenia in a patient with COVID-19 infection; however, platelet clumping resolved with use of a citrate tube, and the EDTA-dependent pseudothrombocytopenia phenomenon resolved with patient recovery.11 The frequency of COVID-19-related pseudothrombocytopenia is currently unknown.
Although the understanding of COVID-19-associated CAC continues to evolve, it seems that initial reports support the idea that hemostatic dysfunction tends to more thrombosis than to bleeding.12 Rather than overt disseminated intravascular coagulation with reduced fibrinogen and bleeding, CAC is more closely associated with blood clotting, as demonstrated by autopsy studies revealing microvascular thrombosis in the lungs.13 The D-dimer test has been identified as the most useful biomarker by the International Society of Thrombosis and Hemostasis to screen for CAC and stratify patients who warrant admission or closer monitoring.12 Other identified features of CAC include prolonged prothrombin time and thrombocytopenia.12
There have been varying clinical approaches to CAC management. A retrospective review found that prophylactic heparin doses were associated with improved mortality in those with elevated D-dimer > 3.0 mg/L.14 There continues to be a diversity of varying clinical approaches with many medical centers advocating for an intensified prophylactic twice daily low molecular-weight heparin compared with others advocating for full therapeutic dose anticoagulation for patients with elevated D-dimer.15 This patient was treated aggressively with full-dose anticoagulation, and despite his having a down-trend in D-dimer, he suffered a lethal arterial thrombosis in the form of a STEMI.
Varatharajah and Rajah
Conclusions
This patient’s case highlights the presence of pan-pseudothrombocytopenia despite the use of a sodium citrate and heparin containing tube in a COVID-19 infection with multiorgan dysfunction. This developed 1 week prior to the patient suffering a STEMI despite therapeutic anticoagulation. Although the exact nature of CAC remains to be worked out, it is possible that platelet agglutination/clumping seen on the peripheral blood smear is representative of in vivo activity and serves as a harbinger for worsening thrombosis. The frequency of such phenomenon and efficacy of further interventions has yet to be explored.
In late 2019 a new pandemic started in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarities with the virus responsible for the SARS outbreak of 2003. The disease manifestations are named coronavirus disease 2019 (COVID-19).1
Pseudothrombocytopenia, or platelet clumping, visualized on the peripheral blood smear, is a common cause for artificial thrombocytopenia laboratory reporting and is frequently attributed to laboratory artifact. In this case presentation, a critically ill patient with COVID-19 developed pan-pseudothrombocytopenia (ethylenediaminetetraacetic acid [EDTA], sodium citrate, and heparin tubes) just prior to his death from a ST-segment elevation myocardial infarction (STEMI) in the setting of therapeutic anticoagulation during a prolonged hospitalization. This case raises the possibility that pseudothrombocytopenia in the setting of COVID-19 critical illness may represent an ominous feature of COVID-19-associated coagulopathy (CAC). Furthermore, it prompts the question whether pseudothrombocytopenia in this setting is representative of increased platelet aggregation activity in vivo.
Case Presentation
A 50-year-old African American man who was diagnosed with COVID-19 3 days prior to admission presented to the emergency department of the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, with worsening dyspnea and fever. His primary chronic medical problems included obesity (body mass index, 33), type 2 diabetes mellitus (hemoglobin A1c 2 months prior of 6.6%), migraine headaches, and obstructive sleep apnea. Shortly after presentation, his respiratory status declined, requiring intubation. He was admitted to the medical intensive care unit for further management.
Notable findings at admission included > 20 mcg/mL FEU D-dimer (normal range, 0-0.56 mcg/mL FEU), 20.4 mg/dL C-reactive protein (normal range, < 1 mg/dL), 30 mm/h erythrocyte sedimentation rate (normal range, 0-25 mm/h), and 3.56 ng/mL procalcitonin (normal range, 0.05-1.99 ng/mL). Patient’s hemoglobin and platelet counts were normal. Empiric antimicrobial therapy was initiated with ceftriaxone (2 g IV daily) and doxycycline (100 mg IV twice daily) due to concern of superimposed infection in the setting of an elevated procalcitonin.
