M. Alexander Otto

SAN DIEGO – Three days of acetaminophen seemed to lower creatinine levels in severely septic patients, suggesting a renoprotective effect, according to results from a phase II study out of Vanderbilt University in Nashville, Tenn.

Investigators there randomized 18 septic ICU patients to acetaminophen 1 g every 6 hours for 3 days and 22 patients to placebo, both delivered by mouth or feeding tube. The patients had all been in the ICU for less than 24 hours, and had detectable levels of plasma cell-free hemoglobin (CFH).

©Ingram Publishing/thinkstockphotos.com

The findings were presented at an international conference of the American Thoracic Society.

CFH has been associated with death in a number of conditions. The iron separates, radicalizes, and causes oxidative injury, especially to the kidneys. Acetaminophen chemically reduces the iron, and has been shown to counter the harm.

In an earlier observational study, the Vanderbilt team found that detectible CFH is common in ICU sepsis patients, as well as elevated plasma levels of F₂-isoprostanes, an indicator of oxidative injury. They also observed that CFH was associated with death, and that exposure to acetaminophen seemed to reduce F₂-isoprostanes levels and improve survival.

The findings prompted the phase II investigation. The team found that the acetaminophen group had lower levels of F₂-isoprostanes on study day 2 (mean 24.9 pg/mL vs. 41.2 pg/mL; P = .022) and lower levels of serum creatinine on study day 3 (mean 1.0 mg/dL vs. 1.3 mg/dL, P = .039). These differences were significant and the renal benefit persisted throughout hospitalization.

Acetaminophen patients overall started with a lower mean baseline creatinine level (1.63 mg/dL vs. 2.06 mg/dL), so the investigators reran their analysis, excluding patients on renal replacement therapy. "The baseline imbalance went away, and the story remained the same: There was still a significant decrease in serum creatinine in the acetaminophen group," said lead investigator Dr. David Janz, a critical care fellow at Vanderbilt.

Despite a favorable trend, acetaminophen did not improve survival, a secondary outcome; one (5.6%) acetaminophen and four (18.2%) placebo patients died (P = .355).

Still, the results are strong enough to suggest that acetaminophen might one day prove to be "a potent intervention to improve sepsis outcomes. Even small creatinine changes are associated with increased length of stay and mortality," Dr. Janz said.

"Our trial contains some negative results" – most notably no significant effect on day 3 F₂-isoprostanes levels – but "the consistent reduction in creatinine across a number of different analyses and the biologic plausibility underlying this signal prompt further investigation. We need larger studies that focus on length of stay and mortality," he said.

Vanderbilt University

Acetaminophen patients were slightly younger (50 vs. 58 years), but besides that and the baseline creatinine difference, the groups were well matched. Both had mean Apache II scores in the low 20s. Nine acetaminophen patients (50%) and seven placebo patients (32%) were intubated.

Both groups received a median of 12 study doses. There was no statistical between-group difference in the number of patients whose AST/ALT topped 400 U/L, a stop-point hit by two acetaminophen patients and one placebo patient (P = .599). No one in the acetaminophen group developed a rash.

Patients who had liver disease or who had gotten acetaminophen within 48 hours were among those excluded from the study.

The work was funded by the National Institutes of Health and the American Heart Association. Dr. Janz had no disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Three days of acetaminophen seemed to lower creatinine levels in severely septic patients, suggesting a renoprotective effect, according to results from a phase II study out of Vanderbilt University in Nashville, Tenn.

Investigators there randomized 18 septic ICU patients to acetaminophen 1 g every 6 hours for 3 days and 22 patients to placebo, both delivered by mouth or feeding tube. The patients had all been in the ICU for less than 24 hours, and had detectable levels of plasma cell-free hemoglobin (CFH).

©Ingram Publishing/thinkstockphotos.com

The findings were presented at an international conference of the American Thoracic Society.

CFH has been associated with death in a number of conditions. The iron separates, radicalizes, and causes oxidative injury, especially to the kidneys. Acetaminophen chemically reduces the iron, and has been shown to counter the harm.

In an earlier observational study, the Vanderbilt team found that detectible CFH is common in ICU sepsis patients, as well as elevated plasma levels of F₂-isoprostanes, an indicator of oxidative injury. They also observed that CFH was associated with death, and that exposure to acetaminophen seemed to reduce F₂-isoprostanes levels and improve survival.

The findings prompted the phase II investigation. The team found that the acetaminophen group had lower levels of F₂-isoprostanes on study day 2 (mean 24.9 pg/mL vs. 41.2 pg/mL; P = .022) and lower levels of serum creatinine on study day 3 (mean 1.0 mg/dL vs. 1.3 mg/dL, P = .039). These differences were significant and the renal benefit persisted throughout hospitalization.

Acetaminophen patients overall started with a lower mean baseline creatinine level (1.63 mg/dL vs. 2.06 mg/dL), so the investigators reran their analysis, excluding patients on renal replacement therapy. "The baseline imbalance went away, and the story remained the same: There was still a significant decrease in serum creatinine in the acetaminophen group," said lead investigator Dr. David Janz, a critical care fellow at Vanderbilt.

Despite a favorable trend, acetaminophen did not improve survival, a secondary outcome; one (5.6%) acetaminophen and four (18.2%) placebo patients died (P = .355).

Still, the results are strong enough to suggest that acetaminophen might one day prove to be "a potent intervention to improve sepsis outcomes. Even small creatinine changes are associated with increased length of stay and mortality," Dr. Janz said.

"Our trial contains some negative results" – most notably no significant effect on day 3 F₂-isoprostanes levels – but "the consistent reduction in creatinine across a number of different analyses and the biologic plausibility underlying this signal prompt further investigation. We need larger studies that focus on length of stay and mortality," he said.

Vanderbilt University

Acetaminophen patients were slightly younger (50 vs. 58 years), but besides that and the baseline creatinine difference, the groups were well matched. Both had mean Apache II scores in the low 20s. Nine acetaminophen patients (50%) and seven placebo patients (32%) were intubated.

Both groups received a median of 12 study doses. There was no statistical between-group difference in the number of patients whose AST/ALT topped 400 U/L, a stop-point hit by two acetaminophen patients and one placebo patient (P = .599). No one in the acetaminophen group developed a rash.

Patients who had liver disease or who had gotten acetaminophen within 48 hours were among those excluded from the study.

The work was funded by the National Institutes of Health and the American Heart Association. Dr. Janz had no disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Three days of acetaminophen seemed to lower creatinine levels in severely septic patients, suggesting a renoprotective effect, according to results from a phase II study out of Vanderbilt University in Nashville, Tenn.

Investigators there randomized 18 septic ICU patients to acetaminophen 1 g every 6 hours for 3 days and 22 patients to placebo, both delivered by mouth or feeding tube. The patients had all been in the ICU for less than 24 hours, and had detectable levels of plasma cell-free hemoglobin (CFH).

©Ingram Publishing/thinkstockphotos.com

The findings were presented at an international conference of the American Thoracic Society.

CFH has been associated with death in a number of conditions. The iron separates, radicalizes, and causes oxidative injury, especially to the kidneys. Acetaminophen chemically reduces the iron, and has been shown to counter the harm.

In an earlier observational study, the Vanderbilt team found that detectible CFH is common in ICU sepsis patients, as well as elevated plasma levels of F₂-isoprostanes, an indicator of oxidative injury. They also observed that CFH was associated with death, and that exposure to acetaminophen seemed to reduce F₂-isoprostanes levels and improve survival.

The findings prompted the phase II investigation. The team found that the acetaminophen group had lower levels of F₂-isoprostanes on study day 2 (mean 24.9 pg/mL vs. 41.2 pg/mL; P = .022) and lower levels of serum creatinine on study day 3 (mean 1.0 mg/dL vs. 1.3 mg/dL, P = .039). These differences were significant and the renal benefit persisted throughout hospitalization.

Acetaminophen patients overall started with a lower mean baseline creatinine level (1.63 mg/dL vs. 2.06 mg/dL), so the investigators reran their analysis, excluding patients on renal replacement therapy. "The baseline imbalance went away, and the story remained the same: There was still a significant decrease in serum creatinine in the acetaminophen group," said lead investigator Dr. David Janz, a critical care fellow at Vanderbilt.

Despite a favorable trend, acetaminophen did not improve survival, a secondary outcome; one (5.6%) acetaminophen and four (18.2%) placebo patients died (P = .355).

Still, the results are strong enough to suggest that acetaminophen might one day prove to be "a potent intervention to improve sepsis outcomes. Even small creatinine changes are associated with increased length of stay and mortality," Dr. Janz said.

"Our trial contains some negative results" – most notably no significant effect on day 3 F₂-isoprostanes levels – but "the consistent reduction in creatinine across a number of different analyses and the biologic plausibility underlying this signal prompt further investigation. We need larger studies that focus on length of stay and mortality," he said.

Vanderbilt University

Acetaminophen patients were slightly younger (50 vs. 58 years), but besides that and the baseline creatinine difference, the groups were well matched. Both had mean Apache II scores in the low 20s. Nine acetaminophen patients (50%) and seven placebo patients (32%) were intubated.

Both groups received a median of 12 study doses. There was no statistical between-group difference in the number of patients whose AST/ALT topped 400 U/L, a stop-point hit by two acetaminophen patients and one placebo patient (P = .599). No one in the acetaminophen group developed a rash.

Patients who had liver disease or who had gotten acetaminophen within 48 hours were among those excluded from the study.

The work was funded by the National Institutes of Health and the American Heart Association. Dr. Janz had no disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Although hospitals in recent years have done a good job catching severe sepsis, less severe cases are falling through the cracks and ultimately proving fatal, according to a retrospective database study.

That’s probably the main reason investigators at Kaiser Permanente Northern California (KPNC) found that up to half of hospital deaths are sepsis related. Of 14,206 adult inpatient deaths at KPNC hospitals between 2010 and 2012, 36.9% had sepsis-related codes. When the team included patients without sepsis codes but with evidence of both infection and acute organ failure – implying sepsis – the number rose to 55.9%. 

