SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

lnikolaides@mdedge.com





 

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

lnikolaides@mdedge.com





 

The Food and Drug Administration has approved enzalutamide (Xtandi) for patients with metastatic castration-sensitive prostate cancer (mCSPC).

The drug was previously approved for patients with castration-resistant prostate cancer.

Approval was based on radiographic progression-free survival (rPFS) improvement in ARCHES, a trial of 1,150 patients with mCSPC randomized to receive either enzalutamide or placebo daily. All patients received a gonadotropin-releasing hormone analogue or had a prior bilateral orchiectomy.

Median rPFS was not reached in the enzalutamide, arm compared with 19.4 months (95% confidence interval, 16.6 to not reached) in the placebo arm (HR 0.39; 95% CI, 0.30-0.50; P less than .0001), the FDA said in a statement.

The most common adverse reactions in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.

The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily with or without food, the FDA said.

lnikolaides@mdedge.com





 

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

dbrunk@mdedge.com

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

dbrunk@mdedge.com

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

dbrunk@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

While identifying overt bacterial infections in patients with atopic dermatitis is straightforward, wide variations in clinical presentation of infections in AD and features common to both can make it difficult to make a clinical diagnosis of infections.

Addressing this issue, the International Eczema Council Skin Infection Group reviewed the most current evidence on the clinical features of bacterial infections and the interaction between host and bacterial factors that affect severity and morbidity in people with atopic dermatitis (AD). Recurrent skin infections, especially from Staphylococcus aureus and occasionally from beta-hemolytic streptococci, are more common in people with AD than those who do not have AD for a variety of reasons, Helen Alexander, MD, from the unit for population-based dermatology research at St. John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and associates wrote in the review article published in the British Journal of Dermatology.

“The reduced skin barrier, cutaneous innate and adaptive immune abnormalities and trauma from scratching all contribute to the increased risk of skin infection,” they wrote. “However, the wide variability in clinical presentation of bacterial infection in AD and the inherent features of AD – cutaneous erythema and warmth, oozing associated with edema, and regional lymphadenopathy – overlap with those of infection, making clinical diagnosis challenging.”

The clinical appearance of AD may also mask signs of the bacterial infection, they added, and providers cannot rely on positive skin swab culture from the possibly infected area since S. aureus is so common in AD. An added challenge can occur in patients of different ethnicities, in whom both AD and bacterial infection may manifest differently. For example, perifollicular accentuation often occurs with AD in dark-skinned patients with violet-colored, often muted erythema.

An estimated 70% of lesional and 39% of nonlesional AD skin is colonized with S. aureus, the authors noted, but it’s not clear how best to recognize and manage asymptomatic S. aureus colonization. Among the factors that can increase susceptibility to S. aureus colonization and infection are impaired skin barriers, type 2 inflammation and lower levels of microbial diversity in the skin microbiome.

Specific clinical features of S. aureus in patients with AD include “weeping, honey-colored crusts and pustules, both interfollicular and follicular based,” and the pustules, though not common, can involve pain and itching. By comparison, signs of beta-hemolytic streptococcal infection may include “well-defined, bright red erythema, thick-walled pustules and heavy crusting,” the authors wrote.

Fever and lymphadenopathy may occur in severe cases, as well as abscesses, particularly with methicillin-resistant S. aureus (MRSA) infection. It’s unclear whether MRSA occurs more often in people with AD since its incidence varies so widely geographically, they noted.

In the differential diagnosis, providers should consider the possibility that a patient has a concomitant viral or fungal infection. Eczema herpeticum from herpes simplex virus is a common viral infection with risk factors that include “moderate to severe AD, filaggrin loss-of-function mutation, a history of S. aureus skin infection, greater allergen sensitization and type 2 immunity,” the authors wrote.

The yeast Malassezia is implicated in inflammation in patients with dermatitis that affects the head, neck, upper chest, back, and other areas high in sebaceous glands. Some patients have greater sensitivity to Malassezia, and “cross-reactivity between Malassezia-specific IgE and Candida albicans” has occurred as well, they wrote. Current evidence favors benefit from antifungal drugs, though not conclusively.