A heparin infusion was initiated (5,000 U IV bolus followed by continuous infusion with goal partial thromboplastin time [PTT] of 1.5x the upper limit of normal) on admission to treat CAC. Renal function worsened requiring intermittent renal replacement therapy on day 3. His lactate dehydrogenase was elevated to 1,188 U/L (normal range: 100-240 U/L) and ferritin was elevated to 2,603 ng/mL (normal range: 25-350 ng/mL) (Table). Initial neuromuscular blockade and prone positioning maneuvers were instituted to optimize oxygenation based on the latest literature for respiratory distress in the COVID-19 management.2
Intermittent norepinephrine infusion (5 mcg/min with a 2 mcg/min titration every 5 minutes as needed to maintain mean arterial pressure of > 65 mm Hg) was required for hemodynamic support throughout the patient’s course. Several therapies for COVID-19 were considered and were a reflection of the rapidly evolving literature during the care of patients with this disease. The patient originally received hydroxychloroquine (200 mg by mouth twice daily) in accordance with the US Department of Veterans Affairs (VA) institutional protocol between day 2 and day 4; however, hydroxychloroquine was stopped due to concerns of QTc prolongation. The patient also received 1 unit of convalescent plasma on day 6 after being enrolled in the expanded access program.3 The patient was not a candidate for remdesivir due to his unstable renal function and need for vasopressors. Finally, interleukin-6 inhibitors also were considered; however, the risk of superimposed infection precluded its use.
On day 7 antimicrobial therapy was transitioned to linezolid (600 mg IV twice daily) due to the persistence of fever and a portable chest radiograph revealing diffuse infiltrates throughout the bilateral lungs, worse compared with prior radiograph on day 5, suggesting a worsening of pneumonia. On day 12, the patient was transitioned to cefepime (1 gram IV daily) to broaden antimicrobial coverage and was continued thereafter. Blood cultures were negative throughout his hospitalization.
Given his worsening clinical scenario there was a question about whether or not the patient was still shedding virus for prognostic and therapeutic implications. Therefore, his SARS-CoV-2 test by polymerase chain reaction nasopharyngeal was positive again on day 18. On day 20, the patient developed leukocytosis, his fever persisted, and a portable chest radiograph revealed extensive bilateral pulmonary opacities with focal worsening in left lower base. Due to this constellation of findings, a vancomycin IV (1,500 mg once) was started for empirical treatment of hospital-acquired pneumonia. Sputum samples obtained on day 20 revealed Staphylococcus aureus on subsequent days.
From a hematologic perspective, on day 9 due to challenges to maintain a therapeutic level of anticoagulation with heparin infusion thought to be related to antithrombin deficiency, anticoagulation was changed to argatroban infusion (0.5 mcg/kg/min targeting a PTT of 70-105 seconds) for ongoing management of CAC. Although D-dimer was > 20 mcg/mL FEU on admission and on days 4 and 5, D-dimer trended down to 12.5 mcg/mL FEU on day 16.
Throughout the patient’s hospital stay, no significant bleeding was seen. Hemoglobin was 15.2 g/dL on admission, but anemia developed with a nadir of 6.5 g/dL, warranting transfusion of red blood cells on day 22. Platelet count was 165,000 per microliter on admission and remained within normal limits until platelet clumping was noted on day 15 laboratory collection.
Hematology was consulted on day 20 to obtain an accurate platelet count. A peripheral blood smear from a sodium citrate containing tube was remarkable for prominent platelet clumping, particularly at the periphery of the slide (Figure 1). Platelet clumping was reproduced in samples containing EDTA and heparin. Other features of the peripheral blood smear included the presence of echinocytes with rare schistocytes. To investigate for presence of disseminated intravascular coagulation on day 22, fibrinogen was found to be mildly elevated at 538 mg/dL (normal range: 243-517 mg/dL) and a D-dimer value of 11.96 mcg/mL FEU.
On day 22, the patient’s ventilator requirements escalated to requiring 100% FiO2 and 10 cm H20 of positive end-expiratory pressure with mean arterial pressures in the 50 to 60 mm Hg range. Within 30 minutes an electrocardiogram (EKG) obtained revealed a STEMI (Figure 2). Troponin was measured at 0.65 ng/mL (normal range: 0.02-0.06 ng/mL). Just after an EKG was performed, the patient developed a ventricular fibrillation arrest and was unable to obtain return of spontaneous circulation. The patient was pronounced dead. The family declined an autopsy.