Most patients had indications of sepsis at admission, and patients with initially less severe sepsis made up the majority of sepsis deaths. About 56% of sepsis-related deaths were in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission. Patients who met the criteria for early goal-directed therapy at admission, but for whatever reason did not get it, accounted for 21% of the deaths (JAMA 18 May 2014 [doi:10.1001/jama.2014.5804]).

The story was similar when the team looked at 143,312 deaths in the 2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, which captures about 20% of U.S. community hospitals: 34.7% had sepsis codes, and 52% had codes or evidence of both infection and acute organ failure.

Sepsis could have been the final common pathway in already-ill patients, but the numbers hint that at least in some cases, sepsis that could have been extinguished early got out of hand before it was recognized.

The Surviving Sepsis Campaign and other efforts "have had a huge impact on how we treat the most severely ill sepsis patients. We’ve seen about a halving of mortality in the past 15 years. Now we need to broaden our perspective to focus intervention on the less severely ill, who tend to be less severe up front and underidentified," said lead investigator Dr. Liu, with the KPNC division of research, Oakland, Calif.

Based on the results, KPNC has started applying its sepsis bundle to patients with intermediate-lactate levels, "but there is very limited data about the benefit of bundle care in less severe sepsis patients, so we are still tracking our outcomes," he said. There’s also a culture shift involved, which includes heightening clinician awareness, updating communication protocols, and other measures, Dr. Liu said, in presenting the results at an international conference of the American Thoracic Society.

There’s a role for more research dollars as well, and education efforts to make the public aware of sepsis and the need for early intervention, similar to what’s been done for stroke, he said.

The work was funded by the Kaiser Foundation, the Department of Veterans Affairs, and others. One author disclosed personal fees from Pfizer, MedImmune, Eli Lilly, Ferring Pharmaceuticals, and Roche Diagnostics. Dr. Liu and the other authors said they had no financial disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Although hospitals in recent years have done a good job catching severe sepsis, less severe cases are falling through the cracks and ultimately proving fatal, according to a retrospective database study.

That’s probably the main reason investigators at Kaiser Permanente Northern California (KPNC) found that up to half of hospital deaths are sepsis related. Of 14,206 adult inpatient deaths at KPNC hospitals between 2010 and 2012, 36.9% had sepsis-related codes. When the team included patients without sepsis codes but with evidence of both infection and acute organ failure – implying sepsis – the number rose to 55.9%. 

Most patients had indications of sepsis at admission, and patients with initially less severe sepsis made up the majority of sepsis deaths. About 56% of sepsis-related deaths were in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission. Patients who met the criteria for early goal-directed therapy at admission, but for whatever reason did not get it, accounted for 21% of the deaths (JAMA 18 May 2014 [doi:10.1001/jama.2014.5804]).

The story was similar when the team looked at 143,312 deaths in the 2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, which captures about 20% of U.S. community hospitals: 34.7% had sepsis codes, and 52% had codes or evidence of both infection and acute organ failure.

Sepsis could have been the final common pathway in already-ill patients, but the numbers hint that at least in some cases, sepsis that could have been extinguished early got out of hand before it was recognized.

The Surviving Sepsis Campaign and other efforts "have had a huge impact on how we treat the most severely ill sepsis patients. We’ve seen about a halving of mortality in the past 15 years. Now we need to broaden our perspective to focus intervention on the less severely ill, who tend to be less severe up front and underidentified," said lead investigator Dr. Liu, with the KPNC division of research, Oakland, Calif.

Based on the results, KPNC has started applying its sepsis bundle to patients with intermediate-lactate levels, "but there is very limited data about the benefit of bundle care in less severe sepsis patients, so we are still tracking our outcomes," he said. There’s also a culture shift involved, which includes heightening clinician awareness, updating communication protocols, and other measures, Dr. Liu said, in presenting the results at an international conference of the American Thoracic Society.

There’s a role for more research dollars as well, and education efforts to make the public aware of sepsis and the need for early intervention, similar to what’s been done for stroke, he said.

The work was funded by the Kaiser Foundation, the Department of Veterans Affairs, and others. One author disclosed personal fees from Pfizer, MedImmune, Eli Lilly, Ferring Pharmaceuticals, and Roche Diagnostics. Dr. Liu and the other authors said they had no financial disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Although hospitals in recent years have done a good job catching severe sepsis, less severe cases are falling through the cracks and ultimately proving fatal, according to a retrospective database study.

That’s probably the main reason investigators at Kaiser Permanente Northern California (KPNC) found that up to half of hospital deaths are sepsis related. Of 14,206 adult inpatient deaths at KPNC hospitals between 2010 and 2012, 36.9% had sepsis-related codes. When the team included patients without sepsis codes but with evidence of both infection and acute organ failure – implying sepsis – the number rose to 55.9%. 

Most patients had indications of sepsis at admission, and patients with initially less severe sepsis made up the majority of sepsis deaths. About 56% of sepsis-related deaths were in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission. Patients who met the criteria for early goal-directed therapy at admission, but for whatever reason did not get it, accounted for 21% of the deaths (JAMA 18 May 2014 [doi:10.1001/jama.2014.5804]).

The story was similar when the team looked at 143,312 deaths in the 2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, which captures about 20% of U.S. community hospitals: 34.7% had sepsis codes, and 52% had codes or evidence of both infection and acute organ failure.

Sepsis could have been the final common pathway in already-ill patients, but the numbers hint that at least in some cases, sepsis that could have been extinguished early got out of hand before it was recognized.

The Surviving Sepsis Campaign and other efforts "have had a huge impact on how we treat the most severely ill sepsis patients. We’ve seen about a halving of mortality in the past 15 years. Now we need to broaden our perspective to focus intervention on the less severely ill, who tend to be less severe up front and underidentified," said lead investigator Dr. Liu, with the KPNC division of research, Oakland, Calif.

Based on the results, KPNC has started applying its sepsis bundle to patients with intermediate-lactate levels, "but there is very limited data about the benefit of bundle care in less severe sepsis patients, so we are still tracking our outcomes," he said. There’s also a culture shift involved, which includes heightening clinician awareness, updating communication protocols, and other measures, Dr. Liu said, in presenting the results at an international conference of the American Thoracic Society.

There’s a role for more research dollars as well, and education efforts to make the public aware of sepsis and the need for early intervention, similar to what’s been done for stroke, he said.

The work was funded by the Kaiser Foundation, the Department of Veterans Affairs, and others. One author disclosed personal fees from Pfizer, MedImmune, Eli Lilly, Ferring Pharmaceuticals, and Roche Diagnostics. Dr. Liu and the other authors said they had no financial disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – About half of sepsis-related deaths are in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission, suggesting that perhaps in some cases, sepsis that could have been extinguished early got out of hand before it was recognized, according to a review of about 7 million adult hospital admissions by Kaiser Permanente researchers.

In other words, even though death rates have come down for patients with severe sepsis, there’s still a ways to go to recognize and treat less severe cases in time. Lead investigator Dr. Vincent Liu of the Kaiser Permanente division of research, Oakland, Calif., explained the problem – and what Kaiser’s doing about it – at an international conference of the American Thoracic Society.

aotto@frontlinemedcom.com

SAN DIEGO – About half of sepsis-related deaths are in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission, suggesting that perhaps in some cases, sepsis that could have been extinguished early got out of hand before it was recognized, according to a review of about 7 million adult hospital admissions by Kaiser Permanente researchers.

In other words, even though death rates have come down for patients with severe sepsis, there’s still a ways to go to recognize and treat less severe cases in time. Lead investigator Dr. Vincent Liu of the Kaiser Permanente division of research, Oakland, Calif., explained the problem – and what Kaiser’s doing about it – at an international conference of the American Thoracic Society.

aotto@frontlinemedcom.com

SAN DIEGO – About half of sepsis-related deaths are in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission, suggesting that perhaps in some cases, sepsis that could have been extinguished early got out of hand before it was recognized, according to a review of about 7 million adult hospital admissions by Kaiser Permanente researchers.

In other words, even though death rates have come down for patients with severe sepsis, there’s still a ways to go to recognize and treat less severe cases in time. Lead investigator Dr. Vincent Liu of the Kaiser Permanente division of research, Oakland, Calif., explained the problem – and what Kaiser’s doing about it – at an international conference of the American Thoracic Society.

aotto@frontlinemedcom.com

SAN DIEGO – Pirfenidone, an oral antifibrotic therapy not yet for sale in the United States, helped preserve lung function, exercise tolerance, and progression-free survival in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented by Dr. Talmadge King Jr. at an international conference of the American Thoracic Society.

The study randomized 278 patients to 2,403 mg of pirfenidone daily and 277 patients to placebo. There were no significant baseline differences between groups; the mean baseline forced vital capacity (FVC) was about 68% of predicted in both arms.

At 52 weeks, 16.5% of pirfenidone patients vs. 31.8% of placebo patients had a decline of 10% or more in their predicted FVC or had died. Conversely, 22.7% of pirfenidone patients vs. 9.7% of placebo patients had no FVC decline. The mean FVC decline from baseline was 235 mL in the pirfenidone group and 428 mL in the placebo group. Also at 52 weeks, fewer pirfenidone patients had a drop of 50 m or more in their 6-minute walk test (16.5% vs. 19.5%). All of the differences were statistically significant, the investigators reported (N. Eng. J. Med. 2014 May 18 [doi: 10.1056/NEJMoa1402582]).

There also were fewer deaths in the pirfenidone group, but the difference was not significant (4.0% vs. 7.2%; P = .10), including three (1.1%) deaths from idiopathic pulmonary fibrosis in the pirfenidone group and seven (2.5%) in the placebo group (P = .23).

