Cardiology

PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.

This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.

“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.

The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”

The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.

The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.

However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.

While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.

“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.

While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.

“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.

Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.

SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.

PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.

This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.

“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.

The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”

The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.

The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.

However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.

While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.

“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.

While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.

“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.

Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.

SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.

PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.

This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.

“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.

The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”

The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.

The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.

However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.

While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.

“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.

While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.

“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.

Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.

SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.

ANSWER

This ECG shows normal sinus rhythm, an anterior myocardial infarction, and inferolateral injury consistent with an acute ST-elevation myocardial infarction (STEMI).

A P wave for every QRS complex and a QRS complex with every P wave, with a consistent PR interval and a rate > 60 and < 100 beats/min, signifies sinus rhythm.

Criteria for an anterior STEMI include new ST elevation (≥ 2 mm [0.2 mV]) at the J point in leads V₃ and V₄. Inferolateral injury is indicated inferiorly by ST changes in leads II, III, and aVL and laterally by the ST elevation in leads V₅ and V₆.

Subsequent cardiac catheterization showed an occluded proximal left anterior descending artery and significant diagonal and obtuse marginal disease.

ANSWER

This ECG shows normal sinus rhythm, an anterior myocardial infarction, and inferolateral injury consistent with an acute ST-elevation myocardial infarction (STEMI).

A P wave for every QRS complex and a QRS complex with every P wave, with a consistent PR interval and a rate > 60 and < 100 beats/min, signifies sinus rhythm.

Criteria for an anterior STEMI include new ST elevation (≥ 2 mm [0.2 mV]) at the J point in leads V₃ and V₄. Inferolateral injury is indicated inferiorly by ST changes in leads II, III, and aVL and laterally by the ST elevation in leads V₅ and V₆.

Subsequent cardiac catheterization showed an occluded proximal left anterior descending artery and significant diagonal and obtuse marginal disease.

ANSWER

This ECG shows normal sinus rhythm, an anterior myocardial infarction, and inferolateral injury consistent with an acute ST-elevation myocardial infarction (STEMI).

A P wave for every QRS complex and a QRS complex with every P wave, with a consistent PR interval and a rate > 60 and < 100 beats/min, signifies sinus rhythm.

Criteria for an anterior STEMI include new ST elevation (≥ 2 mm [0.2 mV]) at the J point in leads V₃ and V₄. Inferolateral injury is indicated inferiorly by ST changes in leads II, III, and aVL and laterally by the ST elevation in leads V₅ and V₆.

Subsequent cardiac catheterization showed an occluded proximal left anterior descending artery and significant diagonal and obtuse marginal disease.

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

msullivan@mdedge.com

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

msullivan@mdedge.com

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

msullivan@mdedge.com

Angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) is present in from 0.1% to 0.7% of treated patients and more often involves the head, neck, face, lips, tongue, and larynx.¹ ACEI-induced angioedema results from inhibition of angiotensin-converting enzyme (ACE), which results in reduced degradation and resultant accumulation of bradykinin, a potent inflammatory mediator.²

The treatment of choice is discontinuing all ACEIs; however, the patient may be at increased risk of a subsequent angioedema attack for many weeks.³ Antihistamines (H₁ and H₂ receptor blockade), epinephrine, and glucocorticoids are effective in allergic/histaminergic angioedema but are usually ineffective for hereditary angioedema or ACEI angioedema and are not recommended for acute therapy.⁴ Kallikrein-bradykinin pathway targeted therapies are now approved by the Food and Drug Administration (FDA) for hereditary angioedema attacks and have been studied for ACEI-induced angioedema. Ecallantide and icatibant inhibit conversion of precursors to bradykinin. Multiple randomized trials of ecallantide have not shown any advantage over traditional therapies.⁵ On the other hand, icatibant has shown resolution of angioedema in several case reports and in a randomized trial.⁶ Icatibant for ACEI-induced angioedema continues to be off-label because the data are conflicting.

Case Presentation

A 67-year-old man presented with a medical history of arterial hypertension (diagnosed 17 years previously), hypercholesterolemia, type 2 diabetes mellitus, alcohol dependence, and obesity. His outpatient medications included simvastatin, aripiprazole, losartan/hydrochlorothiazide, and amlodipine. He was voluntarily admitted for inpatient detoxification. After evaluation by the internist, medication reconciliation was done, and the therapy was adjusted according to medication availability. He reported having no drug allergies, and the losartan was changed for lisinopril. About 24 hours after the first dose of lisinopril, the patient developed swelling of the lips. Antihistamine and IV steroids were administered, and the ACEI was discontinued. His baseline vital signs were temperature 98° F, heart rate 83 beats per minute, respiratory rate 19 breaths per minute, blood pressure 150/94, and oxygen saturation 98% by pulse oximeter.

During the night shift the patient’s symptoms worsened, developing difficulty swallowing and shortness of breath. He was transferred to the medicine intensive care unit (MICU), intubated, and placed on mechanical ventilation to protect his airway. Laryngoscopic examination was notable for edematous tongue, uvula, and larynx. Also, the patient had mild stridor. His laboratory test results showed normal levels of complement, tryptase, and C1 esterase. On the fourth day after admission to MICU (Figure 1), the patient extubated himself. At that time, he did not present stridor or respiratory distress and remained at the MICU for 24 hours for close monitoring.

Thirty-six hours after self-extubation the patient developed stridor and shortness of breath at the general medicine ward. In view of his clinical presentation of recurrent ACEI-induced angioedema, the Anesthesiology Service was consulted. Direct visualization of the airways showed edema of the epiglottis and vocal cords, requiring nasotracheal intubation. Two units of fresh frozen plasma (FFP) were administered. Complete resolution of angioedema took at least 72 hours even after the administration of FFP. As part of the ventilator-associated pneumonia prevention bundle, the patient continued with daily spontaneous breathing trials. On the fourth day, he was he was extubated after a cuff-leak test was positive and his rapid shallow breathing index was adequate.

The cuff-leak test is usually done to predict postextubation stridor. It consists of deflating the endotracheal tube cuff to verify if gas can pass around the tube. Absence of cuff leak is suggestive of airway edema, a risk factor for postextubation stridor and failure of extubation. For example, if the patient has an endotracheal tube that is too large in relation to the patient’s airway, the leak test can result in a false negative. In this case, fiber optic visualization of the airway can confirm the endotracheal tube occluding all the airway even with the cuff deflated and without evidence of swelling of the vocal cords. The rapid shallow breathing index is a ratio of respiratory rate over tidal volume in liters and is used to predict successful extubation. Values < 105 have a high sensitivity for successful extubation.

The patient remained under observation for 24 hours in the MICU and then was transferred to the general medicine ward. Unfortunately, 36 hours after, the patient had a new episode of angioedema requiring endotracheal intubation and placement on mechanical ventilation. This was his third episode of angioedema; he had a difficult airway classified as a Cormack-Lehane grade 3, requiring intubation with fiber-optic laryngoscope. In view of the recurrent events, a tracheostomy was done several days later. Figure 2 shows posttracheostomy X-ray with adequate position of the tracheostomy tube.

The patient was transferred to the Respiratory Care Unit and weaned off mechanical ventilation. He completed an intensive physical rehabilitation program and was discharged home. On discharge, he was followed by the Otorhinolaryngology Service and was decannulated about 5 months after. After tracheostomy decannulation, he developed asymptomatic stridor. A neck computer tomography scan revealed soft tissue thickening at the anterior and lateral aspects of the proximal tracheal likely representing granulation tissue/scarring. The findings were consistent with proximal tracheal stenosis sequelae of tracheostomy and intubation. In Figure 3, the upper portion of the curve represents the expiratory limb of the forced vital capacity and the lower portion represents inspiration. The flow-volume loop graph showed flattening of the inspiratory limb. There was a plateau in the inspiratory limb, suggestive of limitation of inspiratory flow as seen in variable extrathoracic lesions, such as glotticstricture, tumors, and vocal cord paralysis.⁷ The findings on the flow-volume loop were consistent with the subglottic stenosis identified by laryngoscopic examination. The patient was reluctant to undergo further interventions.

Discussion

The standard therapy for ACEI-inducedangioedema continues to be airway management and discontinuation of medication. However, life-threatening progression of symptoms have led to the use of off-label therapies, including FFP and bradykinin receptor antagonists, such as icatibant, which has been approved by the FDA for the treatment of hereditary angioedema. Icatibant is expensive and most hospitals do not have access to it. When considering the bradykinin pathway for therapy, FFP is commonly used. The cases described in the literature that have reported success with the use of FFP have used up to 2 units. There is no reported benefit of its use beyond 2 units. The initial randomized trials of icatibant for ACEI angioedema showed decreased time of resolution of angioedema.⁶ However, repeated trials showed conflicting results. At Veterans Affairs Caribbean Healthcare System, this medication was not available, and we decided to use FFP to improve the patient’s symptoms.

The administration of 2 units of FFP has been documented on case reports as a method to decrease the time of resolution of angioedema and the risk of recurrence. The mechanism of action thought to be involved includes the degradation of bradykinin by the enzyme ACE into inactive peptides and by supplying C1 inhibitor.⁸ No randomized clinical trial has investigated the use of FFP for the treatment of ACEI-induced angioedema. However, a retrospective cohort study report compared patients who presented with acute (nonhereditary) angioedema and airway compromise and received FFP with patients who were not treated with FFP.⁹ The study suggested a shorter ICU stay in the group treated with FFP, but the findings did not present statistical outcomes.

Nevertheless, our patient had recurrent ACEI-induced angioedema refractory to FFP. In addition to ACE or kininase II, FFP contains high-molecular weight-kininogen and kallikrein, the substrates that form bradykinin, which explained the mechanism of worsening angioedema.¹⁰ No randomized trials have investigated the use of FFP for the treatment of bradykinin-induced angioedema nor the appropriate dose.

Conclusion

In view of the emerging case reports of the effectiveness of FFP, this case of refractory angioedema raises concern for its true effectiveness and other possible factors involved in the mechanism of recurrence. Probably it would be unwise to conduct randomized studies in clinical situations such as the ones outlined. A collection of case series where FFP administration was done may be a more reasonable source of conclusions to be analyzed by a panel of experts.

Angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) is present in from 0.1% to 0.7% of treated patients and more often involves the head, neck, face, lips, tongue, and larynx.¹ ACEI-induced angioedema results from inhibition of angiotensin-converting enzyme (ACE), which results in reduced degradation and resultant accumulation of bradykinin, a potent inflammatory mediator.²

The treatment of choice is discontinuing all ACEIs; however, the patient may be at increased risk of a subsequent angioedema attack for many weeks.³ Antihistamines (H₁ and H₂ receptor blockade), epinephrine, and glucocorticoids are effective in allergic/histaminergic angioedema but are usually ineffective for hereditary angioedema or ACEI angioedema and are not recommended for acute therapy.⁴ Kallikrein-bradykinin pathway targeted therapies are now approved by the Food and Drug Administration (FDA) for hereditary angioedema attacks and have been studied for ACEI-induced angioedema. Ecallantide and icatibant inhibit conversion of precursors to bradykinin. Multiple randomized trials of ecallantide have not shown any advantage over traditional therapies.⁵ On the other hand, icatibant has shown resolution of angioedema in several case reports and in a randomized trial.⁶ Icatibant for ACEI-induced angioedema continues to be off-label because the data are conflicting.

Case Presentation

A 67-year-old man presented with a medical history of arterial hypertension (diagnosed 17 years previously), hypercholesterolemia, type 2 diabetes mellitus, alcohol dependence, and obesity. His outpatient medications included simvastatin, aripiprazole, losartan/hydrochlorothiazide, and amlodipine. He was voluntarily admitted for inpatient detoxification. After evaluation by the internist, medication reconciliation was done, and the therapy was adjusted according to medication availability. He reported having no drug allergies, and the losartan was changed for lisinopril. About 24 hours after the first dose of lisinopril, the patient developed swelling of the lips. Antihistamine and IV steroids were administered, and the ACEI was discontinued. His baseline vital signs were temperature 98° F, heart rate 83 beats per minute, respiratory rate 19 breaths per minute, blood pressure 150/94, and oxygen saturation 98% by pulse oximeter.