Discussion
Pseudothrombocytopenia, or platelet clumping (agglutination), is estimated to be present in up to 2% of hospitalized patients.4 Pseudothrombocytopenia was found to be the root cause of thrombocytopenia hematology consultations in up to 4% of hospitalized patients.5 The etiology is commonly ascribed to EDTA inducing a conformational change in the GpIIb-IIIa platelet complex, rendering it susceptible to binding of autoantibodies, which cause subsequent platelet agglutination.6 In most cases (83%), the use of a non-EDTA anticoagulant, such as sodium citrate, resolves the platelet agglutination and allows for accurate platelet count reporting.4 Pseudothrombocytopenia in most cases is considered an in vitro finding without clinical relevance.7 However, in this patient’s case, his pan-pseudothrombocytopenia was temporally associated with an arterial occlusive event (STEMI) leading to his demise despite therapeutic anticoagulation in the setting of CAC. This temporal association raises the possibility that pseudothrombocytopenia seen on the peripheral blood smear is an accurate representation of in vivo activity.
Pseudothrombocytopenia has been associated with sepsis from bacterial and viral causes as well as autoimmune and medication effect.4,8-10 Li and colleagues reported transient EDTA-dependent pseudothrombocytopenia in a patient with COVID-19 infection; however, platelet clumping resolved with use of a citrate tube, and the EDTA-dependent pseudothrombocytopenia phenomenon resolved with patient recovery.11 The frequency of COVID-19-related pseudothrombocytopenia is currently unknown.
Although the understanding of COVID-19-associated CAC continues to evolve, it seems that initial reports support the idea that hemostatic dysfunction tends to more thrombosis than to bleeding.12 Rather than overt disseminated intravascular coagulation with reduced fibrinogen and bleeding, CAC is more closely associated with blood clotting, as demonstrated by autopsy studies revealing microvascular thrombosis in the lungs.13 The D-dimer test has been identified as the most useful biomarker by the International Society of Thrombosis and Hemostasis to screen for CAC and stratify patients who warrant admission or closer monitoring.12 Other identified features of CAC include prolonged prothrombin time and thrombocytopenia.12
There have been varying clinical approaches to CAC management. A retrospective review found that prophylactic heparin doses were associated with improved mortality in those with elevated D-dimer > 3.0 mg/L.14 There continues to be a diversity of varying clinical approaches with many medical centers advocating for an intensified prophylactic twice daily low molecular-weight heparin compared with others advocating for full therapeutic dose anticoagulation for patients with elevated D-dimer.15 This patient was treated aggressively with full-dose anticoagulation, and despite his having a down-trend in D-dimer, he suffered a lethal arterial thrombosis in the form of a STEMI.
Varatharajah and Rajah
Conclusions
This patient’s case highlights the presence of pan-pseudothrombocytopenia despite the use of a sodium citrate and heparin containing tube in a COVID-19 infection with multiorgan dysfunction. This developed 1 week prior to the patient suffering a STEMI despite therapeutic anticoagulation. Although the exact nature of CAC remains to be worked out, it is possible that platelet agglutination/clumping seen on the peripheral blood smear is representative of in vivo activity and serves as a harbinger for worsening thrombosis. The frequency of such phenomenon and efficacy of further interventions has yet to be explored.
1. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(COVID-2019)-and-the-virus-that-causes-it. Accessed July 15, 2020.
2. Ghelichkhani P, Esmaeili M. Prone position in management of COVID-19 patients; a commentary. Arch Acad Emerg Med. 2020;8(1):e48. Published 2020 April 11.
3. National Library of Medicine, Clinicaltrials.gov. Expanded access to convalescent plasma for the treatment of patients with COVID-19. NCT04338360. https://clinicaltrials.gov/ct2/show/nct04338360. Update April 20, 2020. Accessed July 15, 2020.