Overall, the advantage of pirfenidone "was evident by week 13 and increased throughout the duration of the trial. ... We found that pirfenidone as compared with placebo reduced disease progression in patients with idiopathic pulmonary fibrosis. Treatment was generally safe, had an acceptable side-effect profile, and was associated with fewer deaths," said the investigators, led by Dr. King, chair of the department of medicine at the University of California, San Francisco.

"We enrolled patients with mild to moderate physiological impairment; the degree to which our findings can be generalized to a population of patients with advanced disease is therefore uncertain," they noted.

The study was funded by the California biotech company InterMune to support its Food and Drug Administration application. The company currently markets the agent in Europe and Canada.

It’s the fourth phase III trial for pirfenidone; two of the earlier trials showed an FVC benefit, but a third did not, leading the FDA to request another investigation. To "confirm the effect of pirfenidone," the investigators adjusted their study design to include "centralized procedures for diagnosis, spirometry, and adjudication of deaths" and to enroll patients at higher risk for disease progression. They also limited the trial to 1 year.

Pirfenidone did significantly reduce the risk of death at 1 year when the new results were pooled with results from earlier studies (hazard ratio, 0.52; 95% confidence interval, 0.31-0.87; P = .01).

About 80% of the subjects in both treatment arms were men. The large majority of subjects were white, and about 70% were over age 65.

About 14% of pirfenidone patients and 10.8% of placebo patients quit the study because of side effects, most commonly worsening of idiopathic pulmonary fibrosis in 1.1% of pirfenidone patients and 5.4% of placebo patients. Grade 3 (severe or medically significant but not immediately life-threatening) gastrointestinal adverse events were reported in 5.4% of pirfenidone patients and 1.4% of placebo patients. Grade 3 skin-related adverse events were reported in 1.8% of pirfenidone patients and 0.4% of placebo patients. Liver enzyme elevations three times the normal limit occurred in 2.9% of pirfenidone patients and 0.7% of placebo patients.

Also, six pirfenidone patients discontinued to undergo lung transplant, vs. one placebo patient.

The study was funded by InterMune, the maker of pirfenidone. Dr. King reported personal fees from InterMune and other companies. Three of his 16 coauthors are InterMune employees, and almost all of the rest reported personal payments or grants from the company, as well as other pharmaceutical companies.

aotto@frontlinemedcom.com

SAN DIEGO – Pirfenidone, an oral antifibrotic therapy not yet for sale in the United States, helped preserve lung function, exercise tolerance, and progression-free survival in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented by Dr. Talmadge King Jr. at an international conference of the American Thoracic Society.

The study randomized 278 patients to 2,403 mg of pirfenidone daily and 277 patients to placebo. There were no significant baseline differences between groups; the mean baseline forced vital capacity (FVC) was about 68% of predicted in both arms.

At 52 weeks, 16.5% of pirfenidone patients vs. 31.8% of placebo patients had a decline of 10% or more in their predicted FVC or had died. Conversely, 22.7% of pirfenidone patients vs. 9.7% of placebo patients had no FVC decline. The mean FVC decline from baseline was 235 mL in the pirfenidone group and 428 mL in the placebo group. Also at 52 weeks, fewer pirfenidone patients had a drop of 50 m or more in their 6-minute walk test (16.5% vs. 19.5%). All of the differences were statistically significant, the investigators reported (N. Eng. J. Med. 2014 May 18 [doi: 10.1056/NEJMoa1402582]).

There also were fewer deaths in the pirfenidone group, but the difference was not significant (4.0% vs. 7.2%; P = .10), including three (1.1%) deaths from idiopathic pulmonary fibrosis in the pirfenidone group and seven (2.5%) in the placebo group (P = .23).

Overall, the advantage of pirfenidone "was evident by week 13 and increased throughout the duration of the trial. ... We found that pirfenidone as compared with placebo reduced disease progression in patients with idiopathic pulmonary fibrosis. Treatment was generally safe, had an acceptable side-effect profile, and was associated with fewer deaths," said the investigators, led by Dr. King, chair of the department of medicine at the University of California, San Francisco.

"We enrolled patients with mild to moderate physiological impairment; the degree to which our findings can be generalized to a population of patients with advanced disease is therefore uncertain," they noted.

The study was funded by the California biotech company InterMune to support its Food and Drug Administration application. The company currently markets the agent in Europe and Canada.

It’s the fourth phase III trial for pirfenidone; two of the earlier trials showed an FVC benefit, but a third did not, leading the FDA to request another investigation. To "confirm the effect of pirfenidone," the investigators adjusted their study design to include "centralized procedures for diagnosis, spirometry, and adjudication of deaths" and to enroll patients at higher risk for disease progression. They also limited the trial to 1 year.

Pirfenidone did significantly reduce the risk of death at 1 year when the new results were pooled with results from earlier studies (hazard ratio, 0.52; 95% confidence interval, 0.31-0.87; P = .01).

About 80% of the subjects in both treatment arms were men. The large majority of subjects were white, and about 70% were over age 65.

About 14% of pirfenidone patients and 10.8% of placebo patients quit the study because of side effects, most commonly worsening of idiopathic pulmonary fibrosis in 1.1% of pirfenidone patients and 5.4% of placebo patients. Grade 3 (severe or medically significant but not immediately life-threatening) gastrointestinal adverse events were reported in 5.4% of pirfenidone patients and 1.4% of placebo patients. Grade 3 skin-related adverse events were reported in 1.8% of pirfenidone patients and 0.4% of placebo patients. Liver enzyme elevations three times the normal limit occurred in 2.9% of pirfenidone patients and 0.7% of placebo patients.

Also, six pirfenidone patients discontinued to undergo lung transplant, vs. one placebo patient.

The study was funded by InterMune, the maker of pirfenidone. Dr. King reported personal fees from InterMune and other companies. Three of his 16 coauthors are InterMune employees, and almost all of the rest reported personal payments or grants from the company, as well as other pharmaceutical companies.

aotto@frontlinemedcom.com

SAN DIEGO – Pirfenidone, an oral antifibrotic therapy not yet for sale in the United States, helped preserve lung function, exercise tolerance, and progression-free survival in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented by Dr. Talmadge King Jr. at an international conference of the American Thoracic Society.

The study randomized 278 patients to 2,403 mg of pirfenidone daily and 277 patients to placebo. There were no significant baseline differences between groups; the mean baseline forced vital capacity (FVC) was about 68% of predicted in both arms.

At 52 weeks, 16.5% of pirfenidone patients vs. 31.8% of placebo patients had a decline of 10% or more in their predicted FVC or had died. Conversely, 22.7% of pirfenidone patients vs. 9.7% of placebo patients had no FVC decline. The mean FVC decline from baseline was 235 mL in the pirfenidone group and 428 mL in the placebo group. Also at 52 weeks, fewer pirfenidone patients had a drop of 50 m or more in their 6-minute walk test (16.5% vs. 19.5%). All of the differences were statistically significant, the investigators reported (N. Eng. J. Med. 2014 May 18 [doi: 10.1056/NEJMoa1402582]).

There also were fewer deaths in the pirfenidone group, but the difference was not significant (4.0% vs. 7.2%; P = .10), including three (1.1%) deaths from idiopathic pulmonary fibrosis in the pirfenidone group and seven (2.5%) in the placebo group (P = .23).

Overall, the advantage of pirfenidone "was evident by week 13 and increased throughout the duration of the trial. ... We found that pirfenidone as compared with placebo reduced disease progression in patients with idiopathic pulmonary fibrosis. Treatment was generally safe, had an acceptable side-effect profile, and was associated with fewer deaths," said the investigators, led by Dr. King, chair of the department of medicine at the University of California, San Francisco.

"We enrolled patients with mild to moderate physiological impairment; the degree to which our findings can be generalized to a population of patients with advanced disease is therefore uncertain," they noted.

The study was funded by the California biotech company InterMune to support its Food and Drug Administration application. The company currently markets the agent in Europe and Canada.

It’s the fourth phase III trial for pirfenidone; two of the earlier trials showed an FVC benefit, but a third did not, leading the FDA to request another investigation. To "confirm the effect of pirfenidone," the investigators adjusted their study design to include "centralized procedures for diagnosis, spirometry, and adjudication of deaths" and to enroll patients at higher risk for disease progression. They also limited the trial to 1 year.

Pirfenidone did significantly reduce the risk of death at 1 year when the new results were pooled with results from earlier studies (hazard ratio, 0.52; 95% confidence interval, 0.31-0.87; P = .01).

About 80% of the subjects in both treatment arms were men. The large majority of subjects were white, and about 70% were over age 65.

About 14% of pirfenidone patients and 10.8% of placebo patients quit the study because of side effects, most commonly worsening of idiopathic pulmonary fibrosis in 1.1% of pirfenidone patients and 5.4% of placebo patients. Grade 3 (severe or medically significant but not immediately life-threatening) gastrointestinal adverse events were reported in 5.4% of pirfenidone patients and 1.4% of placebo patients. Grade 3 skin-related adverse events were reported in 1.8% of pirfenidone patients and 0.4% of placebo patients. Liver enzyme elevations three times the normal limit occurred in 2.9% of pirfenidone patients and 0.7% of placebo patients.

Also, six pirfenidone patients discontinued to undergo lung transplant, vs. one placebo patient.

The study was funded by InterMune, the maker of pirfenidone. Dr. King reported personal fees from InterMune and other companies. Three of his 16 coauthors are InterMune employees, and almost all of the rest reported personal payments or grants from the company, as well as other pharmaceutical companies.

aotto@frontlinemedcom.com

SAN DIEGO – Although hospitals in recent years have done a good job catching severe sepsis, less severe cases are falling through the cracks and ultimately proving fatal, according to a retrospective database study.