During the night shift the patient’s symptoms worsened, developing difficulty swallowing and shortness of breath. He was transferred to the medicine intensive care unit (MICU), intubated, and placed on mechanical ventilation to protect his airway. Laryngoscopic examination was notable for edematous tongue, uvula, and larynx. Also, the patient had mild stridor. His laboratory test results showed normal levels of complement, tryptase, and C1 esterase. On the fourth day after admission to MICU (Figure 1), the patient extubated himself. At that time, he did not present stridor or respiratory distress and remained at the MICU for 24 hours for close monitoring.

Thirty-six hours after self-extubation the patient developed stridor and shortness of breath at the general medicine ward. In view of his clinical presentation of recurrent ACEI-induced angioedema, the Anesthesiology Service was consulted. Direct visualization of the airways showed edema of the epiglottis and vocal cords, requiring nasotracheal intubation. Two units of fresh frozen plasma (FFP) were administered. Complete resolution of angioedema took at least 72 hours even after the administration of FFP. As part of the ventilator-associated pneumonia prevention bundle, the patient continued with daily spontaneous breathing trials. On the fourth day, he was he was extubated after a cuff-leak test was positive and his rapid shallow breathing index was adequate.

The cuff-leak test is usually done to predict postextubation stridor. It consists of deflating the endotracheal tube cuff to verify if gas can pass around the tube. Absence of cuff leak is suggestive of airway edema, a risk factor for postextubation stridor and failure of extubation. For example, if the patient has an endotracheal tube that is too large in relation to the patient’s airway, the leak test can result in a false negative. In this case, fiber optic visualization of the airway can confirm the endotracheal tube occluding all the airway even with the cuff deflated and without evidence of swelling of the vocal cords. The rapid shallow breathing index is a ratio of respiratory rate over tidal volume in liters and is used to predict successful extubation. Values < 105 have a high sensitivity for successful extubation.

The patient remained under observation for 24 hours in the MICU and then was transferred to the general medicine ward. Unfortunately, 36 hours after, the patient had a new episode of angioedema requiring endotracheal intubation and placement on mechanical ventilation. This was his third episode of angioedema; he had a difficult airway classified as a Cormack-Lehane grade 3, requiring intubation with fiber-optic laryngoscope. In view of the recurrent events, a tracheostomy was done several days later. Figure 2 shows posttracheostomy X-ray with adequate position of the tracheostomy tube.

The patient was transferred to the Respiratory Care Unit and weaned off mechanical ventilation. He completed an intensive physical rehabilitation program and was discharged home. On discharge, he was followed by the Otorhinolaryngology Service and was decannulated about 5 months after. After tracheostomy decannulation, he developed asymptomatic stridor. A neck computer tomography scan revealed soft tissue thickening at the anterior and lateral aspects of the proximal tracheal likely representing granulation tissue/scarring. The findings were consistent with proximal tracheal stenosis sequelae of tracheostomy and intubation. In Figure 3, the upper portion of the curve represents the expiratory limb of the forced vital capacity and the lower portion represents inspiration. The flow-volume loop graph showed flattening of the inspiratory limb. There was a plateau in the inspiratory limb, suggestive of limitation of inspiratory flow as seen in variable extrathoracic lesions, such as glotticstricture, tumors, and vocal cord paralysis.⁷ The findings on the flow-volume loop were consistent with the subglottic stenosis identified by laryngoscopic examination. The patient was reluctant to undergo further interventions.

Discussion

The standard therapy for ACEI-inducedangioedema continues to be airway management and discontinuation of medication. However, life-threatening progression of symptoms have led to the use of off-label therapies, including FFP and bradykinin receptor antagonists, such as icatibant, which has been approved by the FDA for the treatment of hereditary angioedema. Icatibant is expensive and most hospitals do not have access to it. When considering the bradykinin pathway for therapy, FFP is commonly used. The cases described in the literature that have reported success with the use of FFP have used up to 2 units. There is no reported benefit of its use beyond 2 units. The initial randomized trials of icatibant for ACEI angioedema showed decreased time of resolution of angioedema.⁶ However, repeated trials showed conflicting results. At Veterans Affairs Caribbean Healthcare System, this medication was not available, and we decided to use FFP to improve the patient’s symptoms.

The administration of 2 units of FFP has been documented on case reports as a method to decrease the time of resolution of angioedema and the risk of recurrence. The mechanism of action thought to be involved includes the degradation of bradykinin by the enzyme ACE into inactive peptides and by supplying C1 inhibitor.⁸ No randomized clinical trial has investigated the use of FFP for the treatment of ACEI-induced angioedema. However, a retrospective cohort study report compared patients who presented with acute (nonhereditary) angioedema and airway compromise and received FFP with patients who were not treated with FFP.⁹ The study suggested a shorter ICU stay in the group treated with FFP, but the findings did not present statistical outcomes.

Nevertheless, our patient had recurrent ACEI-induced angioedema refractory to FFP. In addition to ACE or kininase II, FFP contains high-molecular weight-kininogen and kallikrein, the substrates that form bradykinin, which explained the mechanism of worsening angioedema.¹⁰ No randomized trials have investigated the use of FFP for the treatment of bradykinin-induced angioedema nor the appropriate dose.

Conclusion

In view of the emerging case reports of the effectiveness of FFP, this case of refractory angioedema raises concern for its true effectiveness and other possible factors involved in the mechanism of recurrence. Probably it would be unwise to conduct randomized studies in clinical situations such as the ones outlined. A collection of case series where FFP administration was done may be a more reasonable source of conclusions to be analyzed by a panel of experts.

Angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) is present in from 0.1% to 0.7% of treated patients and more often involves the head, neck, face, lips, tongue, and larynx.¹ ACEI-induced angioedema results from inhibition of angiotensin-converting enzyme (ACE), which results in reduced degradation and resultant accumulation of bradykinin, a potent inflammatory mediator.²

The treatment of choice is discontinuing all ACEIs; however, the patient may be at increased risk of a subsequent angioedema attack for many weeks.³ Antihistamines (H₁ and H₂ receptor blockade), epinephrine, and glucocorticoids are effective in allergic/histaminergic angioedema but are usually ineffective for hereditary angioedema or ACEI angioedema and are not recommended for acute therapy.⁴ Kallikrein-bradykinin pathway targeted therapies are now approved by the Food and Drug Administration (FDA) for hereditary angioedema attacks and have been studied for ACEI-induced angioedema. Ecallantide and icatibant inhibit conversion of precursors to bradykinin. Multiple randomized trials of ecallantide have not shown any advantage over traditional therapies.⁵ On the other hand, icatibant has shown resolution of angioedema in several case reports and in a randomized trial.⁶ Icatibant for ACEI-induced angioedema continues to be off-label because the data are conflicting.

Case Presentation

A 67-year-old man presented with a medical history of arterial hypertension (diagnosed 17 years previously), hypercholesterolemia, type 2 diabetes mellitus, alcohol dependence, and obesity. His outpatient medications included simvastatin, aripiprazole, losartan/hydrochlorothiazide, and amlodipine. He was voluntarily admitted for inpatient detoxification. After evaluation by the internist, medication reconciliation was done, and the therapy was adjusted according to medication availability. He reported having no drug allergies, and the losartan was changed for lisinopril. About 24 hours after the first dose of lisinopril, the patient developed swelling of the lips. Antihistamine and IV steroids were administered, and the ACEI was discontinued. His baseline vital signs were temperature 98° F, heart rate 83 beats per minute, respiratory rate 19 breaths per minute, blood pressure 150/94, and oxygen saturation 98% by pulse oximeter.

During the night shift the patient’s symptoms worsened, developing difficulty swallowing and shortness of breath. He was transferred to the medicine intensive care unit (MICU), intubated, and placed on mechanical ventilation to protect his airway. Laryngoscopic examination was notable for edematous tongue, uvula, and larynx. Also, the patient had mild stridor. His laboratory test results showed normal levels of complement, tryptase, and C1 esterase. On the fourth day after admission to MICU (Figure 1), the patient extubated himself. At that time, he did not present stridor or respiratory distress and remained at the MICU for 24 hours for close monitoring.

Thirty-six hours after self-extubation the patient developed stridor and shortness of breath at the general medicine ward. In view of his clinical presentation of recurrent ACEI-induced angioedema, the Anesthesiology Service was consulted. Direct visualization of the airways showed edema of the epiglottis and vocal cords, requiring nasotracheal intubation. Two units of fresh frozen plasma (FFP) were administered. Complete resolution of angioedema took at least 72 hours even after the administration of FFP. As part of the ventilator-associated pneumonia prevention bundle, the patient continued with daily spontaneous breathing trials. On the fourth day, he was he was extubated after a cuff-leak test was positive and his rapid shallow breathing index was adequate.

The cuff-leak test is usually done to predict postextubation stridor. It consists of deflating the endotracheal tube cuff to verify if gas can pass around the tube. Absence of cuff leak is suggestive of airway edema, a risk factor for postextubation stridor and failure of extubation. For example, if the patient has an endotracheal tube that is too large in relation to the patient’s airway, the leak test can result in a false negative. In this case, fiber optic visualization of the airway can confirm the endotracheal tube occluding all the airway even with the cuff deflated and without evidence of swelling of the vocal cords. The rapid shallow breathing index is a ratio of respiratory rate over tidal volume in liters and is used to predict successful extubation. Values < 105 have a high sensitivity for successful extubation.

The patient remained under observation for 24 hours in the MICU and then was transferred to the general medicine ward. Unfortunately, 36 hours after, the patient had a new episode of angioedema requiring endotracheal intubation and placement on mechanical ventilation. This was his third episode of angioedema; he had a difficult airway classified as a Cormack-Lehane grade 3, requiring intubation with fiber-optic laryngoscope. In view of the recurrent events, a tracheostomy was done several days later. Figure 2 shows posttracheostomy X-ray with adequate position of the tracheostomy tube.

The patient was transferred to the Respiratory Care Unit and weaned off mechanical ventilation. He completed an intensive physical rehabilitation program and was discharged home. On discharge, he was followed by the Otorhinolaryngology Service and was decannulated about 5 months after. After tracheostomy decannulation, he developed asymptomatic stridor. A neck computer tomography scan revealed soft tissue thickening at the anterior and lateral aspects of the proximal tracheal likely representing granulation tissue/scarring. The findings were consistent with proximal tracheal stenosis sequelae of tracheostomy and intubation. In Figure 3, the upper portion of the curve represents the expiratory limb of the forced vital capacity and the lower portion represents inspiration. The flow-volume loop graph showed flattening of the inspiratory limb. There was a plateau in the inspiratory limb, suggestive of limitation of inspiratory flow as seen in variable extrathoracic lesions, such as glotticstricture, tumors, and vocal cord paralysis.⁷ The findings on the flow-volume loop were consistent with the subglottic stenosis identified by laryngoscopic examination. The patient was reluctant to undergo further interventions.

Discussion

The standard therapy for ACEI-inducedangioedema continues to be airway management and discontinuation of medication. However, life-threatening progression of symptoms have led to the use of off-label therapies, including FFP and bradykinin receptor antagonists, such as icatibant, which has been approved by the FDA for the treatment of hereditary angioedema. Icatibant is expensive and most hospitals do not have access to it. When considering the bradykinin pathway for therapy, FFP is commonly used. The cases described in the literature that have reported success with the use of FFP have used up to 2 units. There is no reported benefit of its use beyond 2 units. The initial randomized trials of icatibant for ACEI angioedema showed decreased time of resolution of angioedema.⁶ However, repeated trials showed conflicting results. At Veterans Affairs Caribbean Healthcare System, this medication was not available, and we decided to use FFP to improve the patient’s symptoms.

The administration of 2 units of FFP has been documented on case reports as a method to decrease the time of resolution of angioedema and the risk of recurrence. The mechanism of action thought to be involved includes the degradation of bradykinin by the enzyme ACE into inactive peptides and by supplying C1 inhibitor.⁸ No randomized clinical trial has investigated the use of FFP for the treatment of ACEI-induced angioedema. However, a retrospective cohort study report compared patients who presented with acute (nonhereditary) angioedema and airway compromise and received FFP with patients who were not treated with FFP.⁹ The study suggested a shorter ICU stay in the group treated with FFP, but the findings did not present statistical outcomes.