“Although we have some understanding of how S. aureus colonizes the skin and causes inflammation in AD, many questions related to this complex relationship remain unanswered,” the authors concluded. They added that better understanding the mechanisms of S. aureus and downstream host immune mediators of inflammatory pathways involving S. aureus could potentially lead to new therapeutic targets for infection in AD patients.

The statement was funded in part by the senior author’s fellowships from the National Institutes of Health Research, and the International Eczema Council received sponsorship from AbbVie, Amgen, Asana Biosciences, Celgene, Chugai, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, LEO Pharma, Kyowa Kirin, Novartis, Pierre Fabre, Pfizer, Sanofi Genzyme, Regeneron Pharmaceuticals, Sienna and Valeant. Of the 16 authors, 13 disclosed financial ties to a wide range of pharmaceutical companies, including those listed above.

SOURCE: Alexander H et al. Br J Dermatol. 2019 Nov 1. doi: 10.1111/bjd.1864319.

While identifying overt bacterial infections in patients with atopic dermatitis is straightforward, wide variations in clinical presentation of infections in AD and features common to both can make it difficult to make a clinical diagnosis of infections.

Addressing this issue, the International Eczema Council Skin Infection Group reviewed the most current evidence on the clinical features of bacterial infections and the interaction between host and bacterial factors that affect severity and morbidity in people with atopic dermatitis (AD). Recurrent skin infections, especially from Staphylococcus aureus and occasionally from beta-hemolytic streptococci, are more common in people with AD than those who do not have AD for a variety of reasons, Helen Alexander, MD, from the unit for population-based dermatology research at St. John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and associates wrote in the review article published in the British Journal of Dermatology.

“The reduced skin barrier, cutaneous innate and adaptive immune abnormalities and trauma from scratching all contribute to the increased risk of skin infection,” they wrote. “However, the wide variability in clinical presentation of bacterial infection in AD and the inherent features of AD – cutaneous erythema and warmth, oozing associated with edema, and regional lymphadenopathy – overlap with those of infection, making clinical diagnosis challenging.”

The clinical appearance of AD may also mask signs of the bacterial infection, they added, and providers cannot rely on positive skin swab culture from the possibly infected area since S. aureus is so common in AD. An added challenge can occur in patients of different ethnicities, in whom both AD and bacterial infection may manifest differently. For example, perifollicular accentuation often occurs with AD in dark-skinned patients with violet-colored, often muted erythema.

An estimated 70% of lesional and 39% of nonlesional AD skin is colonized with S. aureus, the authors noted, but it’s not clear how best to recognize and manage asymptomatic S. aureus colonization. Among the factors that can increase susceptibility to S. aureus colonization and infection are impaired skin barriers, type 2 inflammation and lower levels of microbial diversity in the skin microbiome.

Specific clinical features of S. aureus in patients with AD include “weeping, honey-colored crusts and pustules, both interfollicular and follicular based,” and the pustules, though not common, can involve pain and itching. By comparison, signs of beta-hemolytic streptococcal infection may include “well-defined, bright red erythema, thick-walled pustules and heavy crusting,” the authors wrote.

Fever and lymphadenopathy may occur in severe cases, as well as abscesses, particularly with methicillin-resistant S. aureus (MRSA) infection. It’s unclear whether MRSA occurs more often in people with AD since its incidence varies so widely geographically, they noted.

In the differential diagnosis, providers should consider the possibility that a patient has a concomitant viral or fungal infection. Eczema herpeticum from herpes simplex virus is a common viral infection with risk factors that include “moderate to severe AD, filaggrin loss-of-function mutation, a history of S. aureus skin infection, greater allergen sensitization and type 2 immunity,” the authors wrote.

The yeast Malassezia is implicated in inflammation in patients with dermatitis that affects the head, neck, upper chest, back, and other areas high in sebaceous glands. Some patients have greater sensitivity to Malassezia, and “cross-reactivity between Malassezia-specific IgE and Candida albicans” has occurred as well, they wrote. Current evidence favors benefit from antifungal drugs, though not conclusively.

“Although we have some understanding of how S. aureus colonizes the skin and causes inflammation in AD, many questions related to this complex relationship remain unanswered,” the authors concluded. They added that better understanding the mechanisms of S. aureus and downstream host immune mediators of inflammatory pathways involving S. aureus could potentially lead to new therapeutic targets for infection in AD patients.