4. Tan GC, Stalling M, Dennis G, Nunez M, Kahwash SB. Pseudothrombocytopenia due to platelet clumping: a case report and brief review of the literature. Case Rep Hematol. 2016;2016:3036476. doi:10.1155/2016/3036476
5. Boxer M, Biuso TJ. Etiologies of thrombocytopenia in the community hospital: the experience of 1 hematologist. Am J Med. 2020;133(5):e183-e186. doi:10.1016/j.amjmed.2019.10.027
6. Fiorin F, Steffan A, Pradella P, Bizzaro N, Potenza R, De Angelis V. IgG platelet antibodies in EDTA-dependent pseudothrombocytopenia bind to platelet membrane glycoprotein IIb. Am J Clin Pathol. 1998;110(2):178-183. doi:10.1093/ajcp/110.2.178
7. Nagler M, Keller P, Siegrist S, Alberio L. A case of EDTA-Dependent pseudothrombocytopenia: simple recognition of an underdiagnosed and misleading phenomenon. BMC Clin Pathol. 2014;14:19. doi:10.1186/1472-6890-14-19
8. Mori M, Kudo H, Yoshitake S, Ito K, Shinguu C, Noguchi T. Transient EDTA-dependent pseudothrombocytopenia in a patient with sepsis. Intensive Care Med. 2000;26(2):218-220. doi:10.1007/s001340050050.
9. Choe W-H, Cho Y-U, Chae J-D, Kim S-H. 2013. Pseudothrombocytopenia or platelet clumping as a possible cause of low platelet count in patients with viral infection: a case series from single institution focusing on hepatitis A virus infection. Int J Lab Hematol. 2013;35(1):70-76. doi:10.1111/j.1751-553x.2012.01466.
10. Hsieh AT, Chao TY, Chen YC. Pseudothrombocytopenia associated with infectious mononucleosis. Arch Pathol Lab Med. 2003;127(1):e17-e18. doi:10.1043/0003-9985(2003)1272.0.CO;2
11. Li H, Wang B, Ning L, Luo Y, Xiang S. Transient appearance of EDTA dependent pseudothrombocytopenia in a patient with 2019 novel coronavirus pneumonia [published online ahead of print, 2020 May 5]. Platelets. 2020;1-2. doi:10.1080/09537104.2020.1760231
12. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/jth.14810
13. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1-13. doi:10.1016/j.trsl.2020.04.007
14. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. doi:10.1111/jth.14817
15. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;125(23):2033-2040. doi.org/10.1182/blood.2020006000.
16. Varatharajah N, Rajah S. Microthrombotic complications of COVID-19 are likely due to embolism of circulating endothelial derived ultralarge von Willebrand factor (eULVWF) Decorated-Platelet Strings. Fed Pract. 2020;37(6):258-259. doi:10.12788/fp.0001
17. Bernardo A, Ball C, Nolasco L, Choi H, Moake JL, Dong JF. Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost. 2005;3(3):562-570. doi:10.1111/j.1538-7836.2005.01122.x
1. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(COVID-2019)-and-the-virus-that-causes-it. Accessed July 15, 2020.
2. Ghelichkhani P, Esmaeili M. Prone position in management of COVID-19 patients; a commentary. Arch Acad Emerg Med. 2020;8(1):e48. Published 2020 April 11.
3. National Library of Medicine, Clinicaltrials.gov. Expanded access to convalescent plasma for the treatment of patients with COVID-19. NCT04338360. https://clinicaltrials.gov/ct2/show/nct04338360. Update April 20, 2020. Accessed July 15, 2020.
4. Tan GC, Stalling M, Dennis G, Nunez M, Kahwash SB. Pseudothrombocytopenia due to platelet clumping: a case report and brief review of the literature. Case Rep Hematol. 2016;2016:3036476. doi:10.1155/2016/3036476
5. Boxer M, Biuso TJ. Etiologies of thrombocytopenia in the community hospital: the experience of 1 hematologist. Am J Med. 2020;133(5):e183-e186. doi:10.1016/j.amjmed.2019.10.027
6. Fiorin F, Steffan A, Pradella P, Bizzaro N, Potenza R, De Angelis V. IgG platelet antibodies in EDTA-dependent pseudothrombocytopenia bind to platelet membrane glycoprotein IIb. Am J Clin Pathol. 1998;110(2):178-183. doi:10.1093/ajcp/110.2.178
7. Nagler M, Keller P, Siegrist S, Alberio L. A case of EDTA-Dependent pseudothrombocytopenia: simple recognition of an underdiagnosed and misleading phenomenon. BMC Clin Pathol. 2014;14:19. doi:10.1186/1472-6890-14-19
8. Mori M, Kudo H, Yoshitake S, Ito K, Shinguu C, Noguchi T. Transient EDTA-dependent pseudothrombocytopenia in a patient with sepsis. Intensive Care Med. 2000;26(2):218-220. doi:10.1007/s001340050050.