Nevertheless, our patient had recurrent ACEI-induced angioedema refractory to FFP. In addition to ACE or kininase II, FFP contains high-molecular weight-kininogen and kallikrein, the substrates that form bradykinin, which explained the mechanism of worsening angioedema.¹⁰ No randomized trials have investigated the use of FFP for the treatment of bradykinin-induced angioedema nor the appropriate dose.

Conclusion

In view of the emerging case reports of the effectiveness of FFP, this case of refractory angioedema raises concern for its true effectiveness and other possible factors involved in the mechanism of recurrence. Probably it would be unwise to conduct randomized studies in clinical situations such as the ones outlined. A collection of case series where FFP administration was done may be a more reasonable source of conclusions to be analyzed by a panel of experts.

Study Overview

Objective. To compare the benefit of apixaban with a vitamin K antagonist and compare aspirin with placebo in patients with atrial fibrillation who had acute coronary syndrome or underwent percutaneous coronary intervention (PCI) and were planning to take a P2Y12 inhibitor.

Design. Multicenter, international, open-label, prospective randomized controlled trial with a 2-by-2 factorial design.

Setting and participants. 4614 patients who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor.

Intervention. Patients were assigned by means of an interactive voice-response system to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months.

Main outcome measures. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.

Main results. At 6 months, major or clinically relevant nonmajor bleeding had occurred in 10.5% of the patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.58-0.81, P < 0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (HR 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR 0.83; 95% CI, 0.74-0.93; P = 0.002) and similar incidence of ischemic events.

Conclusion. Among patients with atrial fibrillation and recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban without aspirin resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than the regimens that included a vitamin K antagonist, aspirin, or both.

 

 

Commentary

PCI is performed in about 20% of patients with atrial fibrillation. These patients require dual antiplatelet therapy to prevent ischemic events, combined with long-term anticoagulation to prevent stroke due to atrial fibrillation. Because the combination of anticoagulation and antiplatelet therapy is associated with a higher risk of bleeding, balancing the risk and benefit of dual antiplatelet therapy and anticoagulation in this population is crucial.

Previous studies have assessed the risk and benefit associated with anticoagulation and antiplatelet therapy. When warfarin plus clopidogrel (double therapy) was compared with warfarin, aspirin, and clopidogrel (triple therapy) in patients with acute coronary syndromes and stable ischemic coronary disease undergoing PCI, use of clopidogrel without aspirin (double therapy) was associated with a significant reduction in bleeding complications (19.4% versus 44.4%, HR, 0.36; 95% CI, 0.26-0.20; P < 0.0001) without increasing thrombotic events.¹ Recent studies have compared triple therapy with warfarin to double therapy using direct oral anticoagulants (DOAC). The PIONEER AF-PCI study, which compared low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor to vitamin K antagonist plus dual antiplatelet therapy, found that the rates of clinically significant bleeding were lower in the low-dose rivaroxaban group compared to the triple-therapy group with a vitamin K antagonist (16.8% versus 26.7%; HR, 0.59; 95% CI, 0.47-0.76; P < 0.001).² Similarly, the RE-DUAL PCI studied dabigatran and showed that the dual therapy group with dabigatran had a lower incidence of major or clinically relevant nonmajor bleeding events during follow-up compared to triple therapy including a vitamin K antagonist (15.4% versus 26.9%; HR, 0.52; 95% CI, 0.42-0.63; P < 0.001).³

In this context, Lopes at al investigated the clinical question of dual therapy versus triple therapy by performing a well-designed randomized clinical trial. In this trial with a 2-by-2 factorial design, the authors studied the effect of apixaban compared to vitamin K antagonist and the effect of aspirin compared to placebo. Major or clinically relevant nonmajor bleeding occurred in 10.5% of patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (HR 0.69; 95% CI, 0.58-0.81; P < 0.001). The incidence of major or clinically relevant nonmajor bleeding was higher in patients receiving aspirin than in those receiving placebo (16.1% versus 9.0%; HR, 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR, 0.83; 95% CI, 0.74-0.93; P = 0.002). The incidence of ischemic events was similar between the apixaban group and vitamin K antagonist group and between the aspirin group and placebo group.

The strengths of this current study include the large number of patients it enrolled. Taking the results from the PIONEER-AF, RE-DUAL PCI, and AUGUSTUS trials, it is clear that DOAC reduces the risk of bleeding compared to vitamin K antagonist. In addition, the AUGUSTUS trial was the first that evaluated the effect of aspirin in patients treated with DOAC and antiplatelet therapy. Aspirin was associated with increased risk of bleeding, with a similar rate of ischemic events compared to placebo.

The AUGUSTUS trial has several limitations. Although the incidence of ischemic events was similar between the apixaban group and the vitamin K antagonist group, the study was not powered to evaluate for individual ischemic outcomes. However, there was no clear evidence of an increase in harm. Since more than 90% of P2Y12 inhibitors used were clopidogrel, the safety and efficacy of combining apixaban with ticagrelor or prasugrel will require further study.

Applications for Clinical Practice

In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, dual therapy with a P2Y12 inhibitor and DOAC should be favored over a regimen that includes a vitamin K antagonist and/or aspirin.

—Taishi Hirai, MD, University of Missouri Medical Center, and John Blair, MD, University of Chicago Medical Center

Study Overview

Objective. To compare the benefit of apixaban with a vitamin K antagonist and compare aspirin with placebo in patients with atrial fibrillation who had acute coronary syndrome or underwent percutaneous coronary intervention (PCI) and were planning to take a P2Y12 inhibitor.

Design. Multicenter, international, open-label, prospective randomized controlled trial with a 2-by-2 factorial design.

Setting and participants. 4614 patients who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor.

Intervention. Patients were assigned by means of an interactive voice-response system to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months.

Main outcome measures. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.

Main results. At 6 months, major or clinically relevant nonmajor bleeding had occurred in 10.5% of the patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.58-0.81, P < 0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (HR 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR 0.83; 95% CI, 0.74-0.93; P = 0.002) and similar incidence of ischemic events.

Conclusion. Among patients with atrial fibrillation and recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban without aspirin resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than the regimens that included a vitamin K antagonist, aspirin, or both.

 

 

Commentary

PCI is performed in about 20% of patients with atrial fibrillation. These patients require dual antiplatelet therapy to prevent ischemic events, combined with long-term anticoagulation to prevent stroke due to atrial fibrillation. Because the combination of anticoagulation and antiplatelet therapy is associated with a higher risk of bleeding, balancing the risk and benefit of dual antiplatelet therapy and anticoagulation in this population is crucial.

Previous studies have assessed the risk and benefit associated with anticoagulation and antiplatelet therapy. When warfarin plus clopidogrel (double therapy) was compared with warfarin, aspirin, and clopidogrel (triple therapy) in patients with acute coronary syndromes and stable ischemic coronary disease undergoing PCI, use of clopidogrel without aspirin (double therapy) was associated with a significant reduction in bleeding complications (19.4% versus 44.4%, HR, 0.36; 95% CI, 0.26-0.20; P < 0.0001) without increasing thrombotic events.¹ Recent studies have compared triple therapy with warfarin to double therapy using direct oral anticoagulants (DOAC). The PIONEER AF-PCI study, which compared low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor to vitamin K antagonist plus dual antiplatelet therapy, found that the rates of clinically significant bleeding were lower in the low-dose rivaroxaban group compared to the triple-therapy group with a vitamin K antagonist (16.8% versus 26.7%; HR, 0.59; 95% CI, 0.47-0.76; P < 0.001).² Similarly, the RE-DUAL PCI studied dabigatran and showed that the dual therapy group with dabigatran had a lower incidence of major or clinically relevant nonmajor bleeding events during follow-up compared to triple therapy including a vitamin K antagonist (15.4% versus 26.9%; HR, 0.52; 95% CI, 0.42-0.63; P < 0.001).³

In this context, Lopes at al investigated the clinical question of dual therapy versus triple therapy by performing a well-designed randomized clinical trial. In this trial with a 2-by-2 factorial design, the authors studied the effect of apixaban compared to vitamin K antagonist and the effect of aspirin compared to placebo. Major or clinically relevant nonmajor bleeding occurred in 10.5% of patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (HR 0.69; 95% CI, 0.58-0.81; P < 0.001). The incidence of major or clinically relevant nonmajor bleeding was higher in patients receiving aspirin than in those receiving placebo (16.1% versus 9.0%; HR, 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR, 0.83; 95% CI, 0.74-0.93; P = 0.002). The incidence of ischemic events was similar between the apixaban group and vitamin K antagonist group and between the aspirin group and placebo group.

The strengths of this current study include the large number of patients it enrolled. Taking the results from the PIONEER-AF, RE-DUAL PCI, and AUGUSTUS trials, it is clear that DOAC reduces the risk of bleeding compared to vitamin K antagonist. In addition, the AUGUSTUS trial was the first that evaluated the effect of aspirin in patients treated with DOAC and antiplatelet therapy. Aspirin was associated with increased risk of bleeding, with a similar rate of ischemic events compared to placebo.

The AUGUSTUS trial has several limitations. Although the incidence of ischemic events was similar between the apixaban group and the vitamin K antagonist group, the study was not powered to evaluate for individual ischemic outcomes. However, there was no clear evidence of an increase in harm. Since more than 90% of P2Y12 inhibitors used were clopidogrel, the safety and efficacy of combining apixaban with ticagrelor or prasugrel will require further study.

Applications for Clinical Practice

In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, dual therapy with a P2Y12 inhibitor and DOAC should be favored over a regimen that includes a vitamin K antagonist and/or aspirin.

—Taishi Hirai, MD, University of Missouri Medical Center, and John Blair, MD, University of Chicago Medical Center

Study Overview

Objective. To compare the benefit of apixaban with a vitamin K antagonist and compare aspirin with placebo in patients with atrial fibrillation who had acute coronary syndrome or underwent percutaneous coronary intervention (PCI) and were planning to take a P2Y12 inhibitor.

Design. Multicenter, international, open-label, prospective randomized controlled trial with a 2-by-2 factorial design.

Setting and participants. 4614 patients who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor.

Intervention. Patients were assigned by means of an interactive voice-response system to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months.

Main outcome measures. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.

Main results. At 6 months, major or clinically relevant nonmajor bleeding had occurred in 10.5% of the patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.58-0.81, P < 0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (HR 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR 0.83; 95% CI, 0.74-0.93; P = 0.002) and similar incidence of ischemic events.

Conclusion. Among patients with atrial fibrillation and recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban without aspirin resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than the regimens that included a vitamin K antagonist, aspirin, or both.

 

 

Commentary

PCI is performed in about 20% of patients with atrial fibrillation. These patients require dual antiplatelet therapy to prevent ischemic events, combined with long-term anticoagulation to prevent stroke due to atrial fibrillation. Because the combination of anticoagulation and antiplatelet therapy is associated with a higher risk of bleeding, balancing the risk and benefit of dual antiplatelet therapy and anticoagulation in this population is crucial.