The statement was funded in part by the senior author’s fellowships from the National Institutes of Health Research, and the International Eczema Council received sponsorship from AbbVie, Amgen, Asana Biosciences, Celgene, Chugai, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, LEO Pharma, Kyowa Kirin, Novartis, Pierre Fabre, Pfizer, Sanofi Genzyme, Regeneron Pharmaceuticals, Sienna and Valeant. Of the 16 authors, 13 disclosed financial ties to a wide range of pharmaceutical companies, including those listed above.

SOURCE: Alexander H et al. Br J Dermatol. 2019 Nov 1. doi: 10.1111/bjd.1864319.

While identifying overt bacterial infections in patients with atopic dermatitis is straightforward, wide variations in clinical presentation of infections in AD and features common to both can make it difficult to make a clinical diagnosis of infections.

Addressing this issue, the International Eczema Council Skin Infection Group reviewed the most current evidence on the clinical features of bacterial infections and the interaction between host and bacterial factors that affect severity and morbidity in people with atopic dermatitis (AD). Recurrent skin infections, especially from Staphylococcus aureus and occasionally from beta-hemolytic streptococci, are more common in people with AD than those who do not have AD for a variety of reasons, Helen Alexander, MD, from the unit for population-based dermatology research at St. John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and associates wrote in the review article published in the British Journal of Dermatology.

“The reduced skin barrier, cutaneous innate and adaptive immune abnormalities and trauma from scratching all contribute to the increased risk of skin infection,” they wrote. “However, the wide variability in clinical presentation of bacterial infection in AD and the inherent features of AD – cutaneous erythema and warmth, oozing associated with edema, and regional lymphadenopathy – overlap with those of infection, making clinical diagnosis challenging.”

The clinical appearance of AD may also mask signs of the bacterial infection, they added, and providers cannot rely on positive skin swab culture from the possibly infected area since S. aureus is so common in AD. An added challenge can occur in patients of different ethnicities, in whom both AD and bacterial infection may manifest differently. For example, perifollicular accentuation often occurs with AD in dark-skinned patients with violet-colored, often muted erythema.

An estimated 70% of lesional and 39% of nonlesional AD skin is colonized with S. aureus, the authors noted, but it’s not clear how best to recognize and manage asymptomatic S. aureus colonization. Among the factors that can increase susceptibility to S. aureus colonization and infection are impaired skin barriers, type 2 inflammation and lower levels of microbial diversity in the skin microbiome.

Specific clinical features of S. aureus in patients with AD include “weeping, honey-colored crusts and pustules, both interfollicular and follicular based,” and the pustules, though not common, can involve pain and itching. By comparison, signs of beta-hemolytic streptococcal infection may include “well-defined, bright red erythema, thick-walled pustules and heavy crusting,” the authors wrote.

Fever and lymphadenopathy may occur in severe cases, as well as abscesses, particularly with methicillin-resistant S. aureus (MRSA) infection. It’s unclear whether MRSA occurs more often in people with AD since its incidence varies so widely geographically, they noted.

In the differential diagnosis, providers should consider the possibility that a patient has a concomitant viral or fungal infection. Eczema herpeticum from herpes simplex virus is a common viral infection with risk factors that include “moderate to severe AD, filaggrin loss-of-function mutation, a history of S. aureus skin infection, greater allergen sensitization and type 2 immunity,” the authors wrote.

The yeast Malassezia is implicated in inflammation in patients with dermatitis that affects the head, neck, upper chest, back, and other areas high in sebaceous glands. Some patients have greater sensitivity to Malassezia, and “cross-reactivity between Malassezia-specific IgE and Candida albicans” has occurred as well, they wrote. Current evidence favors benefit from antifungal drugs, though not conclusively.

“Although we have some understanding of how S. aureus colonizes the skin and causes inflammation in AD, many questions related to this complex relationship remain unanswered,” the authors concluded. They added that better understanding the mechanisms of S. aureus and downstream host immune mediators of inflammatory pathways involving S. aureus could potentially lead to new therapeutic targets for infection in AD patients.

The statement was funded in part by the senior author’s fellowships from the National Institutes of Health Research, and the International Eczema Council received sponsorship from AbbVie, Amgen, Asana Biosciences, Celgene, Chugai, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, LEO Pharma, Kyowa Kirin, Novartis, Pierre Fabre, Pfizer, Sanofi Genzyme, Regeneron Pharmaceuticals, Sienna and Valeant. Of the 16 authors, 13 disclosed financial ties to a wide range of pharmaceutical companies, including those listed above.