9. Choe W-H, Cho Y-U, Chae J-D, Kim S-H. 2013. Pseudothrombocytopenia or platelet clumping as a possible cause of low platelet count in patients with viral infection: a case series from single institution focusing on hepatitis A virus infection. Int J Lab Hematol. 2013;35(1):70-76. doi:10.1111/j.1751-553x.2012.01466.
10. Hsieh AT, Chao TY, Chen YC. Pseudothrombocytopenia associated with infectious mononucleosis. Arch Pathol Lab Med. 2003;127(1):e17-e18. doi:10.1043/0003-9985(2003)1272.0.CO;2
11. Li H, Wang B, Ning L, Luo Y, Xiang S. Transient appearance of EDTA dependent pseudothrombocytopenia in a patient with 2019 novel coronavirus pneumonia [published online ahead of print, 2020 May 5]. Platelets. 2020;1-2. doi:10.1080/09537104.2020.1760231
12. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/jth.14810
13. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1-13. doi:10.1016/j.trsl.2020.04.007
14. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. doi:10.1111/jth.14817
15. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;125(23):2033-2040. doi.org/10.1182/blood.2020006000.
16. Varatharajah N, Rajah S. Microthrombotic complications of COVID-19 are likely due to embolism of circulating endothelial derived ultralarge von Willebrand factor (eULVWF) Decorated-Platelet Strings. Fed Pract. 2020;37(6):258-259. doi:10.12788/fp.0001
17. Bernardo A, Ball C, Nolasco L, Choi H, Moake JL, Dong JF. Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost. 2005;3(3):562-570. doi:10.1111/j.1538-7836.2005.01122.x
Antibiotic resistance: Personal responsibility in somewhat short supply
Most primary care physicians agree that antibiotic resistance and inappropriate prescribing are problems in the United States, but they are much less inclined to recognize these issues in their own practices, according to the results of a nationwide survey.
Rachel M. Zetts, MPH, of the Pew Charitable Trusts, Washington, D.C., and associates wrote in Open Forum Infectious Diseases.
Almost all (94%) of the 1,550 internists, family physicians, and pediatricians who responded to the survey said that antibiotic resistance is a national problem, and nearly that many (91%) agreed that “inappropriate antibiotic prescribing is a problem in outpatient health care settings,” the investigators acknowledged.
Narrowing the focus to their own practices, however, changed some opinions. At that level, only 55% of the respondents said that resistance was a problem for their practices, and just 37% said that there any sort of inappropriate prescribing going on, based on data from the survey, which was conducted from August to October 2018 by Pew and the American Medical Association.
Antibiotic stewardship, defined as activities meant to ensure appropriate prescribing of antibiotics, should include “staff and patient education, clinician-level antibiotic prescribing feedback, and communications training on how to discuss antibiotic prescribing with patients,” Ms. Zetts and associates explained.
The need for such stewardship in health care settings was acknowledged by 72% of respondents, but 53% of those surveyed also said that all they need to do to support such efforts “is to talk with their patients about the value of an antibiotic for their symptoms,” they noted.
The bacteria, it seems, are not the only ones with some resistance. Half of the primary care physicians believe that it would be difficult to fairly and accurately track the appropriate use of antibiotics, and 52% agreed with the statement that “practice-based reporting requirements for antibiotic use would be too onerous,” the researchers pointed out.
“Antibiotic resistance is an impending public health crisis. We are seeing today, as we respond to the COVID-19 pandemic, what our health system looks like with no or limited treatments available to tackle an outbreak. … We must all remain vigilant in combating the spread of antibiotic resistant bacteria and be prudent when prescribing antibiotics,” AMA President Susan R. Bailey, MD, said in a written statement.
SOURCE: Zetts RM et al. Open Forum Infect Dis. 2020 July;7(7). doi: 10.1093/ofid/ofaa244.
Most primary care physicians agree that antibiotic resistance and inappropriate prescribing are problems in the United States, but they are much less inclined to recognize these issues in their own practices, according to the results of a nationwide survey.
Rachel M. Zetts, MPH, of the Pew Charitable Trusts, Washington, D.C., and associates wrote in Open Forum Infectious Diseases.
Almost all (94%) of the 1,550 internists, family physicians, and pediatricians who responded to the survey said that antibiotic resistance is a national problem, and nearly that many (91%) agreed that “inappropriate antibiotic prescribing is a problem in outpatient health care settings,” the investigators acknowledged.