Previous studies have assessed the risk and benefit associated with anticoagulation and antiplatelet therapy. When warfarin plus clopidogrel (double therapy) was compared with warfarin, aspirin, and clopidogrel (triple therapy) in patients with acute coronary syndromes and stable ischemic coronary disease undergoing PCI, use of clopidogrel without aspirin (double therapy) was associated with a significant reduction in bleeding complications (19.4% versus 44.4%, HR, 0.36; 95% CI, 0.26-0.20; P < 0.0001) without increasing thrombotic events.¹ Recent studies have compared triple therapy with warfarin to double therapy using direct oral anticoagulants (DOAC). The PIONEER AF-PCI study, which compared low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor to vitamin K antagonist plus dual antiplatelet therapy, found that the rates of clinically significant bleeding were lower in the low-dose rivaroxaban group compared to the triple-therapy group with a vitamin K antagonist (16.8% versus 26.7%; HR, 0.59; 95% CI, 0.47-0.76; P < 0.001).² Similarly, the RE-DUAL PCI studied dabigatran and showed that the dual therapy group with dabigatran had a lower incidence of major or clinically relevant nonmajor bleeding events during follow-up compared to triple therapy including a vitamin K antagonist (15.4% versus 26.9%; HR, 0.52; 95% CI, 0.42-0.63; P < 0.001).³

In this context, Lopes at al investigated the clinical question of dual therapy versus triple therapy by performing a well-designed randomized clinical trial. In this trial with a 2-by-2 factorial design, the authors studied the effect of apixaban compared to vitamin K antagonist and the effect of aspirin compared to placebo. Major or clinically relevant nonmajor bleeding occurred in 10.5% of patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (HR 0.69; 95% CI, 0.58-0.81; P < 0.001). The incidence of major or clinically relevant nonmajor bleeding was higher in patients receiving aspirin than in those receiving placebo (16.1% versus 9.0%; HR, 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR, 0.83; 95% CI, 0.74-0.93; P = 0.002). The incidence of ischemic events was similar between the apixaban group and vitamin K antagonist group and between the aspirin group and placebo group.

The strengths of this current study include the large number of patients it enrolled. Taking the results from the PIONEER-AF, RE-DUAL PCI, and AUGUSTUS trials, it is clear that DOAC reduces the risk of bleeding compared to vitamin K antagonist. In addition, the AUGUSTUS trial was the first that evaluated the effect of aspirin in patients treated with DOAC and antiplatelet therapy. Aspirin was associated with increased risk of bleeding, with a similar rate of ischemic events compared to placebo.

The AUGUSTUS trial has several limitations. Although the incidence of ischemic events was similar between the apixaban group and the vitamin K antagonist group, the study was not powered to evaluate for individual ischemic outcomes. However, there was no clear evidence of an increase in harm. Since more than 90% of P2Y12 inhibitors used were clopidogrel, the safety and efficacy of combining apixaban with ticagrelor or prasugrel will require further study.

Applications for Clinical Practice

In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, dual therapy with a P2Y12 inhibitor and DOAC should be favored over a regimen that includes a vitamin K antagonist and/or aspirin.

—Taishi Hirai, MD, University of Missouri Medical Center, and John Blair, MD, University of Chicago Medical Center

From the University of Miami, Department of Pediatrics and Department of Medicine, Miami, FL.

Abstract

• Objective: Pediatric fungemia is associated with a low risk of fungal endocarditis and renal infections. The majority of current guidelines do not recommend routine abdominal imaging/echocardiograms in the evaluation of fungemia, but such imaging has been routinely ordered for patients on the pediatric gastroenterology service at our institution. Our goals were to assess the financial impact of this deviation from current clinical guidelines and redefine the standard work to reduce overutilization of abdominal ultrasounds and echocardiograms. Specifically, our goal was to reduce imaging by 50% by 18 months.
• Methods: Root cause analysis showed a lack of familiarity with current evidence. Using this data, countermeasures were implemented, including practitioner education of guidelines and creation of a readily accessible clinical pathway and an electronic order set for pediatric fungemia management. Balancing measures were missed episodes of fungal endocarditis and renal infection.
• Results: During the period January 1, 2016 to November 19, 2017, 18 of 21 episodes of fungemia in our pediatric institution occurred in patients admitted to the pediatric gastroenterology service. Abdominal imaging and echocardiograms were done 100% of the time, with no positive findings and an estimated cost of approximately $58,000. Post-intervention from November 20, 2017 to April 3, 2019, 7 of 13 episodes of fungemia occurred on this service. Frequency of abdominal imaging and echocardiograms decreased to 43% and 57%, respectively. No episodes of fungal endocarditis or renal infection were identified.
• Conclusion: Overutilization of abdominal imaging and echocardiograms in pediatric fungemia evaluation can be safely decreased.

Keywords: guidelines; cost; candidemia; endocarditis.

Practitioners may remain under the impression that routine abdominal ultrasounds (US) and echocardiograms (echo) are indicated in fungemia to evaluate for fungal endocarditis and renal infection, although these conditions are rare and limited to a subset of the population.^1-10 Risk factors include prematurity, immunosuppression, prior bacterial endocarditis, abnormal cardiac valves, and previous urogenital surgeries.¹¹

The 2016 Infectious Diseases Society of America (IDSA) guidelines do not recommend routine US or echo but rather provide scenarios in which Candida endocarditis should be suspected, and these include: persistently positive blood cultures, persistent fevers despite appropriate therapy, and clinical signs that may suggest endocarditis, such as a new heart murmur, heart failure, or embolic phenomena.¹¹ IDSA recommends abdominal imaging in neonates with persistently positive blood cultures to evaluate the urogenital system, in addition to the liver and spleen. They also recommend abdominal imaging in symptomatic ascending Candida pyelonephritis beyond the neonatal period and in chronic disseminated candidiasis; the latter is uncommon and seen almost exclusively in patients recovering from neutropenia with a hematologic malignancy.¹¹

We also reviewed guidelines on fungemia originating outside the United States. The 2010 Canadian clinical guidelines on invasive candidiasis do not explicitly recommend routine imaging, but rather state that various imaging studies, including US and echo among others, may be helpful.¹² The German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy published a joint recommendation against routine US and echo in uncomplicated candidemia in 2011.¹³

The European Society for Clinical Microbiology and Infectious Diseases is the only society that recommends routine echo. Their 2012 guidelines on candidiasis recommend transesophageal echo in adults¹⁴ and echocardiography in children,¹⁵ as well as abdominal imaging in the diagnosis of chronic disseminated candidiasis in adults with hematological malignancies/hematopoietic stem cell transplantation.¹⁶

The 2013 Brazilian guidelines explicitly recommend against routine abdominal imaging and echo because of the low frequency of visceral lesions in adults with candidemia and recommend reserving imaging for those with persistently positive blood cultures or with clinical signs/symptoms suggestive of endocarditis/abdominal infection or clinical deterioration.¹⁷ The 2014 Japanese guidelines recommend ruling out chronic disseminated candidiasis in these patients with symptoms during the neutrophil recovery phase, but do not mention routinely imaging other patients. They do not address the role of echocardiography.¹⁸

Although physicians in the United Sates typically follow IDSA guidelines, abdominal US and echo were ordered routinely for patients with fungemia on the pediatric gastroenterology service at our institution, leading to higher medical costs and waste of medical resources. Our goals were to assess the current standard work for fungemia evaluation on this service, assess the impact of its deviation from current clinical guidelines, and redefine the standard work by (1) presenting current evidence to practitioners taking care of patients on this service, (2) providing a clinical pathway that allowed for variations where appropriate, and (3) providing a plan for pediatric fungemia management. Our SMART (Specific, Measurable, Attainable, Relevant and Timely) goal was to reduce overutilization of abdominal US and echo in pediatric patients with fungemia on the pediatric gastroenterology service by 50%.

Methods

Study, Setting, and Participants

We executed this quality improvement project at a quaternary care pediatric hospital affiliated with a school of medicine. The project scope consisted of inpatient pediatric patients with fungemia on the pediatric gastroenterology service admitted to the wards or pediatric critical care unit at this institution, along with the practitioners caring for these patients. The project was part of an institutional quality improvement initiative program. The quality improvement team included quality improvement experts from the departments of medicine and pediatrics, a pediatric resident and student, and physicians from the divisions of pediatric infectious disease, pediatric critical care, and pediatric gastroenterology. This study qualified for Institutional Review Board (IRB) exemption based on the University’s IRB stipulations.

Current Condition

Root cause analysis was performed by creating a process map of the current standard work and a fishbone diagram (Figure 1). We incorporated feedback from voice of the customer in the root cause analysis. In this analysis, the voice of the customer came from the bedside floor nurses, ultrasound clerk and sonographer, echo technician, cardiology fellow, and microbiology medical technician. We got their feedback on our process map, its accuracy and ways to expand, their thoughts on the problem and why we have this problem, and any solutions they could offer to help improve the problem. Some of the key points obtained were: echos were not routinely done on the floors and were not considered urgent as they often did not change management; the sonographer and those from the cardiology department felt imaging was often overutilized because of misconceptions and lack of available hospital guidelines. Suggested solutions included provider education with reference to Duke’s criteria and establishing a clinical pathway approved by all concerned departments.

Prior to education, we surveyed current practices of practitioners on teams caring for these patients, which included physicians of all levels (attendings, fellows, residents) as well as nurse practitioners and medical students from the department of pediatrics and divisions of pediatric gastroenterology, pediatric infectious disease, and pediatric critical care medicine.

 

 

Countermeasures

Practitioner Education. In October 2017 practitioners were given a 20-minute presentation on the latest international guidelines on fungemia. Fifty-nine practitioners completed pre- and post-test surveys. Eight respondents were excluded due to incomplete surveys. We compared self-reported frequencies of ordering abdominal imaging and echo before the presentation with intention to order post education. Intention to change clinical practice after the presentation was also surveyed.

Clinical Pathway. Education alone may not result in sustainability, and thus we provided a readily accessible clinical pathway and an electronic order set for pediatric fungemia management. Inter-department buy-in was also necessary for success. It was important to get the input from the various teams (infectious disease, cardiology, gastroenterology, and critical care), which was done by incorporating members from those divisions in the project or getting their feedback through voice of the customer analysis.

We redefined standard work based on current evidence and created a clinical pathway during March 2018 that included variations when appropriate (Figure 2). We presented the clinical pathway to practitioners and distributed it via email. We also made it available to pediatric residents and fellows on their mobile institutional work resource application.

Electronic Order Set. We created an electronic order set for pediatric fungemia management and made it available in the electronic health record May 2018.

Measurement

Cases of fungemia were identified through the electronic health record pre-intervention (January 1, 2016 through November 19, 2017) and post-intervention (November 20, 2019 through April 3, 2019). An episode of fungemia was defined as an encounter with 1 or more positive blood culture(s) for Candida species or Cryptococcus species. We manually identified patients belonging to the pediatric gastroenterology service and reviewed these charts to determine the presenting complaint, organism isolated, transplant status, central lines status, risk factors, if abdominal imaging or echocardiography were done for the episode of fungemia, and their corresponding results. We calculated overall and per patient medical charges by using the average charges at our institution of US and echocardiography with a cardiology consult. These average charges were provided by patient financial services and the pediatric cardiology department, respectively. To address non-technical expenditures, we calculated the average time taken for transport to and from radiology and the echo suite for each identified patient. We identified missed fungal endocarditis and fungal balls as balancing measures.

 

 

Results

Survey

Among the 51 practitioners surveyed, 36% were performing routine echo and 22% self-reported performing routine abdominal imaging. After education, no respondents planned to routinely do echo or abdominal imaging. All but 1 respondent planned to change their practice for evaluation of fungemia patients based on the presentation (eFigure 1).

Baseline Data

Over the 23-month period from January 1, 2016 to November 19, 2017, there were 21 episodes of fungemia, 18 of which occurred in patients on the pediatric gastroenterology service (2 of the 18 were transplant recipients). For the 18 episodes on this service, abdominal imaging and echo were done 100% of the time, with 0 positive findings (eFigure 2).

Of those 18 episodes, the average age was 4.6 years, with two-thirds of the population being male. There were 3 patients with multiple episodes that accounted for 8 of the episodes (3, 3, and 2 episodes each). Fever was the most common presenting complaint. The most common organism was Candida parapsilosis (6 of the 18 episodes). All episodes but one involved a central line, and all central lines were removed when present except for one case. Of the risk factors, 3 episodes occurred in neutropenic patients, and for 1 episode the patient had a questionable history of fungal endocarditis (and was on fungal prophylaxis). There were no patients with recent cardiac/urogenital surgery or prior fungal balls. No episodes had clinical symptoms suggestive of fungal endocarditis or fungal balls.

Post-Intervention Data

Over the subsequent 17-month period (November 11, 2017 to April 3, 2019), there were 13 episodes of candidemia. There were no episodes of Cryptococcus fungemia. Seven episodes occurred in patients on the pediatric gastroenterology service (2 of the 7 occurred in transplant recipients). Abdominal imaging was done in 3 of these episodes (43%), and in 2 of these 3 episodes, imaging was done at an outside institution prior to arrival, with no positive results (eFigure 2).