SOURCE: Alexander H et al. Br J Dermatol. 2019 Nov 1. doi: 10.1111/bjd.1864319.

Cynodon dactylon (also known as Indian doab, Bermuda grass, Bahama grass, and several other appellations) has been used in traditional Ayurvedic medicine to treat cutaneous diseases, fevers, and rheumatism,as well as a variety of chronic inflammatory conditions.^1,2 The Ayurvedic armamentarium is thought to be the most abundant source of botanically based drugs used to treat wounds.³ Unrelated to health concerns, with the possible exception of allergic reactions, C. dactylon – which originated in Africa, is widely dispersed in Europe, and became an invasive species in locations such as Bermuda – is also used on putting greens on golf courses in subtropical and tropical climates.⁴ This grass has been shown to be safe and effective for treating induced RA in rats.^1,2 Recent findings are encouraging in the area of wound healing.

Chemical constituents

Among the numerous ingredients contained in C. dactylon are proteins, carbohydrates, minerals, terpenoids, vitamin C, palmitic acid, and alkaloids.³ Other key phytoconstituents known to impart beneficial health effects that are present in the plant include flavonoids (such as apigenin and luteolin), carotenoids (such as beta-carotene and neoxanthin), phenolics, phytosterols, glycosides, saponins, and volatile oils.³ Given such components, it should not be surprising that C. dactylon has demonstrated antioxidant activity by scavenging the 2,2-diphenyl-1-picrylhydrazyl radical.³

Wound healing

Given the reputation of C. dactylon as an effective compound used in traditional medicine for wound healing as a hemostatic agent, Biswas et al. set out in 2017 to determine if they could provide scientific validation of the botanical as a viable wound-healing option. The investigators first undertook to compare a 15% ointment of the extract with a placebo control and the standard framycetin on full-thickness punch wounds in Wistar rats. Across all parameters, results for the C. dactylon–treated group far exceeded the control group and were comparable with the framycetin group. Subsequently, in a pilot clinical study, the researchers assessed the botanical ointment in a small cohort (n = 12) of men and women aged 65-75 years (n = 12) with chronic and complicated wounds. Half were treated with a topical C. dactylon ointment and half were treated with a topical framycetin sulfate ointment. Comparable effects were seen across the groups, with significant contraction of wounds and wound area noted, along with significant development of granulation and epithelial tissues. Hematologic parameters indicating improvement were comparable between the groups. The investigators concluded that all patients treated with C. dactylon healed successfully. They added that the antioxidant activity of the constituent phenolic acids and flavonoids in C. dactylon likely play a key role in conferring potent wound-healing effects by promoting collagenesis.³

In 2018, Perumal et al. created a collagen-silica biocomposite enriched with C. dactylon extract and studied its wound-healing potential in vitro and in vivo in comparison with collagen as well as collagen-silica scaffold controls. The investigators found that the stability of the enriched product surpassed that of native collagen by virtue of the intermolecular interactions between the botanical ingredient and collagen. In a full-thickness excision wound model using Wistar rats, the biocomposite was associated with more rapid healing than wounds treated with collagen and the scaffold control.⁵

Arthritis

In 2009, Sindhu et al. orally administered C. dactylon to rats after intradermally inducing arthritis. The induction produced inflammation, and a marked rise in the levels of inflammatory mediators, C-reactive protein, myeloperoxidase, and nitrite. Resultant oxidative stress was noted with substantial declines in the activity of catalase, superoxide dismutase, and glutathione peroxidase, as well as levels of glutathione, vitamins C and E, and an increase in lipid peroxidation. Administration of C. dactylon yielded substantial changes, with mitigation of the inflammatory response and oxidative stress as well as diminution of the arthritic response nearly to the baseline condition. The investigators concluded that the botanical agent clearly demonstrates potential to protect against arthritis.²

A subsequent study in rats by Bhangale and Acharya supported the use of C. dactylon for RA, as its oral administration was found safe at all dose levels (100, 200 and 400 mg/kg), with 400 mg/kg as the most effective at ameliorating hemoglobin and red blood cell levels and C-reactive protein, as well as lowering tumor necrosis factor–alpha. The authors also noted that the ethanolic extract of C. dactylon contained alkaloids, flavonoids, and glycosides, all of which are known to confer health benefits.¹