That’s probably the main reason investigators at Kaiser Permanente Northern California (KPNC) found that up to half of hospital deaths are sepsis related. Of 14,206 adult inpatient deaths at KPNC hospitals between 2010 and 2012, 36.9% had sepsis-related codes. When the team included patients without sepsis codes but with evidence of both infection and acute organ failure – implying sepsis – the number rose to 55.9%.

Most patients had indications of sepsis at admission, and patients with initially less severe sepsis made up the majority of sepsis deaths. About 56% of sepsis-related deaths were in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission. Patients who met the criteria for early goal-directed therapy at admission, but for whatever reason did not get it, accounted for 21% of the deaths (JAMA 18 May 2014 [doi:10.1001/jama.2014.5804]).

The story was similar when the team looked at 143,312 deaths in the 2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, which captures about 20% of U.S. community hospitals: 34.7% had sepsis codes, and 52% had codes or evidence of both infection and acute organ failure.

Sepsis could have been the final common pathway in already-ill patients, but the numbers hint that at least in some cases, sepsis that could have been extinguished early got out of hand before it was recognized.

The Surviving Sepsis Campaign and other efforts "have had a huge impact on how we treat the most severely ill sepsis patients. We’ve seen about a halving of mortality in the past 15 years. Now we need to broaden our perspective to focus intervention on the less severely ill, who tend to be less severe up front and underidentified," said lead investigator Dr. Liu, with the KPNC division of research, Oakland, Calif.

Based on the results, KPNC has started applying its sepsis bundle to patients with intermediate-lactate levels, "but there is very limited data about the benefit of bundle care in less severe sepsis patients, so we are still tracking our outcomes," he said. There’s also a culture shift involved, which includes heightening clinician awareness, updating communication protocols, and other measures, Dr. Liu said, in presenting the results at an international conference of the American Thoracic Society.

There’s a role for more research dollars as well, and education efforts to make the public aware of sepsis and the need for early intervention, similar to what’s been done for stroke, he said.

The work was funded by the Kaiser Foundation, the Department of Veterans Affairs, and others. One author disclosed personal fees from Pfizer, MedImmune, Eli Lilly, Ferring Pharmaceuticals, and Roche Diagnostics. Dr. Liu and the other authors said they had no financial disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Although hospitals in recent years have done a good job catching severe sepsis, less severe cases are falling through the cracks and ultimately proving fatal, according to a retrospective database study.

That’s probably the main reason investigators at Kaiser Permanente Northern California (KPNC) found that up to half of hospital deaths are sepsis related. Of 14,206 adult inpatient deaths at KPNC hospitals between 2010 and 2012, 36.9% had sepsis-related codes. When the team included patients without sepsis codes but with evidence of both infection and acute organ failure – implying sepsis – the number rose to 55.9%.

Most patients had indications of sepsis at admission, and patients with initially less severe sepsis made up the majority of sepsis deaths. About 56% of sepsis-related deaths were in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission. Patients who met the criteria for early goal-directed therapy at admission, but for whatever reason did not get it, accounted for 21% of the deaths (JAMA 18 May 2014 [doi:10.1001/jama.2014.5804]).

The story was similar when the team looked at 143,312 deaths in the 2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, which captures about 20% of U.S. community hospitals: 34.7% had sepsis codes, and 52% had codes or evidence of both infection and acute organ failure.

Sepsis could have been the final common pathway in already-ill patients, but the numbers hint that at least in some cases, sepsis that could have been extinguished early got out of hand before it was recognized.

The Surviving Sepsis Campaign and other efforts "have had a huge impact on how we treat the most severely ill sepsis patients. We’ve seen about a halving of mortality in the past 15 years. Now we need to broaden our perspective to focus intervention on the less severely ill, who tend to be less severe up front and underidentified," said lead investigator Dr. Liu, with the KPNC division of research, Oakland, Calif.

Based on the results, KPNC has started applying its sepsis bundle to patients with intermediate-lactate levels, "but there is very limited data about the benefit of bundle care in less severe sepsis patients, so we are still tracking our outcomes," he said. There’s also a culture shift involved, which includes heightening clinician awareness, updating communication protocols, and other measures, Dr. Liu said, in presenting the results at an international conference of the American Thoracic Society.

There’s a role for more research dollars as well, and education efforts to make the public aware of sepsis and the need for early intervention, similar to what’s been done for stroke, he said.

The work was funded by the Kaiser Foundation, the Department of Veterans Affairs, and others. One author disclosed personal fees from Pfizer, MedImmune, Eli Lilly, Ferring Pharmaceuticals, and Roche Diagnostics. Dr. Liu and the other authors said they had no financial disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Although hospitals in recent years have done a good job catching severe sepsis, less severe cases are falling through the cracks and ultimately proving fatal, according to a retrospective database study.

That’s probably the main reason investigators at Kaiser Permanente Northern California (KPNC) found that up to half of hospital deaths are sepsis related. Of 14,206 adult inpatient deaths at KPNC hospitals between 2010 and 2012, 36.9% had sepsis-related codes. When the team included patients without sepsis codes but with evidence of both infection and acute organ failure – implying sepsis – the number rose to 55.9%.

Most patients had indications of sepsis at admission, and patients with initially less severe sepsis made up the majority of sepsis deaths. About 56% of sepsis-related deaths were in people with normal blood pressure and normal or intermediate serum lactate levels (less than 4 mmol/L) on admission. Patients who met the criteria for early goal-directed therapy at admission, but for whatever reason did not get it, accounted for 21% of the deaths (JAMA 18 May 2014 [doi:10.1001/jama.2014.5804]).

The story was similar when the team looked at 143,312 deaths in the 2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, which captures about 20% of U.S. community hospitals: 34.7% had sepsis codes, and 52% had codes or evidence of both infection and acute organ failure.

Sepsis could have been the final common pathway in already-ill patients, but the numbers hint that at least in some cases, sepsis that could have been extinguished early got out of hand before it was recognized.

The Surviving Sepsis Campaign and other efforts "have had a huge impact on how we treat the most severely ill sepsis patients. We’ve seen about a halving of mortality in the past 15 years. Now we need to broaden our perspective to focus intervention on the less severely ill, who tend to be less severe up front and underidentified," said lead investigator Dr. Liu, with the KPNC division of research, Oakland, Calif.

Based on the results, KPNC has started applying its sepsis bundle to patients with intermediate-lactate levels, "but there is very limited data about the benefit of bundle care in less severe sepsis patients, so we are still tracking our outcomes," he said. There’s also a culture shift involved, which includes heightening clinician awareness, updating communication protocols, and other measures, Dr. Liu said, in presenting the results at an international conference of the American Thoracic Society.

There’s a role for more research dollars as well, and education efforts to make the public aware of sepsis and the need for early intervention, similar to what’s been done for stroke, he said.

The work was funded by the Kaiser Foundation, the Department of Veterans Affairs, and others. One author disclosed personal fees from Pfizer, MedImmune, Eli Lilly, Ferring Pharmaceuticals, and Roche Diagnostics. Dr. Liu and the other authors said they had no financial disclosures.

aotto@frontlinemedcom.com

SAN DIEGO – Acetylcysteine does not preserve forced vital capacity in idiopathic pulmonary fibrosis patients with mild to moderate lung function impairment, according to a placebo-controlled trial published online May 18 in the New England Journal of Medicine and presented by Dr. Ganesh Raghu at an international conference of the American Thoracic Society.

At 60 weeks, there was no significant difference in the change in FVC between 133 patients who had been randomized to acetylcysteine 600 mg three times daily and 131 randomized to placebo (–0.18 L and –0.19 L, respectively; P = .77). There also were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, respectively; P =.30) or acute exacerbations (2.3% in each group; P greater than .99) (N. Eng. J. Med. 2014 May 18 [doi: 10.1056/NEJMoa1401739]).

University of Washington

"It must be emphasized that our results are applicable only to patients with idiopathic pulmonary fibrosis who met the inclusion and exclusion criteria of this trial, and not to patients with more advanced disease or other forms of idiopathic interstitial pneumonia or interstitial lung disease," said the investigators, all members of the Idiopathic Pulmonary Fibrosis Clinical Research Network and led by Dr. Raghu, director of the interstitial lung disease/sarcoid/pulmonary fibrosis program at the University of Washington, Seattle.

The study originally included a third arm in which patients received prednisone, azathioprine, and acetylcysteine. A once-promising combination, the arm was halted after the data and safety monitoring board detected an increased risk of hospitalization and death, which led the National Institutes of Health to warn against using the combination for idiopathic pulmonary fibrosis (IPF).

Some clinicians, however, continued to use acetylcysteine, an over-the-counter antioxidant supplement, as monotherapy.

Overall, cardiac problems were more common in the acetylcysteine group than in the placebo patients (6.8% vs. 1.5%; P = .03), but gastrointestinal disorders were less common (0% vs. 4.6%; P = .01).

There were trends favoring acetylcysteine in 6-minute walk distance and quality of life measures. Patients in the acetylcysteine group reported having better mental well-being as well.

Baseline characteristics were well matched in the two study groups. The mean age was 67 years, 22% of the patients were women, and 96% were white. The mean baseline FVC was 73% of the predicted value, and the mean carbon monoxide diffusing capacity was 45% of the predicted value. The mean distance on the 6-minute walk test was 373 m.

At 60 weeks, 90.4% of the acetylcysteine group and 94.4% of the placebo group reported taking more than 80% of the recommended doses of the study drug.

The work was funded by the National Heart, Lung, and Blood Institute, among others. Dr. Raghu reported grant support and personal fees from Gilead; personal fees from Biogen, Boehringer Ingelheim, and other companies; and other support from MedImmune outside the submitted work. The other authors disclosed payments for various services from those or other companies.

aotto@frontlinemedcom.com

SAN DIEGO – Acetylcysteine does not preserve forced vital capacity in idiopathic pulmonary fibrosis patients with mild to moderate lung function impairment, according to a placebo-controlled trial published online May 18 in the New England Journal of Medicine and presented by Dr. Ganesh Raghu at an international conference of the American Thoracic Society.