Echocardiography was done 57% of the time (n = 4), with echo being done at an outside institution prior to arrival half of the time (n = 2), with no endocarditis identified. The cases of abdominal imaging and echo done at outside institutions prior to arrival were not impacted by the countermeasures. Excluding those 2 patients who had both abdominal imaging and echocardiography done prior to arrival, the overall rate of imaging (both abdominal imaging and echo) done after countermeasures were instituted was 30% (Figure 3).

Of those 7 episodes, the average age was 6.8 years (57% female). There were no patients with multiple episodes. The most common presenting complaint was fever. The most common organism was Candida albicans (3 of the 7 episodes). All episodes involved a central line, which was removed in all cases except for one. Of the risk factors, 2 episodes were in neutropenic patients, and 1 episode had a history of bacterial endocarditis (not related to fungemia). No episodes occurred in patients with prior fungal renal infection, urogenital malformations, or recent cardiac/urogenital surgery. No episodes had clinical symptoms suggestive of fungal endocarditis or renal infection. No episodes of fungal endocarditis or renal infection were identified.

On average, a patient at our institution undergoing abdominal US and echo with a cardiology consult results in medical waste of approximately $3200 per patient. This cost does not take into account other miscellaneous charges possibly incurred, such as the radiologist interpreting the findings and transportation. Baseline data calculations show that patients waste on average 55 minutes in physical transport, and this does not take into account wait times.

Discussion

Candidemia contributes to 10% of central-line associated blood stream infections (CLABSI).¹⁹ Increased usage of indwelling central catheters for administration of parenteral nutrition will inevitably result in practitioners encountering cases of candidemia when caring for this population. As seen from our results, the majority of episodes of candidemia at our institution occurred on the pediatric gastroenterology service, and thus redefining standard work on this service will be impactful.

Candida parapsilosis and Candida albicans were the most common causative agents before and after intervention, respectively, but overall the most common organism was Candida albicans, which is in keeping with that of CLABSI in the literature.¹⁹ Growth of Candida parapsilosis has been particularly linked to CLABSI.¹⁹ The third most common organism in our study was Candida glabrata, which is the second most common cause of candidemia in CLABSI.¹⁹

The cases of positive abdominal imaging in fungemia in the literature are limited to the neonatal population^1-4 and chronic disseminated candidiasis in patients with hematologic malignancies/neutropenia/immunosuppression.^5,6 In fungal endocarditis, the reported cases were generally in neonates,^1,3,7 critically ill patients,⁸ patients with hematologic malignancies/neutropenia/immunosuppression,^6,9 or those with a cardiac history.^9,10 This population differs from the patient population on the pediatric gastroenterology service. Patients on this service may not need US or echo. Performing abdominal US and echo in fungemia patients in whom such imaging is not indicated may result in medical waste of approximately $3200 per patient. There is also a waste of medical resources and time.

We found almost all practitioners are willing to change clinical practice once provided with current guidelines. Face-to-face oral presentations allowed for questions and interaction, making this form of information dissemination better than e-mails or handouts.

Though the numbers were small over the short study period, we were able to decrease overutilization of abdominal imaging and echo after implementing countermeasures. Frequency decreased from 100% to 43% and 57% for abdominal imaging and echo, respectively. Imaging that was done after the countermeasures were implemented was mainly attributed to imaging patients underwent prior to presenting to our institution. This reinforces the need for education at other institutions as well. Of the balancing measures assessed, there were no missed cases of fungal balls or fungal endocarditis. Additionally, of the total 34 episodes of fungemia assessed (21 before and 13 after), even among those with risk factors, there were no cases of fungal endocarditis or renal infection.

The findings from this quality improvement project underscore current recommendations that, despite common misconceptions, routine abdominal US and echo are not indicated in all cases of fungemia. Case-by-case assessment based on the clinical scenario remains key to management of fungemia to avoid unnecessary medical interventions.

Corresponding author: Donna Cheung, MBBS, 200 Hawkins Drive, BT 1120-G, Iowa City, IA 52242; donna.ann.cheung@gmail.com.

Financial support: None.

From the University of Miami, Department of Pediatrics and Department of Medicine, Miami, FL.

Abstract

• Objective: Pediatric fungemia is associated with a low risk of fungal endocarditis and renal infections. The majority of current guidelines do not recommend routine abdominal imaging/echocardiograms in the evaluation of fungemia, but such imaging has been routinely ordered for patients on the pediatric gastroenterology service at our institution. Our goals were to assess the financial impact of this deviation from current clinical guidelines and redefine the standard work to reduce overutilization of abdominal ultrasounds and echocardiograms. Specifically, our goal was to reduce imaging by 50% by 18 months.
• Methods: Root cause analysis showed a lack of familiarity with current evidence. Using this data, countermeasures were implemented, including practitioner education of guidelines and creation of a readily accessible clinical pathway and an electronic order set for pediatric fungemia management. Balancing measures were missed episodes of fungal endocarditis and renal infection.
• Results: During the period January 1, 2016 to November 19, 2017, 18 of 21 episodes of fungemia in our pediatric institution occurred in patients admitted to the pediatric gastroenterology service. Abdominal imaging and echocardiograms were done 100% of the time, with no positive findings and an estimated cost of approximately $58,000. Post-intervention from November 20, 2017 to April 3, 2019, 7 of 13 episodes of fungemia occurred on this service. Frequency of abdominal imaging and echocardiograms decreased to 43% and 57%, respectively. No episodes of fungal endocarditis or renal infection were identified.
• Conclusion: Overutilization of abdominal imaging and echocardiograms in pediatric fungemia evaluation can be safely decreased.

Keywords: guidelines; cost; candidemia; endocarditis.

Practitioners may remain under the impression that routine abdominal ultrasounds (US) and echocardiograms (echo) are indicated in fungemia to evaluate for fungal endocarditis and renal infection, although these conditions are rare and limited to a subset of the population.^1-10 Risk factors include prematurity, immunosuppression, prior bacterial endocarditis, abnormal cardiac valves, and previous urogenital surgeries.¹¹

The 2016 Infectious Diseases Society of America (IDSA) guidelines do not recommend routine US or echo but rather provide scenarios in which Candida endocarditis should be suspected, and these include: persistently positive blood cultures, persistent fevers despite appropriate therapy, and clinical signs that may suggest endocarditis, such as a new heart murmur, heart failure, or embolic phenomena.¹¹ IDSA recommends abdominal imaging in neonates with persistently positive blood cultures to evaluate the urogenital system, in addition to the liver and spleen. They also recommend abdominal imaging in symptomatic ascending Candida pyelonephritis beyond the neonatal period and in chronic disseminated candidiasis; the latter is uncommon and seen almost exclusively in patients recovering from neutropenia with a hematologic malignancy.¹¹

We also reviewed guidelines on fungemia originating outside the United States. The 2010 Canadian clinical guidelines on invasive candidiasis do not explicitly recommend routine imaging, but rather state that various imaging studies, including US and echo among others, may be helpful.¹² The German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy published a joint recommendation against routine US and echo in uncomplicated candidemia in 2011.¹³

The European Society for Clinical Microbiology and Infectious Diseases is the only society that recommends routine echo. Their 2012 guidelines on candidiasis recommend transesophageal echo in adults¹⁴ and echocardiography in children,¹⁵ as well as abdominal imaging in the diagnosis of chronic disseminated candidiasis in adults with hematological malignancies/hematopoietic stem cell transplantation.¹⁶

The 2013 Brazilian guidelines explicitly recommend against routine abdominal imaging and echo because of the low frequency of visceral lesions in adults with candidemia and recommend reserving imaging for those with persistently positive blood cultures or with clinical signs/symptoms suggestive of endocarditis/abdominal infection or clinical deterioration.¹⁷ The 2014 Japanese guidelines recommend ruling out chronic disseminated candidiasis in these patients with symptoms during the neutrophil recovery phase, but do not mention routinely imaging other patients. They do not address the role of echocardiography.¹⁸

Although physicians in the United Sates typically follow IDSA guidelines, abdominal US and echo were ordered routinely for patients with fungemia on the pediatric gastroenterology service at our institution, leading to higher medical costs and waste of medical resources. Our goals were to assess the current standard work for fungemia evaluation on this service, assess the impact of its deviation from current clinical guidelines, and redefine the standard work by (1) presenting current evidence to practitioners taking care of patients on this service, (2) providing a clinical pathway that allowed for variations where appropriate, and (3) providing a plan for pediatric fungemia management. Our SMART (Specific, Measurable, Attainable, Relevant and Timely) goal was to reduce overutilization of abdominal US and echo in pediatric patients with fungemia on the pediatric gastroenterology service by 50%.

Methods

Study, Setting, and Participants

We executed this quality improvement project at a quaternary care pediatric hospital affiliated with a school of medicine. The project scope consisted of inpatient pediatric patients with fungemia on the pediatric gastroenterology service admitted to the wards or pediatric critical care unit at this institution, along with the practitioners caring for these patients. The project was part of an institutional quality improvement initiative program. The quality improvement team included quality improvement experts from the departments of medicine and pediatrics, a pediatric resident and student, and physicians from the divisions of pediatric infectious disease, pediatric critical care, and pediatric gastroenterology. This study qualified for Institutional Review Board (IRB) exemption based on the University’s IRB stipulations.

Current Condition

Root cause analysis was performed by creating a process map of the current standard work and a fishbone diagram (Figure 1). We incorporated feedback from voice of the customer in the root cause analysis. In this analysis, the voice of the customer came from the bedside floor nurses, ultrasound clerk and sonographer, echo technician, cardiology fellow, and microbiology medical technician. We got their feedback on our process map, its accuracy and ways to expand, their thoughts on the problem and why we have this problem, and any solutions they could offer to help improve the problem. Some of the key points obtained were: echos were not routinely done on the floors and were not considered urgent as they often did not change management; the sonographer and those from the cardiology department felt imaging was often overutilized because of misconceptions and lack of available hospital guidelines. Suggested solutions included provider education with reference to Duke’s criteria and establishing a clinical pathway approved by all concerned departments.

Prior to education, we surveyed current practices of practitioners on teams caring for these patients, which included physicians of all levels (attendings, fellows, residents) as well as nurse practitioners and medical students from the department of pediatrics and divisions of pediatric gastroenterology, pediatric infectious disease, and pediatric critical care medicine.

 

 

Countermeasures

Practitioner Education. In October 2017 practitioners were given a 20-minute presentation on the latest international guidelines on fungemia. Fifty-nine practitioners completed pre- and post-test surveys. Eight respondents were excluded due to incomplete surveys. We compared self-reported frequencies of ordering abdominal imaging and echo before the presentation with intention to order post education. Intention to change clinical practice after the presentation was also surveyed.

Clinical Pathway. Education alone may not result in sustainability, and thus we provided a readily accessible clinical pathway and an electronic order set for pediatric fungemia management. Inter-department buy-in was also necessary for success. It was important to get the input from the various teams (infectious disease, cardiology, gastroenterology, and critical care), which was done by incorporating members from those divisions in the project or getting their feedback through voice of the customer analysis.

We redefined standard work based on current evidence and created a clinical pathway during March 2018 that included variations when appropriate (Figure 2). We presented the clinical pathway to practitioners and distributed it via email. We also made it available to pediatric residents and fellows on their mobile institutional work resource application.

Electronic Order Set. We created an electronic order set for pediatric fungemia management and made it available in the electronic health record May 2018.

Measurement

Cases of fungemia were identified through the electronic health record pre-intervention (January 1, 2016 through November 19, 2017) and post-intervention (November 20, 2019 through April 3, 2019). An episode of fungemia was defined as an encounter with 1 or more positive blood culture(s) for Candida species or Cryptococcus species. We manually identified patients belonging to the pediatric gastroenterology service and reviewed these charts to determine the presenting complaint, organism isolated, transplant status, central lines status, risk factors, if abdominal imaging or echocardiography were done for the episode of fungemia, and their corresponding results. We calculated overall and per patient medical charges by using the average charges at our institution of US and echocardiography with a cardiology consult. These average charges were provided by patient financial services and the pediatric cardiology department, respectively. To address non-technical expenditures, we calculated the average time taken for transport to and from radiology and the echo suite for each identified patient. We identified missed fungal endocarditis and fungal balls as balancing measures.