Allergy

In 2016, López-Matas et al. studied the profiles of sensitization to C. dactylon (as well as Phragmites communis) in subjects sensitized to grasses and evaluated cross-reactivity between these grasses as well as temperate ones. Patients received skin prick tests with a grass mixture, and 24 patients (80%) were found to have had positive results for C. dactylon (and 90% to P. communis). The researchers concluded that sensitization to these species appears to be engendered by allergens other than those present in sweet grasses.⁶

Mehta et al. reported in 2018 on their investigation of common allergens in Ambala, India, using intradermal tests in patients with asthma, allergic rhinitis, and eczema. The study included 100 patients over an 8-year period, with 197 allergens (50 types of pollen, 19 fungi, 17 insects, 14 types of dust, 6 kinds of animal dander, 7 varieties of fabric and feathers, 82 foods, dust mites, and parthenium) tested. Pollens (51%) were the major allergens, followed by foods (28.9%), insects (26.9%), fungi (12.6%), and dusts (6.7%). C. dactylon (5%) was among two other species ranking fourth among pollen allergens.⁷

Also that year, Sánchez et al. investigated whether growing conditions (rural vs. urban) might influence the nasal inflammatory response to C. dactylon among patients with allergic rhinitis. They observed that the urban extract provoked larger wheals, and more patients with rhinitis experienced a positive nasal challenge test than those administered the rural extract. The skin and nasal tests did not elicit reactions in healthy controls. The researchers reached the conclusion that growth of C. dactylon in an urban setting can produce alterations in the protein extract, with potential clinical ramifications for patients who experience allergic rhinitis.⁸

Conclusion

Regular readers of this column know of my interest in botanically sourced topical products. Such ingredients with an extensive history of traditional medical use are particularly compelling. Many of these compounds are found in the modern medical and dermatologic armamentaria. C. dactylon does boast a track record of use in Ayurvedic medicine. However, there is a paucity of modern research at the present time. While there are concerns about its allergenicity, some encouraging results have been seen in relation to RA and wound healing. Much more research is needed, though, before this botanical agent can be included feasibly for standard skin care.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems. Write to her at dermnews@mdedge.com.

References

1. Bhangale J, Acharya S. Pers. Indian J Exp Biol. 2014 Mar;52(3):215-22.

2. Sindhu G et al. Immunopharmacol Immunotoxicol. 2009;31(4):647-53.

3. Biswas TK et al. J Ethnopharmacol. 2017 Feb 2;197:128-37.

4. Reasor EH et al. Planta. 2016 Oct;244(4):761-73.

5. Perumal RK et al. Mater Sci Eng C Mater Biol Appl. 2018 Nov 1;92:297-306.

6. López-Matas MA et al. J Investig Allergol Clin Immunol. 2016;26(5):295-303.

7. Mehta D et al. Indian J Dermatol. 2018 Jul-Aug;63(4):311-6.

8. Sánchez J et al. Allergy Rhinol (Providence). 2018 Dec 17;9:2152656718815870.

Cynodon dactylon (also known as Indian doab, Bermuda grass, Bahama grass, and several other appellations) has been used in traditional Ayurvedic medicine to treat cutaneous diseases, fevers, and rheumatism,as well as a variety of chronic inflammatory conditions.^1,2 The Ayurvedic armamentarium is thought to be the most abundant source of botanically based drugs used to treat wounds.³ Unrelated to health concerns, with the possible exception of allergic reactions, C. dactylon – which originated in Africa, is widely dispersed in Europe, and became an invasive species in locations such as Bermuda – is also used on putting greens on golf courses in subtropical and tropical climates.⁴ This grass has been shown to be safe and effective for treating induced RA in rats.^1,2 Recent findings are encouraging in the area of wound healing.