At 60 weeks, there was no significant difference in the change in FVC between 133 patients who had been randomized to acetylcysteine 600 mg three times daily and 131 randomized to placebo (–0.18 L and –0.19 L, respectively; P = .77). There also were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, respectively; P =.30) or acute exacerbations (2.3% in each group; P greater than .99) (N. Eng. J. Med. 2014 May 18 [doi: 10.1056/NEJMoa1401739]).

University of Washington

"It must be emphasized that our results are applicable only to patients with idiopathic pulmonary fibrosis who met the inclusion and exclusion criteria of this trial, and not to patients with more advanced disease or other forms of idiopathic interstitial pneumonia or interstitial lung disease," said the investigators, all members of the Idiopathic Pulmonary Fibrosis Clinical Research Network and led by Dr. Raghu, director of the interstitial lung disease/sarcoid/pulmonary fibrosis program at the University of Washington, Seattle.

The study originally included a third arm in which patients received prednisone, azathioprine, and acetylcysteine. A once-promising combination, the arm was halted after the data and safety monitoring board detected an increased risk of hospitalization and death, which led the National Institutes of Health to warn against using the combination for idiopathic pulmonary fibrosis (IPF).

Some clinicians, however, continued to use acetylcysteine, an over-the-counter antioxidant supplement, as monotherapy.

Overall, cardiac problems were more common in the acetylcysteine group than in the placebo patients (6.8% vs. 1.5%; P = .03), but gastrointestinal disorders were less common (0% vs. 4.6%; P = .01).

There were trends favoring acetylcysteine in 6-minute walk distance and quality of life measures. Patients in the acetylcysteine group reported having better mental well-being as well.

Baseline characteristics were well matched in the two study groups. The mean age was 67 years, 22% of the patients were women, and 96% were white. The mean baseline FVC was 73% of the predicted value, and the mean carbon monoxide diffusing capacity was 45% of the predicted value. The mean distance on the 6-minute walk test was 373 m.

At 60 weeks, 90.4% of the acetylcysteine group and 94.4% of the placebo group reported taking more than 80% of the recommended doses of the study drug.

The work was funded by the National Heart, Lung, and Blood Institute, among others. Dr. Raghu reported grant support and personal fees from Gilead; personal fees from Biogen, Boehringer Ingelheim, and other companies; and other support from MedImmune outside the submitted work. The other authors disclosed payments for various services from those or other companies.

aotto@frontlinemedcom.com

SAN DIEGO – Acetylcysteine does not preserve forced vital capacity in idiopathic pulmonary fibrosis patients with mild to moderate lung function impairment, according to a placebo-controlled trial published online May 18 in the New England Journal of Medicine and presented by Dr. Ganesh Raghu at an international conference of the American Thoracic Society.

At 60 weeks, there was no significant difference in the change in FVC between 133 patients who had been randomized to acetylcysteine 600 mg three times daily and 131 randomized to placebo (–0.18 L and –0.19 L, respectively; P = .77). There also were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, respectively; P =.30) or acute exacerbations (2.3% in each group; P greater than .99) (N. Eng. J. Med. 2014 May 18 [doi: 10.1056/NEJMoa1401739]).

University of Washington

"It must be emphasized that our results are applicable only to patients with idiopathic pulmonary fibrosis who met the inclusion and exclusion criteria of this trial, and not to patients with more advanced disease or other forms of idiopathic interstitial pneumonia or interstitial lung disease," said the investigators, all members of the Idiopathic Pulmonary Fibrosis Clinical Research Network and led by Dr. Raghu, director of the interstitial lung disease/sarcoid/pulmonary fibrosis program at the University of Washington, Seattle.

The study originally included a third arm in which patients received prednisone, azathioprine, and acetylcysteine. A once-promising combination, the arm was halted after the data and safety monitoring board detected an increased risk of hospitalization and death, which led the National Institutes of Health to warn against using the combination for idiopathic pulmonary fibrosis (IPF).

Some clinicians, however, continued to use acetylcysteine, an over-the-counter antioxidant supplement, as monotherapy.

Overall, cardiac problems were more common in the acetylcysteine group than in the placebo patients (6.8% vs. 1.5%; P = .03), but gastrointestinal disorders were less common (0% vs. 4.6%; P = .01).

There were trends favoring acetylcysteine in 6-minute walk distance and quality of life measures. Patients in the acetylcysteine group reported having better mental well-being as well.

Baseline characteristics were well matched in the two study groups. The mean age was 67 years, 22% of the patients were women, and 96% were white. The mean baseline FVC was 73% of the predicted value, and the mean carbon monoxide diffusing capacity was 45% of the predicted value. The mean distance on the 6-minute walk test was 373 m.

At 60 weeks, 90.4% of the acetylcysteine group and 94.4% of the placebo group reported taking more than 80% of the recommended doses of the study drug.

The work was funded by the National Heart, Lung, and Blood Institute, among others. Dr. Raghu reported grant support and personal fees from Gilead; personal fees from Biogen, Boehringer Ingelheim, and other companies; and other support from MedImmune outside the submitted work. The other authors disclosed payments for various services from those or other companies.

aotto@frontlinemedcom.com

SAN DIEGO – Compared with placebo, the investigative tyrosine kinase inhibitor nintedanib helped preserve forced vital capacity in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented at an international conference of the American Thoracic Society.

Across two trials, a total of 1,066 patients were randomized 3:2 to receive 150 mg of nintedanib twice daily or placebo for 52 weeks. In the first trial, dubbed INPULSIS-1, the adjusted annual rate of change in forced vital capacity (FVC) was –114.7 mL with nintedanib versus –239.9 mL with placebo (difference 125.3 mL; 95% confidence interval, 77.7-172.8; P less than .001). In INPULSIS-2, the second trial, the rate of change was –113.6 mL with nintedanib versus –207.3 mL with placebo (difference 93.7 mL; 95% CI, 44.8 to 142.7; P less than 0.001).

"The curves for changes from baseline in FVC over time in the nintedanib and placebo groups separated early in the two studies and continued to diverge over time," said the investigators (N. Engl. J. Med. 2014 May 18 [doi:10.1056/NEJMoa1402584]). Myocardial infarctions were reported in five (1.6%) nintedanib patients and one (0.5%) placebo patient in the first trial and five (1.5%) nintedanib patients and one (0.5%) placebo patient in the second. Two infarctions in the nintedanib groups and one in the placebo groups were fatal. "The clinical significance of this finding is unknown, and further observation in larger cohorts is needed," the investigators said.

University of Southampton

Idiopathic pulmonary fibrosis (IPF) "is a very serious disease with a high unmet medical need for which there are currently no FDA-approved treatments. We are all very excited by these data because they suggest evidence of nintedanib’s impact on lung function loss in patients with IPF. Overall, [it’s] a positive message that we are making progress," said lead investigator Dr. Luca Richeldi, chair of interstitial lung disease at the University of Southampton (England).

Results were mixed on secondary endpoints. There was no significant between-group difference in death from any cause or respiratory causes; 5.5% of nintedanib patients and 7.8% of placebo patients died.

Likewise, the time to first acute exacerbation and progression on the St. George’s Respiratory Questionnaire (SGRQ) were significantly delayed only in INPULSIS-2, not INPULSIS-1. On pooled analysis, nintedanib offered no advantage over placebo in time to first exacerbation (Hazard Ratio, 0.64; 95% CI, 0.39-1.05; P = .08) or mean 52-week change from baseline SGRO.

The "difference in the key secondary endpoint between [the trials] was not explained by the differences in baseline characteristics." Regarding exacerbations, they "are relatively rare events in patients with idiopathic pulmonary fibrosis who are in clinical trials and are difficult to assess and categorize, which may explain some of the heterogeneity in our findings," the investigators said.

About 62% of nintedanib patients versus about 18% of placebo patients reported diarrhea, which was usually mild to moderate. Less than 5% of nintedanib patients left the trials because of it. Liver enzyme levels three times above normal were found in about 5% of nintedanib patients versus less than 1% of placebo patients.

The study groups were well matched; about 80% of subjects were men, about 67 years old on average. Baseline FVC was about 80% of predicted value in all study arms.

Boehringer Ingelheim – the maker of nintedanib – funded the work, along with the British National Health Service. Six of the 23 authors are employed by Boehringer Ingelheim. Most of the other authors reported consulting fees and other payments from pharmaceutical companies, including Boehringer Ingelheim in some cases. Dr. Richeldi reported advisory or consulting fees from InterMune, MedImmune, Roche, Takeda, Biogen Idec, Sanofi-Aventis, and ImmuneWorks, plus lecture fees from Shionogi and grant support from InterMune.

aotto@frontlinemedcom.com

SAN DIEGO – Compared with placebo, the investigative tyrosine kinase inhibitor nintedanib helped preserve forced vital capacity in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented at an international conference of the American Thoracic Society.

Across two trials, a total of 1,066 patients were randomized 3:2 to receive 150 mg of nintedanib twice daily or placebo for 52 weeks. In the first trial, dubbed INPULSIS-1, the adjusted annual rate of change in forced vital capacity (FVC) was –114.7 mL with nintedanib versus –239.9 mL with placebo (difference 125.3 mL; 95% confidence interval, 77.7-172.8; P less than .001). In INPULSIS-2, the second trial, the rate of change was –113.6 mL with nintedanib versus –207.3 mL with placebo (difference 93.7 mL; 95% CI, 44.8 to 142.7; P less than 0.001).

"The curves for changes from baseline in FVC over time in the nintedanib and placebo groups separated early in the two studies and continued to diverge over time," said the investigators (N. Engl. J. Med. 2014 May 18 [doi:10.1056/NEJMoa1402584]). Myocardial infarctions were reported in five (1.6%) nintedanib patients and one (0.5%) placebo patient in the first trial and five (1.5%) nintedanib patients and one (0.5%) placebo patient in the second. Two infarctions in the nintedanib groups and one in the placebo groups were fatal. "The clinical significance of this finding is unknown, and further observation in larger cohorts is needed," the investigators said.