 

 

Results

Survey

Among the 51 practitioners surveyed, 36% were performing routine echo and 22% self-reported performing routine abdominal imaging. After education, no respondents planned to routinely do echo or abdominal imaging. All but 1 respondent planned to change their practice for evaluation of fungemia patients based on the presentation (eFigure 1).

Baseline Data

Over the 23-month period from January 1, 2016 to November 19, 2017, there were 21 episodes of fungemia, 18 of which occurred in patients on the pediatric gastroenterology service (2 of the 18 were transplant recipients). For the 18 episodes on this service, abdominal imaging and echo were done 100% of the time, with 0 positive findings (eFigure 2).

Of those 18 episodes, the average age was 4.6 years, with two-thirds of the population being male. There were 3 patients with multiple episodes that accounted for 8 of the episodes (3, 3, and 2 episodes each). Fever was the most common presenting complaint. The most common organism was Candida parapsilosis (6 of the 18 episodes). All episodes but one involved a central line, and all central lines were removed when present except for one case. Of the risk factors, 3 episodes occurred in neutropenic patients, and for 1 episode the patient had a questionable history of fungal endocarditis (and was on fungal prophylaxis). There were no patients with recent cardiac/urogenital surgery or prior fungal balls. No episodes had clinical symptoms suggestive of fungal endocarditis or fungal balls.

Post-Intervention Data

Over the subsequent 17-month period (November 11, 2017 to April 3, 2019), there were 13 episodes of candidemia. There were no episodes of Cryptococcus fungemia. Seven episodes occurred in patients on the pediatric gastroenterology service (2 of the 7 occurred in transplant recipients). Abdominal imaging was done in 3 of these episodes (43%), and in 2 of these 3 episodes, imaging was done at an outside institution prior to arrival, with no positive results (eFigure 2).

Echocardiography was done 57% of the time (n = 4), with echo being done at an outside institution prior to arrival half of the time (n = 2), with no endocarditis identified. The cases of abdominal imaging and echo done at outside institutions prior to arrival were not impacted by the countermeasures. Excluding those 2 patients who had both abdominal imaging and echocardiography done prior to arrival, the overall rate of imaging (both abdominal imaging and echo) done after countermeasures were instituted was 30% (Figure 3).

Of those 7 episodes, the average age was 6.8 years (57% female). There were no patients with multiple episodes. The most common presenting complaint was fever. The most common organism was Candida albicans (3 of the 7 episodes). All episodes involved a central line, which was removed in all cases except for one. Of the risk factors, 2 episodes were in neutropenic patients, and 1 episode had a history of bacterial endocarditis (not related to fungemia). No episodes occurred in patients with prior fungal renal infection, urogenital malformations, or recent cardiac/urogenital surgery. No episodes had clinical symptoms suggestive of fungal endocarditis or renal infection. No episodes of fungal endocarditis or renal infection were identified.

On average, a patient at our institution undergoing abdominal US and echo with a cardiology consult results in medical waste of approximately $3200 per patient. This cost does not take into account other miscellaneous charges possibly incurred, such as the radiologist interpreting the findings and transportation. Baseline data calculations show that patients waste on average 55 minutes in physical transport, and this does not take into account wait times.

Discussion

Candidemia contributes to 10% of central-line associated blood stream infections (CLABSI).¹⁹ Increased usage of indwelling central catheters for administration of parenteral nutrition will inevitably result in practitioners encountering cases of candidemia when caring for this population. As seen from our results, the majority of episodes of candidemia at our institution occurred on the pediatric gastroenterology service, and thus redefining standard work on this service will be impactful.

Candida parapsilosis and Candida albicans were the most common causative agents before and after intervention, respectively, but overall the most common organism was Candida albicans, which is in keeping with that of CLABSI in the literature.¹⁹ Growth of Candida parapsilosis has been particularly linked to CLABSI.¹⁹ The third most common organism in our study was Candida glabrata, which is the second most common cause of candidemia in CLABSI.¹⁹

The cases of positive abdominal imaging in fungemia in the literature are limited to the neonatal population^1-4 and chronic disseminated candidiasis in patients with hematologic malignancies/neutropenia/immunosuppression.^5,6 In fungal endocarditis, the reported cases were generally in neonates,^1,3,7 critically ill patients,⁸ patients with hematologic malignancies/neutropenia/immunosuppression,^6,9 or those with a cardiac history.^9,10 This population differs from the patient population on the pediatric gastroenterology service. Patients on this service may not need US or echo. Performing abdominal US and echo in fungemia patients in whom such imaging is not indicated may result in medical waste of approximately $3200 per patient. There is also a waste of medical resources and time.

We found almost all practitioners are willing to change clinical practice once provided with current guidelines. Face-to-face oral presentations allowed for questions and interaction, making this form of information dissemination better than e-mails or handouts.

Though the numbers were small over the short study period, we were able to decrease overutilization of abdominal imaging and echo after implementing countermeasures. Frequency decreased from 100% to 43% and 57% for abdominal imaging and echo, respectively. Imaging that was done after the countermeasures were implemented was mainly attributed to imaging patients underwent prior to presenting to our institution. This reinforces the need for education at other institutions as well. Of the balancing measures assessed, there were no missed cases of fungal balls or fungal endocarditis. Additionally, of the total 34 episodes of fungemia assessed (21 before and 13 after), even among those with risk factors, there were no cases of fungal endocarditis or renal infection.

The findings from this quality improvement project underscore current recommendations that, despite common misconceptions, routine abdominal US and echo are not indicated in all cases of fungemia. Case-by-case assessment based on the clinical scenario remains key to management of fungemia to avoid unnecessary medical interventions.

Corresponding author: Donna Cheung, MBBS, 200 Hawkins Drive, BT 1120-G, Iowa City, IA 52242; donna.ann.cheung@gmail.com.

Financial support: None.

From the University of Miami, Department of Pediatrics and Department of Medicine, Miami, FL.

Abstract

• Objective: Pediatric fungemia is associated with a low risk of fungal endocarditis and renal infections. The majority of current guidelines do not recommend routine abdominal imaging/echocardiograms in the evaluation of fungemia, but such imaging has been routinely ordered for patients on the pediatric gastroenterology service at our institution. Our goals were to assess the financial impact of this deviation from current clinical guidelines and redefine the standard work to reduce overutilization of abdominal ultrasounds and echocardiograms. Specifically, our goal was to reduce imaging by 50% by 18 months.
• Methods: Root cause analysis showed a lack of familiarity with current evidence. Using this data, countermeasures were implemented, including practitioner education of guidelines and creation of a readily accessible clinical pathway and an electronic order set for pediatric fungemia management. Balancing measures were missed episodes of fungal endocarditis and renal infection.
• Results: During the period January 1, 2016 to November 19, 2017, 18 of 21 episodes of fungemia in our pediatric institution occurred in patients admitted to the pediatric gastroenterology service. Abdominal imaging and echocardiograms were done 100% of the time, with no positive findings and an estimated cost of approximately $58,000. Post-intervention from November 20, 2017 to April 3, 2019, 7 of 13 episodes of fungemia occurred on this service. Frequency of abdominal imaging and echocardiograms decreased to 43% and 57%, respectively. No episodes of fungal endocarditis or renal infection were identified.
• Conclusion: Overutilization of abdominal imaging and echocardiograms in pediatric fungemia evaluation can be safely decreased.

Keywords: guidelines; cost; candidemia; endocarditis.

Practitioners may remain under the impression that routine abdominal ultrasounds (US) and echocardiograms (echo) are indicated in fungemia to evaluate for fungal endocarditis and renal infection, although these conditions are rare and limited to a subset of the population.^1-10 Risk factors include prematurity, immunosuppression, prior bacterial endocarditis, abnormal cardiac valves, and previous urogenital surgeries.¹¹

The 2016 Infectious Diseases Society of America (IDSA) guidelines do not recommend routine US or echo but rather provide scenarios in which Candida endocarditis should be suspected, and these include: persistently positive blood cultures, persistent fevers despite appropriate therapy, and clinical signs that may suggest endocarditis, such as a new heart murmur, heart failure, or embolic phenomena.¹¹ IDSA recommends abdominal imaging in neonates with persistently positive blood cultures to evaluate the urogenital system, in addition to the liver and spleen. They also recommend abdominal imaging in symptomatic ascending Candida pyelonephritis beyond the neonatal period and in chronic disseminated candidiasis; the latter is uncommon and seen almost exclusively in patients recovering from neutropenia with a hematologic malignancy.¹¹

We also reviewed guidelines on fungemia originating outside the United States. The 2010 Canadian clinical guidelines on invasive candidiasis do not explicitly recommend routine imaging, but rather state that various imaging studies, including US and echo among others, may be helpful.¹² The German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy published a joint recommendation against routine US and echo in uncomplicated candidemia in 2011.¹³

The European Society for Clinical Microbiology and Infectious Diseases is the only society that recommends routine echo. Their 2012 guidelines on candidiasis recommend transesophageal echo in adults¹⁴ and echocardiography in children,¹⁵ as well as abdominal imaging in the diagnosis of chronic disseminated candidiasis in adults with hematological malignancies/hematopoietic stem cell transplantation.¹⁶

The 2013 Brazilian guidelines explicitly recommend against routine abdominal imaging and echo because of the low frequency of visceral lesions in adults with candidemia and recommend reserving imaging for those with persistently positive blood cultures or with clinical signs/symptoms suggestive of endocarditis/abdominal infection or clinical deterioration.¹⁷ The 2014 Japanese guidelines recommend ruling out chronic disseminated candidiasis in these patients with symptoms during the neutrophil recovery phase, but do not mention routinely imaging other patients. They do not address the role of echocardiography.¹⁸

Although physicians in the United Sates typically follow IDSA guidelines, abdominal US and echo were ordered routinely for patients with fungemia on the pediatric gastroenterology service at our institution, leading to higher medical costs and waste of medical resources. Our goals were to assess the current standard work for fungemia evaluation on this service, assess the impact of its deviation from current clinical guidelines, and redefine the standard work by (1) presenting current evidence to practitioners taking care of patients on this service, (2) providing a clinical pathway that allowed for variations where appropriate, and (3) providing a plan for pediatric fungemia management. Our SMART (Specific, Measurable, Attainable, Relevant and Timely) goal was to reduce overutilization of abdominal US and echo in pediatric patients with fungemia on the pediatric gastroenterology service by 50%.

Methods

Study, Setting, and Participants

We executed this quality improvement project at a quaternary care pediatric hospital affiliated with a school of medicine. The project scope consisted of inpatient pediatric patients with fungemia on the pediatric gastroenterology service admitted to the wards or pediatric critical care unit at this institution, along with the practitioners caring for these patients. The project was part of an institutional quality improvement initiative program. The quality improvement team included quality improvement experts from the departments of medicine and pediatrics, a pediatric resident and student, and physicians from the divisions of pediatric infectious disease, pediatric critical care, and pediatric gastroenterology. This study qualified for Institutional Review Board (IRB) exemption based on the University’s IRB stipulations.

Current Condition

Root cause analysis was performed by creating a process map of the current standard work and a fishbone diagram (Figure 1). We incorporated feedback from voice of the customer in the root cause analysis. In this analysis, the voice of the customer came from the bedside floor nurses, ultrasound clerk and sonographer, echo technician, cardiology fellow, and microbiology medical technician. We got their feedback on our process map, its accuracy and ways to expand, their thoughts on the problem and why we have this problem, and any solutions they could offer to help improve the problem. Some of the key points obtained were: echos were not routinely done on the floors and were not considered urgent as they often did not change management; the sonographer and those from the cardiology department felt imaging was often overutilized because of misconceptions and lack of available hospital guidelines. Suggested solutions included provider education with reference to Duke’s criteria and establishing a clinical pathway approved by all concerned departments.