Narrowing the focus to their own practices, however, changed some opinions. At that level, only 55% of the respondents said that resistance was a problem for their practices, and just 37% said that there any sort of inappropriate prescribing going on, based on data from the survey, which was conducted from August to October 2018 by Pew and the American Medical Association.
Antibiotic stewardship, defined as activities meant to ensure appropriate prescribing of antibiotics, should include “staff and patient education, clinician-level antibiotic prescribing feedback, and communications training on how to discuss antibiotic prescribing with patients,” Ms. Zetts and associates explained.
The need for such stewardship in health care settings was acknowledged by 72% of respondents, but 53% of those surveyed also said that all they need to do to support such efforts “is to talk with their patients about the value of an antibiotic for their symptoms,” they noted.
The bacteria, it seems, are not the only ones with some resistance. Half of the primary care physicians believe that it would be difficult to fairly and accurately track the appropriate use of antibiotics, and 52% agreed with the statement that “practice-based reporting requirements for antibiotic use would be too onerous,” the researchers pointed out.
“Antibiotic resistance is an impending public health crisis. We are seeing today, as we respond to the COVID-19 pandemic, what our health system looks like with no or limited treatments available to tackle an outbreak. … We must all remain vigilant in combating the spread of antibiotic resistant bacteria and be prudent when prescribing antibiotics,” AMA President Susan R. Bailey, MD, said in a written statement.
SOURCE: Zetts RM et al. Open Forum Infect Dis. 2020 July;7(7). doi: 10.1093/ofid/ofaa244.
Most primary care physicians agree that antibiotic resistance and inappropriate prescribing are problems in the United States, but they are much less inclined to recognize these issues in their own practices, according to the results of a nationwide survey.
Rachel M. Zetts, MPH, of the Pew Charitable Trusts, Washington, D.C., and associates wrote in Open Forum Infectious Diseases.
Almost all (94%) of the 1,550 internists, family physicians, and pediatricians who responded to the survey said that antibiotic resistance is a national problem, and nearly that many (91%) agreed that “inappropriate antibiotic prescribing is a problem in outpatient health care settings,” the investigators acknowledged.
Narrowing the focus to their own practices, however, changed some opinions. At that level, only 55% of the respondents said that resistance was a problem for their practices, and just 37% said that there any sort of inappropriate prescribing going on, based on data from the survey, which was conducted from August to October 2018 by Pew and the American Medical Association.
Antibiotic stewardship, defined as activities meant to ensure appropriate prescribing of antibiotics, should include “staff and patient education, clinician-level antibiotic prescribing feedback, and communications training on how to discuss antibiotic prescribing with patients,” Ms. Zetts and associates explained.
The need for such stewardship in health care settings was acknowledged by 72% of respondents, but 53% of those surveyed also said that all they need to do to support such efforts “is to talk with their patients about the value of an antibiotic for their symptoms,” they noted.
The bacteria, it seems, are not the only ones with some resistance. Half of the primary care physicians believe that it would be difficult to fairly and accurately track the appropriate use of antibiotics, and 52% agreed with the statement that “practice-based reporting requirements for antibiotic use would be too onerous,” the researchers pointed out.
“Antibiotic resistance is an impending public health crisis. We are seeing today, as we respond to the COVID-19 pandemic, what our health system looks like with no or limited treatments available to tackle an outbreak. … We must all remain vigilant in combating the spread of antibiotic resistant bacteria and be prudent when prescribing antibiotics,” AMA President Susan R. Bailey, MD, said in a written statement.
SOURCE: Zetts RM et al. Open Forum Infect Dis. 2020 July;7(7). doi: 10.1093/ofid/ofaa244.
FROM OPEN FORUM INFECTIOUS DISEASES
Guidance covers glycemia in dexamethasone-treated COVID-19 patients
New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.
Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”
RECOVERY trial spurs response
The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.
The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.
The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.
They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.
The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.
Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.
Guidance useful for U.S. physicians
Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”
However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.
He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.
But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”
Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.
Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”
RECOVERY trial spurs response
The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.
The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.
The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.
They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.
The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.
Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.
Guidance useful for U.S. physicians
Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”
However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.
He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.
But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”
Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.
Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”
RECOVERY trial spurs response
The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.
The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.
The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.
They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.
The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.
Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.
Guidance useful for U.S. physicians
Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”
However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.
He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.
But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”
Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.