University of Southampton

Idiopathic pulmonary fibrosis (IPF) "is a very serious disease with a high unmet medical need for which there are currently no FDA-approved treatments. We are all very excited by these data because they suggest evidence of nintedanib’s impact on lung function loss in patients with IPF. Overall, [it’s] a positive message that we are making progress," said lead investigator Dr. Luca Richeldi, chair of interstitial lung disease at the University of Southampton (England).

Results were mixed on secondary endpoints. There was no significant between-group difference in death from any cause or respiratory causes; 5.5% of nintedanib patients and 7.8% of placebo patients died.

Likewise, the time to first acute exacerbation and progression on the St. George’s Respiratory Questionnaire (SGRQ) were significantly delayed only in INPULSIS-2, not INPULSIS-1. On pooled analysis, nintedanib offered no advantage over placebo in time to first exacerbation (Hazard Ratio, 0.64; 95% CI, 0.39-1.05; P = .08) or mean 52-week change from baseline SGRO.

The "difference in the key secondary endpoint between [the trials] was not explained by the differences in baseline characteristics." Regarding exacerbations, they "are relatively rare events in patients with idiopathic pulmonary fibrosis who are in clinical trials and are difficult to assess and categorize, which may explain some of the heterogeneity in our findings," the investigators said.

About 62% of nintedanib patients versus about 18% of placebo patients reported diarrhea, which was usually mild to moderate. Less than 5% of nintedanib patients left the trials because of it. Liver enzyme levels three times above normal were found in about 5% of nintedanib patients versus less than 1% of placebo patients.

The study groups were well matched; about 80% of subjects were men, about 67 years old on average. Baseline FVC was about 80% of predicted value in all study arms.

Boehringer Ingelheim – the maker of nintedanib – funded the work, along with the British National Health Service. Six of the 23 authors are employed by Boehringer Ingelheim. Most of the other authors reported consulting fees and other payments from pharmaceutical companies, including Boehringer Ingelheim in some cases. Dr. Richeldi reported advisory or consulting fees from InterMune, MedImmune, Roche, Takeda, Biogen Idec, Sanofi-Aventis, and ImmuneWorks, plus lecture fees from Shionogi and grant support from InterMune.

aotto@frontlinemedcom.com

SAN DIEGO – Compared with placebo, the investigative tyrosine kinase inhibitor nintedanib helped preserve forced vital capacity in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented at an international conference of the American Thoracic Society.

Across two trials, a total of 1,066 patients were randomized 3:2 to receive 150 mg of nintedanib twice daily or placebo for 52 weeks. In the first trial, dubbed INPULSIS-1, the adjusted annual rate of change in forced vital capacity (FVC) was –114.7 mL with nintedanib versus –239.9 mL with placebo (difference 125.3 mL; 95% confidence interval, 77.7-172.8; P less than .001). In INPULSIS-2, the second trial, the rate of change was –113.6 mL with nintedanib versus –207.3 mL with placebo (difference 93.7 mL; 95% CI, 44.8 to 142.7; P less than 0.001).

"The curves for changes from baseline in FVC over time in the nintedanib and placebo groups separated early in the two studies and continued to diverge over time," said the investigators (N. Engl. J. Med. 2014 May 18 [doi:10.1056/NEJMoa1402584]). Myocardial infarctions were reported in five (1.6%) nintedanib patients and one (0.5%) placebo patient in the first trial and five (1.5%) nintedanib patients and one (0.5%) placebo patient in the second. Two infarctions in the nintedanib groups and one in the placebo groups were fatal. "The clinical significance of this finding is unknown, and further observation in larger cohorts is needed," the investigators said.

University of Southampton

Idiopathic pulmonary fibrosis (IPF) "is a very serious disease with a high unmet medical need for which there are currently no FDA-approved treatments. We are all very excited by these data because they suggest evidence of nintedanib’s impact on lung function loss in patients with IPF. Overall, [it’s] a positive message that we are making progress," said lead investigator Dr. Luca Richeldi, chair of interstitial lung disease at the University of Southampton (England).

Results were mixed on secondary endpoints. There was no significant between-group difference in death from any cause or respiratory causes; 5.5% of nintedanib patients and 7.8% of placebo patients died.

Likewise, the time to first acute exacerbation and progression on the St. George’s Respiratory Questionnaire (SGRQ) were significantly delayed only in INPULSIS-2, not INPULSIS-1. On pooled analysis, nintedanib offered no advantage over placebo in time to first exacerbation (Hazard Ratio, 0.64; 95% CI, 0.39-1.05; P = .08) or mean 52-week change from baseline SGRO.

The "difference in the key secondary endpoint between [the trials] was not explained by the differences in baseline characteristics." Regarding exacerbations, they "are relatively rare events in patients with idiopathic pulmonary fibrosis who are in clinical trials and are difficult to assess and categorize, which may explain some of the heterogeneity in our findings," the investigators said.

About 62% of nintedanib patients versus about 18% of placebo patients reported diarrhea, which was usually mild to moderate. Less than 5% of nintedanib patients left the trials because of it. Liver enzyme levels three times above normal were found in about 5% of nintedanib patients versus less than 1% of placebo patients.

The study groups were well matched; about 80% of subjects were men, about 67 years old on average. Baseline FVC was about 80% of predicted value in all study arms.

Boehringer Ingelheim – the maker of nintedanib – funded the work, along with the British National Health Service. Six of the 23 authors are employed by Boehringer Ingelheim. Most of the other authors reported consulting fees and other payments from pharmaceutical companies, including Boehringer Ingelheim in some cases. Dr. Richeldi reported advisory or consulting fees from InterMune, MedImmune, Roche, Takeda, Biogen Idec, Sanofi-Aventis, and ImmuneWorks, plus lecture fees from Shionogi and grant support from InterMune.

aotto@frontlinemedcom.com

SAN DIEGO – Using chronic sinusitis patients’ response to Pneumovax to screen them for specific antibody deficiency may lead to overtreatment with intravenous immunoglobulin, a study showed.

In addition to its traditional use to prevent pneumonia and other infections, Pneumovax (pneumococcal vaccine polyvalent) has found a new role recently: as a screening tool in chronic rhinosinusitis (CRS) patients for specific antibody deficiency (SAD), a type of immune deficiency. If patients have a poor antibody response to the Pneumovax shot, they are thought to have SAD and are placed on intravenous immunoglobulin (IVIG) – sometimes without much regard for their clinical history. The practice has been fueled by the growing suspicion that chronic rhinosinusitis might be driven by a faulty immune system.

Frontline Medical News

However, the severity of SAD does not correlate neatly with the response to Pneumovax, Northwestern University investigators found in a study of 595 adult CRS patients. So, treating patients with IVIG based primarily on how they respond to the vaccine might be overkill. To prevent overuse of IVIG, it’s probably best to limit Pneumovax screening to patients with clinically worse disease, according to lead investigator Dr. Anjeni Keswani, formerly of Northwestern University in Chicago but now an allergist/immunologist at Duke University in Durham, N.C.

Overall, the proper role of Pneumovax screening still needs to be worked out. At least for now, SAD "just can’t be a laboratory diagnosis. It should include clinical history before you make a decision on IVIG therapy," Dr. Keswani said.

In the Lund-MacKay staging system for CRS, higher scores mean worse disease. The 95 patients in the study who had mild SAD (defined as 7-9 protective Streptococcus pneumoniae antibody titers after vaccination, out of 14 serotypes measured) and the 120 patients with moderate SAD (3-6 protective titers after vaccination) had significantly higher Lund-MacKay scores than the 24 patients with severe SAD. Severe SAD was defined as 2 or fewer protective titers following the vaccine.

Mild and moderate SAD patients also had significantly higher rates of asthma and higher, although not significantly higher, rates of allergic rhinitis and nasal polyps, Dr. Keswani said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Meanwhile, patients with more severe SAD were significantly more likely than mild SAD patients to have pneumonia histories and, when present, more severe asthma. And they used significantly more antibiotics in the 2 years following vaccination.

Asthma severity, antibiotic use, and pneumonia history in mild SAD patients were, in fact, similar to rates in CRS patients without immune deficiency. That raises the possibility that what’s now considered mild SAD might not even be an immunodeficiency, hence the notion of limiting Pneumovax screening to patients who are worse off.

As it all gets sorted out, "we don’t want patients diagnosed with SAD to automatically be placed on immunoglobulin replacement," Dr. Keswani said. "I don’t think that’s useful for the majority of patients. There is a proportion who mount a good response to infection; they may have an impaired response to the vaccine, but we can manage them with antibiotic prophylaxis and early assessment.

"We are trying to come up with guidelines to better help determine who should be screened," she added. "If they don’t have evidence of infection, I don’t think we can actually call them SAD."

Dr. Keswani said she had no relevant disclosures, and there was no outside funding involved in the project.

aotto@frontlinemedcom.com

SAN DIEGO – Using chronic sinusitis patients’ response to Pneumovax to screen them for specific antibody deficiency may lead to overtreatment with intravenous immunoglobulin, a study showed.

In addition to its traditional use to prevent pneumonia and other infections, Pneumovax (pneumococcal vaccine polyvalent) has found a new role recently: as a screening tool in chronic rhinosinusitis (CRS) patients for specific antibody deficiency (SAD), a type of immune deficiency. If patients have a poor antibody response to the Pneumovax shot, they are thought to have SAD and are placed on intravenous immunoglobulin (IVIG) – sometimes without much regard for their clinical history. The practice has been fueled by the growing suspicion that chronic rhinosinusitis might be driven by a faulty immune system.