Prior to education, we surveyed current practices of practitioners on teams caring for these patients, which included physicians of all levels (attendings, fellows, residents) as well as nurse practitioners and medical students from the department of pediatrics and divisions of pediatric gastroenterology, pediatric infectious disease, and pediatric critical care medicine.

 

 

Countermeasures

Practitioner Education. In October 2017 practitioners were given a 20-minute presentation on the latest international guidelines on fungemia. Fifty-nine practitioners completed pre- and post-test surveys. Eight respondents were excluded due to incomplete surveys. We compared self-reported frequencies of ordering abdominal imaging and echo before the presentation with intention to order post education. Intention to change clinical practice after the presentation was also surveyed.

Clinical Pathway. Education alone may not result in sustainability, and thus we provided a readily accessible clinical pathway and an electronic order set for pediatric fungemia management. Inter-department buy-in was also necessary for success. It was important to get the input from the various teams (infectious disease, cardiology, gastroenterology, and critical care), which was done by incorporating members from those divisions in the project or getting their feedback through voice of the customer analysis.

We redefined standard work based on current evidence and created a clinical pathway during March 2018 that included variations when appropriate (Figure 2). We presented the clinical pathway to practitioners and distributed it via email. We also made it available to pediatric residents and fellows on their mobile institutional work resource application.

Electronic Order Set. We created an electronic order set for pediatric fungemia management and made it available in the electronic health record May 2018.

Measurement

Cases of fungemia were identified through the electronic health record pre-intervention (January 1, 2016 through November 19, 2017) and post-intervention (November 20, 2019 through April 3, 2019). An episode of fungemia was defined as an encounter with 1 or more positive blood culture(s) for Candida species or Cryptococcus species. We manually identified patients belonging to the pediatric gastroenterology service and reviewed these charts to determine the presenting complaint, organism isolated, transplant status, central lines status, risk factors, if abdominal imaging or echocardiography were done for the episode of fungemia, and their corresponding results. We calculated overall and per patient medical charges by using the average charges at our institution of US and echocardiography with a cardiology consult. These average charges were provided by patient financial services and the pediatric cardiology department, respectively. To address non-technical expenditures, we calculated the average time taken for transport to and from radiology and the echo suite for each identified patient. We identified missed fungal endocarditis and fungal balls as balancing measures.

 

 

Results

Survey

Among the 51 practitioners surveyed, 36% were performing routine echo and 22% self-reported performing routine abdominal imaging. After education, no respondents planned to routinely do echo or abdominal imaging. All but 1 respondent planned to change their practice for evaluation of fungemia patients based on the presentation (eFigure 1).

Baseline Data

Over the 23-month period from January 1, 2016 to November 19, 2017, there were 21 episodes of fungemia, 18 of which occurred in patients on the pediatric gastroenterology service (2 of the 18 were transplant recipients). For the 18 episodes on this service, abdominal imaging and echo were done 100% of the time, with 0 positive findings (eFigure 2).

Of those 18 episodes, the average age was 4.6 years, with two-thirds of the population being male. There were 3 patients with multiple episodes that accounted for 8 of the episodes (3, 3, and 2 episodes each). Fever was the most common presenting complaint. The most common organism was Candida parapsilosis (6 of the 18 episodes). All episodes but one involved a central line, and all central lines were removed when present except for one case. Of the risk factors, 3 episodes occurred in neutropenic patients, and for 1 episode the patient had a questionable history of fungal endocarditis (and was on fungal prophylaxis). There were no patients with recent cardiac/urogenital surgery or prior fungal balls. No episodes had clinical symptoms suggestive of fungal endocarditis or fungal balls.

Post-Intervention Data

Over the subsequent 17-month period (November 11, 2017 to April 3, 2019), there were 13 episodes of candidemia. There were no episodes of Cryptococcus fungemia. Seven episodes occurred in patients on the pediatric gastroenterology service (2 of the 7 occurred in transplant recipients). Abdominal imaging was done in 3 of these episodes (43%), and in 2 of these 3 episodes, imaging was done at an outside institution prior to arrival, with no positive results (eFigure 2).

Echocardiography was done 57% of the time (n = 4), with echo being done at an outside institution prior to arrival half of the time (n = 2), with no endocarditis identified. The cases of abdominal imaging and echo done at outside institutions prior to arrival were not impacted by the countermeasures. Excluding those 2 patients who had both abdominal imaging and echocardiography done prior to arrival, the overall rate of imaging (both abdominal imaging and echo) done after countermeasures were instituted was 30% (Figure 3).

Of those 7 episodes, the average age was 6.8 years (57% female). There were no patients with multiple episodes. The most common presenting complaint was fever. The most common organism was Candida albicans (3 of the 7 episodes). All episodes involved a central line, which was removed in all cases except for one. Of the risk factors, 2 episodes were in neutropenic patients, and 1 episode had a history of bacterial endocarditis (not related to fungemia). No episodes occurred in patients with prior fungal renal infection, urogenital malformations, or recent cardiac/urogenital surgery. No episodes had clinical symptoms suggestive of fungal endocarditis or renal infection. No episodes of fungal endocarditis or renal infection were identified.

On average, a patient at our institution undergoing abdominal US and echo with a cardiology consult results in medical waste of approximately $3200 per patient. This cost does not take into account other miscellaneous charges possibly incurred, such as the radiologist interpreting the findings and transportation. Baseline data calculations show that patients waste on average 55 minutes in physical transport, and this does not take into account wait times.

Discussion

Candidemia contributes to 10% of central-line associated blood stream infections (CLABSI).¹⁹ Increased usage of indwelling central catheters for administration of parenteral nutrition will inevitably result in practitioners encountering cases of candidemia when caring for this population. As seen from our results, the majority of episodes of candidemia at our institution occurred on the pediatric gastroenterology service, and thus redefining standard work on this service will be impactful.

Candida parapsilosis and Candida albicans were the most common causative agents before and after intervention, respectively, but overall the most common organism was Candida albicans, which is in keeping with that of CLABSI in the literature.¹⁹ Growth of Candida parapsilosis has been particularly linked to CLABSI.¹⁹ The third most common organism in our study was Candida glabrata, which is the second most common cause of candidemia in CLABSI.¹⁹

The cases of positive abdominal imaging in fungemia in the literature are limited to the neonatal population^1-4 and chronic disseminated candidiasis in patients with hematologic malignancies/neutropenia/immunosuppression.^5,6 In fungal endocarditis, the reported cases were generally in neonates,^1,3,7 critically ill patients,⁸ patients with hematologic malignancies/neutropenia/immunosuppression,^6,9 or those with a cardiac history.^9,10 This population differs from the patient population on the pediatric gastroenterology service. Patients on this service may not need US or echo. Performing abdominal US and echo in fungemia patients in whom such imaging is not indicated may result in medical waste of approximately $3200 per patient. There is also a waste of medical resources and time.

We found almost all practitioners are willing to change clinical practice once provided with current guidelines. Face-to-face oral presentations allowed for questions and interaction, making this form of information dissemination better than e-mails or handouts.

Though the numbers were small over the short study period, we were able to decrease overutilization of abdominal imaging and echo after implementing countermeasures. Frequency decreased from 100% to 43% and 57% for abdominal imaging and echo, respectively. Imaging that was done after the countermeasures were implemented was mainly attributed to imaging patients underwent prior to presenting to our institution. This reinforces the need for education at other institutions as well. Of the balancing measures assessed, there were no missed cases of fungal balls or fungal endocarditis. Additionally, of the total 34 episodes of fungemia assessed (21 before and 13 after), even among those with risk factors, there were no cases of fungal endocarditis or renal infection.

The findings from this quality improvement project underscore current recommendations that, despite common misconceptions, routine abdominal US and echo are not indicated in all cases of fungemia. Case-by-case assessment based on the clinical scenario remains key to management of fungemia to avoid unnecessary medical interventions.

Corresponding author: Donna Cheung, MBBS, 200 Hawkins Drive, BT 1120-G, Iowa City, IA 52242; donna.ann.cheung@gmail.com.

Financial support: None.

Study Overview

Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.

Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.

Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.

Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² or serum creatinine level of 1.5 mg/dL for men or 1.4 mg/dL for women. Patients were excluded for nonpersistence, defined as 90 days without an antidiabetic drug; censoring, defined as the 181st day of no VHA contact; or study end date of December 31, 2016.

Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.

Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.

For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).

Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.

Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.

Commentary

There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).¹ Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.² Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m², although patients already taking metformin can continue with caution in that setting.^1,3

There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.⁴

In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m². The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.

 

 

Applications for Clinical Practice

The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.

–Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.

Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.

Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.

Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² or serum creatinine level of 1.5 mg/dL for men or 1.4 mg/dL for women. Patients were excluded for nonpersistence, defined as 90 days without an antidiabetic drug; censoring, defined as the 181st day of no VHA contact; or study end date of December 31, 2016.

Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.

Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.

For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).

Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.

Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.

Commentary

There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).¹ Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.² Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m², although patients already taking metformin can continue with caution in that setting.^1,3

There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.⁴

In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m². The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.

 

 

Applications for Clinical Practice

The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.

–Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.

Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.

Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.

Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² or serum creatinine level of 1.5 mg/dL for men or 1.4 mg/dL for women. Patients were excluded for nonpersistence, defined as 90 days without an antidiabetic drug; censoring, defined as the 181st day of no VHA contact; or study end date of December 31, 2016.

Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.

Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.

For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).

Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.

Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.

Commentary

There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).¹ Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.² Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m², although patients already taking metformin can continue with caution in that setting.^1,3

There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.⁴

In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m². The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.

 

 

Applications for Clinical Practice

The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.

–Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess the relative merits of ticagrelor compared to prasugrel in patients with acute coronary syndromes who will undergo invasive evaluation.

Design. Multicenter, open-label, prospective randomized controlled trial.

Setting and participants. A total of 4018 patients who presented with ACS with or without ST-segment elevation.

Intervention. Patients were randomly assigned to receive either ticagrelor or prasugrel.

Main outcome measures. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The secondary end point was bleeding.

Main results. At 1 year, a primary end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.09-1.70; P = 0.006). In the comparison between ticagrelor and prasugrel, the individual components of the primary end point were as follows: death, 4.5% versus 3.7%; myocardial infarction, 4.8% versus 3.0%; and stroke, 1.1% versus 1.0%, respectively. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% in patients assigned to prasugrel. Major bleeding was observed in 5.4% of the patients in the ticagrelor group and 4.8% in the prasugrel group (HR, 1.12; 95% CI, 0.83-1.51, P = 0.46).

Conclusion. In patients who presented with ACS with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel as compared to those who received ticagrelor, and incidence of major bleeding was not significantly different.

 

 

Commentary

Dual antiplatelet therapy combining an adenosine disphosphate (ADP) receptor antagonist and aspirin is standard treatment for patients presenting with ACS. The limitation of clopidogrel has been its modest antiplatelet effect, with substantial interpatient variability. The newer generation thienopyridine prasugrel and the reversible direct-acting oral antagonist of the ADP receptor ticagrelor provide consistent and greater antiplatelet effect compared to clopidogrel. It has been previously reported that these agents are superior in reducing ischemic events when compared to clopidogrel.^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel.^3,4 However, there has been no large randomized controlled study comparing the effect of ticagrelor and prasugrel. In this context, Shupke et al investigated this clinical question by performing a well-designed multicenter randomized controlled trial in patients presenting with ACS. At 12-month follow-up, the composite of death, myocardial infarction, and stroke occurred more frequently in the ticagrelor group compared to the prasugrel group (9.3% versus 6.9%; HR, 1.36; 95% CI, 1.09-1.70; P < 0.01). The incidence of major bleeding was not significantly different between the 2 groups (5.4% versus 4.8%; P = 0.46).

The strengths of this current study include the randomized design and the large number of patients enrolled, with adequate power to evaluate for superiority. This was a multicenter trial in Europe with 23 participating centers (21 from Germany). Furthermore, the interventional technique used by the operators reflects more contemporary technique compared to the previous studies comparing each agent to clopidogrel,^1,2 with more frequent use of radial access (37%) and drug-eluting stents (90%) and reduced use of GPIIb/IIIa inhibitors (12%).