Frontline Medical News

However, the severity of SAD does not correlate neatly with the response to Pneumovax, Northwestern University investigators found in a study of 595 adult CRS patients. So, treating patients with IVIG based primarily on how they respond to the vaccine might be overkill. To prevent overuse of IVIG, it’s probably best to limit Pneumovax screening to patients with clinically worse disease, according to lead investigator Dr. Anjeni Keswani, formerly of Northwestern University in Chicago but now an allergist/immunologist at Duke University in Durham, N.C.

Overall, the proper role of Pneumovax screening still needs to be worked out. At least for now, SAD "just can’t be a laboratory diagnosis. It should include clinical history before you make a decision on IVIG therapy," Dr. Keswani said.

In the Lund-MacKay staging system for CRS, higher scores mean worse disease. The 95 patients in the study who had mild SAD (defined as 7-9 protective Streptococcus pneumoniae antibody titers after vaccination, out of 14 serotypes measured) and the 120 patients with moderate SAD (3-6 protective titers after vaccination) had significantly higher Lund-MacKay scores than the 24 patients with severe SAD. Severe SAD was defined as 2 or fewer protective titers following the vaccine.

Mild and moderate SAD patients also had significantly higher rates of asthma and higher, although not significantly higher, rates of allergic rhinitis and nasal polyps, Dr. Keswani said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Meanwhile, patients with more severe SAD were significantly more likely than mild SAD patients to have pneumonia histories and, when present, more severe asthma. And they used significantly more antibiotics in the 2 years following vaccination.

Asthma severity, antibiotic use, and pneumonia history in mild SAD patients were, in fact, similar to rates in CRS patients without immune deficiency. That raises the possibility that what’s now considered mild SAD might not even be an immunodeficiency, hence the notion of limiting Pneumovax screening to patients who are worse off.

As it all gets sorted out, "we don’t want patients diagnosed with SAD to automatically be placed on immunoglobulin replacement," Dr. Keswani said. "I don’t think that’s useful for the majority of patients. There is a proportion who mount a good response to infection; they may have an impaired response to the vaccine, but we can manage them with antibiotic prophylaxis and early assessment.

"We are trying to come up with guidelines to better help determine who should be screened," she added. "If they don’t have evidence of infection, I don’t think we can actually call them SAD."

Dr. Keswani said she had no relevant disclosures, and there was no outside funding involved in the project.

aotto@frontlinemedcom.com

SAN DIEGO – Using chronic sinusitis patients’ response to Pneumovax to screen them for specific antibody deficiency may lead to overtreatment with intravenous immunoglobulin, a study showed.

In addition to its traditional use to prevent pneumonia and other infections, Pneumovax (pneumococcal vaccine polyvalent) has found a new role recently: as a screening tool in chronic rhinosinusitis (CRS) patients for specific antibody deficiency (SAD), a type of immune deficiency. If patients have a poor antibody response to the Pneumovax shot, they are thought to have SAD and are placed on intravenous immunoglobulin (IVIG) – sometimes without much regard for their clinical history. The practice has been fueled by the growing suspicion that chronic rhinosinusitis might be driven by a faulty immune system.

Frontline Medical News

However, the severity of SAD does not correlate neatly with the response to Pneumovax, Northwestern University investigators found in a study of 595 adult CRS patients. So, treating patients with IVIG based primarily on how they respond to the vaccine might be overkill. To prevent overuse of IVIG, it’s probably best to limit Pneumovax screening to patients with clinically worse disease, according to lead investigator Dr. Anjeni Keswani, formerly of Northwestern University in Chicago but now an allergist/immunologist at Duke University in Durham, N.C.

Overall, the proper role of Pneumovax screening still needs to be worked out. At least for now, SAD "just can’t be a laboratory diagnosis. It should include clinical history before you make a decision on IVIG therapy," Dr. Keswani said.

In the Lund-MacKay staging system for CRS, higher scores mean worse disease. The 95 patients in the study who had mild SAD (defined as 7-9 protective Streptococcus pneumoniae antibody titers after vaccination, out of 14 serotypes measured) and the 120 patients with moderate SAD (3-6 protective titers after vaccination) had significantly higher Lund-MacKay scores than the 24 patients with severe SAD. Severe SAD was defined as 2 or fewer protective titers following the vaccine.

Mild and moderate SAD patients also had significantly higher rates of asthma and higher, although not significantly higher, rates of allergic rhinitis and nasal polyps, Dr. Keswani said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Meanwhile, patients with more severe SAD were significantly more likely than mild SAD patients to have pneumonia histories and, when present, more severe asthma. And they used significantly more antibiotics in the 2 years following vaccination.

Asthma severity, antibiotic use, and pneumonia history in mild SAD patients were, in fact, similar to rates in CRS patients without immune deficiency. That raises the possibility that what’s now considered mild SAD might not even be an immunodeficiency, hence the notion of limiting Pneumovax screening to patients who are worse off.

As it all gets sorted out, "we don’t want patients diagnosed with SAD to automatically be placed on immunoglobulin replacement," Dr. Keswani said. "I don’t think that’s useful for the majority of patients. There is a proportion who mount a good response to infection; they may have an impaired response to the vaccine, but we can manage them with antibiotic prophylaxis and early assessment.

"We are trying to come up with guidelines to better help determine who should be screened," she added. "If they don’t have evidence of infection, I don’t think we can actually call them SAD."

Dr. Keswani said she had no relevant disclosures, and there was no outside funding involved in the project.

aotto@frontlinemedcom.com

VANCOUVER, B.C. – If it’s an option, subcutaneous methotrexate is the way to go for new-onset juvenile idiopathic arthritis, based on a study of 47 patients at Children’s Mercy Hospital in Kansas City, Mo.

In the study, 21 children received subcutaneous methotrexate and 26 received oral methotrexate (MTX). The children, regardless of administration route, were on the same, standard dose of MTX, 15 mg/m² weekly, plus 1 mg/day of folic acid.

At 3 months, 13 (28%) of the 47 children reached an ACR [American College of Rheumatology] pediatric 70. The measure is defined as a 70% improvement in joint counts, global assessments, and other measures from baseline. Nine (69%) of the 13 had been on subcutaneous methotrexate and 4 (31%) had been on the oral formulation.

Additionally, red blood cell concentrations of long-chain MTX polyglutamate, a marker of better response, were higher in the children given subcutaneous methotrexate (82 nmol/L vs. 36 nmol/L) The differences were statistically significant.

"I was a little bit shocked" by the results, said lead investigator Dr. Mara Becker, director of the rheumatology division at Children’s Mercy who is with the department of pediatrics at the University of Missouri–Kansas City. "I’ve been in the camp of saying ‘orally or subcutaneously, however you want to give it.’ This solidified the fact that I’d give SQ first, especially if I want to prevent having to use a biologic."

Although "we are still debating the best way to give methotrexate when it’s started, kids on subcutaneous methotrexate got better faster." That’s likely because of the better bioavailability – and fewer GI side effects – when methotrexate bypasses the gut, she said at the annual meeting of the Pediatric Academic Societies.

Needle phobia, however, is the kicker. "Kids get anxious about having to get a shot each week; that’s why people shy away from it. A lot of times, we start orally and switch to SQ if kids get side effects, but if they have needle phobia, you’re in a difficult place," she said.

The children were, on average, about 10 years old, and the majority of them were girls. There were no significant between-group clinical differences at baseline.

NSAIDS, low-dose prednisone, and steroid joint shots were allowed as needed. At 3 months, NSAID and oral steroid use was statistically the same between the groups, but SQ methotrexate patients were significantly more likely to have gotten joint injections when started on methotrexate. To account for the difference, injected joints were counted as "active joints" in the analysis.

The recent shortage of subcutaneous methotrexate, often the first choice among U.S. physicians, led to the study. About half of the children had to be "on oral because of the shortage, so we said, ‘alright, let’s take a look and see how they do’," Dr. Becker said.

Dr. Becker has no relevant disclosures. The ACR Research Foundation helped fund the work.

aotto@frontlinemedcom.com

VANCOUVER, B.C. – If it’s an option, subcutaneous methotrexate is the way to go for new-onset juvenile idiopathic arthritis, based on a study of 47 patients at Children’s Mercy Hospital in Kansas City, Mo.

In the study, 21 children received subcutaneous methotrexate and 26 received oral methotrexate (MTX). The children, regardless of administration route, were on the same, standard dose of MTX, 15 mg/m² weekly, plus 1 mg/day of folic acid.

At 3 months, 13 (28%) of the 47 children reached an ACR [American College of Rheumatology] pediatric 70. The measure is defined as a 70% improvement in joint counts, global assessments, and other measures from baseline. Nine (69%) of the 13 had been on subcutaneous methotrexate and 4 (31%) had been on the oral formulation.

Additionally, red blood cell concentrations of long-chain MTX polyglutamate, a marker of better response, were higher in the children given subcutaneous methotrexate (82 nmol/L vs. 36 nmol/L) The differences were statistically significant.

"I was a little bit shocked" by the results, said lead investigator Dr. Mara Becker, director of the rheumatology division at Children’s Mercy who is with the department of pediatrics at the University of Missouri–Kansas City. "I’ve been in the camp of saying ‘orally or subcutaneously, however you want to give it.’ This solidified the fact that I’d give SQ first, especially if I want to prevent having to use a biologic."

Although "we are still debating the best way to give methotrexate when it’s started, kids on subcutaneous methotrexate got better faster." That’s likely because of the better bioavailability – and fewer GI side effects – when methotrexate bypasses the gut, she said at the annual meeting of the Pediatric Academic Societies.

Needle phobia, however, is the kicker. "Kids get anxious about having to get a shot each week; that’s why people shy away from it. A lot of times, we start orally and switch to SQ if kids get side effects, but if they have needle phobia, you’re in a difficult place," she said.

The children were, on average, about 10 years old, and the majority of them were girls. There were no significant between-group clinical differences at baseline.

NSAIDS, low-dose prednisone, and steroid joint shots were allowed as needed. At 3 months, NSAID and oral steroid use was statistically the same between the groups, but SQ methotrexate patients were significantly more likely to have gotten joint injections when started on methotrexate. To account for the difference, injected joints were counted as "active joints" in the analysis.

The recent shortage of subcutaneous methotrexate, often the first choice among U.S. physicians, led to the study. About half of the children had to be "on oral because of the shortage, so we said, ‘alright, let’s take a look and see how they do’," Dr. Becker said.

Dr. Becker has no relevant disclosures. The ACR Research Foundation helped fund the work.

aotto@frontlinemedcom.com

VANCOUVER, B.C. – If it’s an option, subcutaneous methotrexate is the way to go for new-onset juvenile idiopathic arthritis, based on a study of 47 patients at Children’s Mercy Hospital in Kansas City, Mo.

In the study, 21 children received subcutaneous methotrexate and 26 received oral methotrexate (MTX). The children, regardless of administration route, were on the same, standard dose of MTX, 15 mg/m² weekly, plus 1 mg/day of folic acid.

At 3 months, 13 (28%) of the 47 children reached an ACR [American College of Rheumatology] pediatric 70. The measure is defined as a 70% improvement in joint counts, global assessments, and other measures from baseline. Nine (69%) of the 13 had been on subcutaneous methotrexate and 4 (31%) had been on the oral formulation.

Additionally, red blood cell concentrations of long-chain MTX polyglutamate, a marker of better response, were higher in the children given subcutaneous methotrexate (82 nmol/L vs. 36 nmol/L) The differences were statistically significant.

"I was a little bit shocked" by the results, said lead investigator Dr. Mara Becker, director of the rheumatology division at Children’s Mercy who is with the department of pediatrics at the University of Missouri–Kansas City. "I’ve been in the camp of saying ‘orally or subcutaneously, however you want to give it.’ This solidified the fact that I’d give SQ first, especially if I want to prevent having to use a biologic."

Although "we are still debating the best way to give methotrexate when it’s started, kids on subcutaneous methotrexate got better faster." That’s likely because of the better bioavailability – and fewer GI side effects – when methotrexate bypasses the gut, she said at the annual meeting of the Pediatric Academic Societies.

Needle phobia, however, is the kicker. "Kids get anxious about having to get a shot each week; that’s why people shy away from it. A lot of times, we start orally and switch to SQ if kids get side effects, but if they have needle phobia, you’re in a difficult place," she said.

The children were, on average, about 10 years old, and the majority of them were girls. There were no significant between-group clinical differences at baseline.

NSAIDS, low-dose prednisone, and steroid joint shots were allowed as needed. At 3 months, NSAID and oral steroid use was statistically the same between the groups, but SQ methotrexate patients were significantly more likely to have gotten joint injections when started on methotrexate. To account for the difference, injected joints were counted as "active joints" in the analysis.

The recent shortage of subcutaneous methotrexate, often the first choice among U.S. physicians, led to the study. About half of the children had to be "on oral because of the shortage, so we said, ‘alright, let’s take a look and see how they do’," Dr. Becker said.

Dr. Becker has no relevant disclosures. The ACR Research Foundation helped fund the work.

aotto@frontlinemedcom.com

VANCOUVER, B.C. – Indomethacin helps prevent intraventricular hemorrhages in infants born before 29 weeks to mothers who do not receive a full course of antenatal steroids, according to a small study at Weill Cornell Medical College in New York.

The study included 72 infants born at an average weight of 866 g and 26 weeks’ gestational age. Among the 17 born without optimal maternal courses of antenatal steroids (ANS), the investigators found that just one of eight children dosed with indomethacin developed a severe brain bleed, compared with six of nine who did not get indomethacin. The nonsteroidal anti-inflammatory drug was dosed in the first 6 hours of life – and continued every 24 hours for a total of three doses, if tolerated – at 0.1 mg/kg; it significantly reduced the risk of intraventricular hemorrhage (odds ratio, 14; 95% confidence interval, 1.73-172; P = .04).

M. Alexander Otto/Frontline Medical News

"The administration of indomethacin to premature infants born at 28 weeks or less in the absence of optimal ANS almost eliminated severe IVH [intraventricular hemorrhage] over a 2- year period," concluded the investigators, led by neonatologist Dr. Morgan Spaight, a fellow at Cornell.

"Most of the time, infants [there] get complete ANS courses" when indicated, "and we’ve seen a huge decline in our rates of severe intraventricular hemorrhages. At the same time, we are still seeing born infants that we need to shunt for post-hemorrhagic hydrocephalus; a majority of them were not exposed to antenatal steroids, either at all or [not completely]. This may be the first time indomethacin has been targeted for infants that did not receive optimal antenatal steroids," she said at the annual meeting of the Pediatric Academic Societies.

"We implemented a plan to target these infants specifically" with indomethacin. "We found that it significantly decreased the amount of severe IVH, although there are times we can’t complete the three doses because we are worried about adverse events," such as spontaneous intestinal perforation, she said.

Earlier studies have questioned the long-term benefit of indomethacin, but "there’s a pretty strong connection between severe IVH and bad outcomes, so we feel that preventing" it with indomethacin, when women don’t get a full course of ANS, "has to be a good thing," she said.

Infants who received indomethacin were born, on average, earlier than those who did not (24 vs. 27 weeks) and at lower average weights (652 vs. 972 g).

Dr. Spaight had no disclosures, and the work had no outside funding.

aotto@frontlinemedcom.com

VANCOUVER, B.C. – Indomethacin helps prevent intraventricular hemorrhages in infants born before 29 weeks to mothers who do not receive a full course of antenatal steroids, according to a small study at Weill Cornell Medical College in New York.

The study included 72 infants born at an average weight of 866 g and 26 weeks’ gestational age. Among the 17 born without optimal maternal courses of antenatal steroids (ANS), the investigators found that just one of eight children dosed with indomethacin developed a severe brain bleed, compared with six of nine who did not get indomethacin. The nonsteroidal anti-inflammatory drug was dosed in the first 6 hours of life – and continued every 24 hours for a total of three doses, if tolerated – at 0.1 mg/kg; it significantly reduced the risk of intraventricular hemorrhage (odds ratio, 14; 95% confidence interval, 1.73-172; P = .04).

M. Alexander Otto/Frontline Medical News

"The administration of indomethacin to premature infants born at 28 weeks or less in the absence of optimal ANS almost eliminated severe IVH [intraventricular hemorrhage] over a 2- year period," concluded the investigators, led by neonatologist Dr. Morgan Spaight, a fellow at Cornell.

"Most of the time, infants [there] get complete ANS courses" when indicated, "and we’ve seen a huge decline in our rates of severe intraventricular hemorrhages. At the same time, we are still seeing born infants that we need to shunt for post-hemorrhagic hydrocephalus; a majority of them were not exposed to antenatal steroids, either at all or [not completely]. This may be the first time indomethacin has been targeted for infants that did not receive optimal antenatal steroids," she said at the annual meeting of the Pediatric Academic Societies.

"We implemented a plan to target these infants specifically" with indomethacin. "We found that it significantly decreased the amount of severe IVH, although there are times we can’t complete the three doses because we are worried about adverse events," such as spontaneous intestinal perforation, she said.

Earlier studies have questioned the long-term benefit of indomethacin, but "there’s a pretty strong connection between severe IVH and bad outcomes, so we feel that preventing" it with indomethacin, when women don’t get a full course of ANS, "has to be a good thing," she said.

Infants who received indomethacin were born, on average, earlier than those who did not (24 vs. 27 weeks) and at lower average weights (652 vs. 972 g).

Dr. Spaight had no disclosures, and the work had no outside funding.

aotto@frontlinemedcom.com

VANCOUVER, B.C. – Indomethacin helps prevent intraventricular hemorrhages in infants born before 29 weeks to mothers who do not receive a full course of antenatal steroids, according to a small study at Weill Cornell Medical College in New York.

The study included 72 infants born at an average weight of 866 g and 26 weeks’ gestational age. Among the 17 born without optimal maternal courses of antenatal steroids (ANS), the investigators found that just one of eight children dosed with indomethacin developed a severe brain bleed, compared with six of nine who did not get indomethacin. The nonsteroidal anti-inflammatory drug was dosed in the first 6 hours of life – and continued every 24 hours for a total of three doses, if tolerated – at 0.1 mg/kg; it significantly reduced the risk of intraventricular hemorrhage (odds ratio, 14; 95% confidence interval, 1.73-172; P = .04).

M. Alexander Otto/Frontline Medical News

"The administration of indomethacin to premature infants born at 28 weeks or less in the absence of optimal ANS almost eliminated severe IVH [intraventricular hemorrhage] over a 2- year period," concluded the investigators, led by neonatologist Dr. Morgan Spaight, a fellow at Cornell.

"Most of the time, infants [there] get complete ANS courses" when indicated, "and we’ve seen a huge decline in our rates of severe intraventricular hemorrhages. At the same time, we are still seeing born infants that we need to shunt for post-hemorrhagic hydrocephalus; a majority of them were not exposed to antenatal steroids, either at all or [not completely]. This may be the first time indomethacin has been targeted for infants that did not receive optimal antenatal steroids," she said at the annual meeting of the Pediatric Academic Societies.

"We implemented a plan to target these infants specifically" with indomethacin. "We found that it significantly decreased the amount of severe IVH, although there are times we can’t complete the three doses because we are worried about adverse events," such as spontaneous intestinal perforation, she said.

Earlier studies have questioned the long-term benefit of indomethacin, but "there’s a pretty strong connection between severe IVH and bad outcomes, so we feel that preventing" it with indomethacin, when women don’t get a full course of ANS, "has to be a good thing," she said.

Infants who received indomethacin were born, on average, earlier than those who did not (24 vs. 27 weeks) and at lower average weights (652 vs. 972 g).

Dr. Spaight had no disclosures, and the work had no outside funding.

aotto@frontlinemedcom.com