There are a few important points to consider due to the differences between the 2 agents compared in this study. First, the loading dose of ticagrelor and prasugrel was administered differently in patients presenting with ACS without ST elevation. Ticagrelor was administered as soon as possible prior to the coronary angiogram, but prasugrel was administered after the coronary anatomy was defined prior to the intervention, which is how this agent is administered in current clinical practice. Therefore, this trial was an open-label study that compared not only different medications, but different administration strategies. Second, ticagrelor and prasugrel have different side-effect profiles. The side effects unique to ticagrelor are dyspnea and bradycardia. On the other hand, a contraindication unique to prasugrel is patients with a history of transient ischemic attack or stroke due to increased risk of thrombotic and hemorrhagic stroke.¹ In addition, prasugrel has increased bleeding risk in patients older than 75 years of age and those with low body weight (< 60 kg). In this study, the overall medication discontinuation rate was higher in the ticagrelor group specifically due to dyspnea, and the reduced dose of 5 mg of prasugrel was used in patients older than 75 years or with low body weight.

Since the timing of administration of ticagrelor (preloading prior to coronary angiography is recommended) is similar to that of clopidogrel, and given the theoretical benefit of reversible inhibition of the ADP receptor, ticagrelor has been used more commonly in clinical practice than prasugrel, and it has been implemented in the ACS protocol in many hospitals. In light of the results from this first head-to-head comparison utilizing more contemporary interventional techniques, these protocols may need to be adjusted in favor of prasugrel for patients presenting with ACS. However, given the difference in timing of administration and the difference in side-effect profile, operators must also tailor these agents depending on the patient profile.

Applications for Clinical Practice

In patients presenting with ACS, prasugrel was superior to ticagrelor, with a lower composite of death, myocardial infarction, and stroke at 12 months. Prasugrel should be considered as a first-line treatment for ACS.

– Taishi Hirai, MD, and Arun Kumar, MD, University of Missouri, Columbia, MO

Study Overview

Objective. To assess the relative merits of ticagrelor compared to prasugrel in patients with acute coronary syndromes who will undergo invasive evaluation.

Design. Multicenter, open-label, prospective randomized controlled trial.

Setting and participants. A total of 4018 patients who presented with ACS with or without ST-segment elevation.

Intervention. Patients were randomly assigned to receive either ticagrelor or prasugrel.

Main outcome measures. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The secondary end point was bleeding.

Main results. At 1 year, a primary end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.09-1.70; P = 0.006). In the comparison between ticagrelor and prasugrel, the individual components of the primary end point were as follows: death, 4.5% versus 3.7%; myocardial infarction, 4.8% versus 3.0%; and stroke, 1.1% versus 1.0%, respectively. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% in patients assigned to prasugrel. Major bleeding was observed in 5.4% of the patients in the ticagrelor group and 4.8% in the prasugrel group (HR, 1.12; 95% CI, 0.83-1.51, P = 0.46).

Conclusion. In patients who presented with ACS with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel as compared to those who received ticagrelor, and incidence of major bleeding was not significantly different.

 

 

Commentary

Dual antiplatelet therapy combining an adenosine disphosphate (ADP) receptor antagonist and aspirin is standard treatment for patients presenting with ACS. The limitation of clopidogrel has been its modest antiplatelet effect, with substantial interpatient variability. The newer generation thienopyridine prasugrel and the reversible direct-acting oral antagonist of the ADP receptor ticagrelor provide consistent and greater antiplatelet effect compared to clopidogrel. It has been previously reported that these agents are superior in reducing ischemic events when compared to clopidogrel.^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel.^3,4 However, there has been no large randomized controlled study comparing the effect of ticagrelor and prasugrel. In this context, Shupke et al investigated this clinical question by performing a well-designed multicenter randomized controlled trial in patients presenting with ACS. At 12-month follow-up, the composite of death, myocardial infarction, and stroke occurred more frequently in the ticagrelor group compared to the prasugrel group (9.3% versus 6.9%; HR, 1.36; 95% CI, 1.09-1.70; P < 0.01). The incidence of major bleeding was not significantly different between the 2 groups (5.4% versus 4.8%; P = 0.46).

The strengths of this current study include the randomized design and the large number of patients enrolled, with adequate power to evaluate for superiority. This was a multicenter trial in Europe with 23 participating centers (21 from Germany). Furthermore, the interventional technique used by the operators reflects more contemporary technique compared to the previous studies comparing each agent to clopidogrel,^1,2 with more frequent use of radial access (37%) and drug-eluting stents (90%) and reduced use of GPIIb/IIIa inhibitors (12%).

There are a few important points to consider due to the differences between the 2 agents compared in this study. First, the loading dose of ticagrelor and prasugrel was administered differently in patients presenting with ACS without ST elevation. Ticagrelor was administered as soon as possible prior to the coronary angiogram, but prasugrel was administered after the coronary anatomy was defined prior to the intervention, which is how this agent is administered in current clinical practice. Therefore, this trial was an open-label study that compared not only different medications, but different administration strategies. Second, ticagrelor and prasugrel have different side-effect profiles. The side effects unique to ticagrelor are dyspnea and bradycardia. On the other hand, a contraindication unique to prasugrel is patients with a history of transient ischemic attack or stroke due to increased risk of thrombotic and hemorrhagic stroke.¹ In addition, prasugrel has increased bleeding risk in patients older than 75 years of age and those with low body weight (< 60 kg). In this study, the overall medication discontinuation rate was higher in the ticagrelor group specifically due to dyspnea, and the reduced dose of 5 mg of prasugrel was used in patients older than 75 years or with low body weight.

Since the timing of administration of ticagrelor (preloading prior to coronary angiography is recommended) is similar to that of clopidogrel, and given the theoretical benefit of reversible inhibition of the ADP receptor, ticagrelor has been used more commonly in clinical practice than prasugrel, and it has been implemented in the ACS protocol in many hospitals. In light of the results from this first head-to-head comparison utilizing more contemporary interventional techniques, these protocols may need to be adjusted in favor of prasugrel for patients presenting with ACS. However, given the difference in timing of administration and the difference in side-effect profile, operators must also tailor these agents depending on the patient profile.

Applications for Clinical Practice

In patients presenting with ACS, prasugrel was superior to ticagrelor, with a lower composite of death, myocardial infarction, and stroke at 12 months. Prasugrel should be considered as a first-line treatment for ACS.

– Taishi Hirai, MD, and Arun Kumar, MD, University of Missouri, Columbia, MO

Study Overview

Objective. To assess the relative merits of ticagrelor compared to prasugrel in patients with acute coronary syndromes who will undergo invasive evaluation.

Design. Multicenter, open-label, prospective randomized controlled trial.

Setting and participants. A total of 4018 patients who presented with ACS with or without ST-segment elevation.

Intervention. Patients were randomly assigned to receive either ticagrelor or prasugrel.

Main outcome measures. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The secondary end point was bleeding.

Main results. At 1 year, a primary end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.09-1.70; P = 0.006). In the comparison between ticagrelor and prasugrel, the individual components of the primary end point were as follows: death, 4.5% versus 3.7%; myocardial infarction, 4.8% versus 3.0%; and stroke, 1.1% versus 1.0%, respectively. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% in patients assigned to prasugrel. Major bleeding was observed in 5.4% of the patients in the ticagrelor group and 4.8% in the prasugrel group (HR, 1.12; 95% CI, 0.83-1.51, P = 0.46).

Conclusion. In patients who presented with ACS with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel as compared to those who received ticagrelor, and incidence of major bleeding was not significantly different.

 

 

Commentary

Dual antiplatelet therapy combining an adenosine disphosphate (ADP) receptor antagonist and aspirin is standard treatment for patients presenting with ACS. The limitation of clopidogrel has been its modest antiplatelet effect, with substantial interpatient variability. The newer generation thienopyridine prasugrel and the reversible direct-acting oral antagonist of the ADP receptor ticagrelor provide consistent and greater antiplatelet effect compared to clopidogrel. It has been previously reported that these agents are superior in reducing ischemic events when compared to clopidogrel.^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel.^3,4 However, there has been no large randomized controlled study comparing the effect of ticagrelor and prasugrel. In this context, Shupke et al investigated this clinical question by performing a well-designed multicenter randomized controlled trial in patients presenting with ACS. At 12-month follow-up, the composite of death, myocardial infarction, and stroke occurred more frequently in the ticagrelor group compared to the prasugrel group (9.3% versus 6.9%; HR, 1.36; 95% CI, 1.09-1.70; P < 0.01). The incidence of major bleeding was not significantly different between the 2 groups (5.4% versus 4.8%; P = 0.46).

The strengths of this current study include the randomized design and the large number of patients enrolled, with adequate power to evaluate for superiority. This was a multicenter trial in Europe with 23 participating centers (21 from Germany). Furthermore, the interventional technique used by the operators reflects more contemporary technique compared to the previous studies comparing each agent to clopidogrel,^1,2 with more frequent use of radial access (37%) and drug-eluting stents (90%) and reduced use of GPIIb/IIIa inhibitors (12%).

There are a few important points to consider due to the differences between the 2 agents compared in this study. First, the loading dose of ticagrelor and prasugrel was administered differently in patients presenting with ACS without ST elevation. Ticagrelor was administered as soon as possible prior to the coronary angiogram, but prasugrel was administered after the coronary anatomy was defined prior to the intervention, which is how this agent is administered in current clinical practice. Therefore, this trial was an open-label study that compared not only different medications, but different administration strategies. Second, ticagrelor and prasugrel have different side-effect profiles. The side effects unique to ticagrelor are dyspnea and bradycardia. On the other hand, a contraindication unique to prasugrel is patients with a history of transient ischemic attack or stroke due to increased risk of thrombotic and hemorrhagic stroke.¹ In addition, prasugrel has increased bleeding risk in patients older than 75 years of age and those with low body weight (< 60 kg). In this study, the overall medication discontinuation rate was higher in the ticagrelor group specifically due to dyspnea, and the reduced dose of 5 mg of prasugrel was used in patients older than 75 years or with low body weight.

Since the timing of administration of ticagrelor (preloading prior to coronary angiography is recommended) is similar to that of clopidogrel, and given the theoretical benefit of reversible inhibition of the ADP receptor, ticagrelor has been used more commonly in clinical practice than prasugrel, and it has been implemented in the ACS protocol in many hospitals. In light of the results from this first head-to-head comparison utilizing more contemporary interventional techniques, these protocols may need to be adjusted in favor of prasugrel for patients presenting with ACS. However, given the difference in timing of administration and the difference in side-effect profile, operators must also tailor these agents depending on the patient profile.

Applications for Clinical Practice

In patients presenting with ACS, prasugrel was superior to ticagrelor, with a lower composite of death, myocardial infarction, and stroke at 12 months. Prasugrel should be considered as a first-line treatment for ACS.

– Taishi Hirai, MD, and Arun Kumar, MD, University of Missouri, Columbia, MO

PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.

Thomas321/iStock/Getty Images Plus

“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.

The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).

“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.

What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.

From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).

“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”

The average daily concentration for PM2.5 was 13.9/m³ across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m³). A 10-mcg/m³ increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.

“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.

The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m³ day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.

PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.

“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.

Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.

SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.

PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.

Thomas321/iStock/Getty Images Plus

“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.

The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).

“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.

What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.

From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).

“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”

The average daily concentration for PM2.5 was 13.9/m³ across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m³). A 10-mcg/m³ increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.

“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.

The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m³ day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.

PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.

“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.

Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.

SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.

PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.

Thomas321/iStock/Getty Images Plus

“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.

The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).

“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.

What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.

From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).

“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”

The average daily concentration for PM2.5 was 13.9/m³ across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m³). A 10-mcg/m³ increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.

“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.

The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m³ day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.

PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.

“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.

Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.

SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.

PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.

Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.

“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”

The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.

“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”

“Almost never,” Dr. Weintraub responded.

REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.

The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.

An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”

The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.

Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.

Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.

SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
 

PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.

Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.

“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”

The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.

“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”

“Almost never,” Dr. Weintraub responded.

REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.

The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.

An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”

The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.

Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.

Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.

SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
 

PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.

Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.

“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”

The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.

“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”

“Almost never,” Dr. Weintraub responded.

REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.

The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.

An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”

The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.

Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.

Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.

SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.