Chemical constituents

Among the numerous ingredients contained in C. dactylon are proteins, carbohydrates, minerals, terpenoids, vitamin C, palmitic acid, and alkaloids.³ Other key phytoconstituents known to impart beneficial health effects that are present in the plant include flavonoids (such as apigenin and luteolin), carotenoids (such as beta-carotene and neoxanthin), phenolics, phytosterols, glycosides, saponins, and volatile oils.³ Given such components, it should not be surprising that C. dactylon has demonstrated antioxidant activity by scavenging the 2,2-diphenyl-1-picrylhydrazyl radical.³

Wound healing

Given the reputation of C. dactylon as an effective compound used in traditional medicine for wound healing as a hemostatic agent, Biswas et al. set out in 2017 to determine if they could provide scientific validation of the botanical as a viable wound-healing option. The investigators first undertook to compare a 15% ointment of the extract with a placebo control and the standard framycetin on full-thickness punch wounds in Wistar rats. Across all parameters, results for the C. dactylon–treated group far exceeded the control group and were comparable with the framycetin group. Subsequently, in a pilot clinical study, the researchers assessed the botanical ointment in a small cohort (n = 12) of men and women aged 65-75 years (n = 12) with chronic and complicated wounds. Half were treated with a topical C. dactylon ointment and half were treated with a topical framycetin sulfate ointment. Comparable effects were seen across the groups, with significant contraction of wounds and wound area noted, along with significant development of granulation and epithelial tissues. Hematologic parameters indicating improvement were comparable between the groups. The investigators concluded that all patients treated with C. dactylon healed successfully. They added that the antioxidant activity of the constituent phenolic acids and flavonoids in C. dactylon likely play a key role in conferring potent wound-healing effects by promoting collagenesis.³

In 2018, Perumal et al. created a collagen-silica biocomposite enriched with C. dactylon extract and studied its wound-healing potential in vitro and in vivo in comparison with collagen as well as collagen-silica scaffold controls. The investigators found that the stability of the enriched product surpassed that of native collagen by virtue of the intermolecular interactions between the botanical ingredient and collagen. In a full-thickness excision wound model using Wistar rats, the biocomposite was associated with more rapid healing than wounds treated with collagen and the scaffold control.⁵

Arthritis

In 2009, Sindhu et al. orally administered C. dactylon to rats after intradermally inducing arthritis. The induction produced inflammation, and a marked rise in the levels of inflammatory mediators, C-reactive protein, myeloperoxidase, and nitrite. Resultant oxidative stress was noted with substantial declines in the activity of catalase, superoxide dismutase, and glutathione peroxidase, as well as levels of glutathione, vitamins C and E, and an increase in lipid peroxidation. Administration of C. dactylon yielded substantial changes, with mitigation of the inflammatory response and oxidative stress as well as diminution of the arthritic response nearly to the baseline condition. The investigators concluded that the botanical agent clearly demonstrates potential to protect against arthritis.²

A subsequent study in rats by Bhangale and Acharya supported the use of C. dactylon for RA, as its oral administration was found safe at all dose levels (100, 200 and 400 mg/kg), with 400 mg/kg as the most effective at ameliorating hemoglobin and red blood cell levels and C-reactive protein, as well as lowering tumor necrosis factor–alpha. The authors also noted that the ethanolic extract of C. dactylon contained alkaloids, flavonoids, and glycosides, all of which are known to confer health benefits.¹

Allergy

In 2016, López-Matas et al. studied the profiles of sensitization to C. dactylon (as well as Phragmites communis) in subjects sensitized to grasses and evaluated cross-reactivity between these grasses as well as temperate ones. Patients received skin prick tests with a grass mixture, and 24 patients (80%) were found to have had positive results for C. dactylon (and 90% to P. communis). The researchers concluded that sensitization to these species appears to be engendered by allergens other than those present in sweet grasses.⁶

Mehta et al. reported in 2018 on their investigation of common allergens in Ambala, India, using intradermal tests in patients with asthma, allergic rhinitis, and eczema. The study included 100 patients over an 8-year period, with 197 allergens (50 types of pollen, 19 fungi, 17 insects, 14 types of dust, 6 kinds of animal dander, 7 varieties of fabric and feathers, 82 foods, dust mites, and parthenium) tested. Pollens (51%) were the major allergens, followed by foods (28.9%), insects (26.9%), fungi (12.6%), and dusts (6.7%). C. dactylon (5%) was among two other species ranking fourth among pollen allergens.⁷

Also that year, Sánchez et al. investigated whether growing conditions (rural vs. urban) might influence the nasal inflammatory response to C. dactylon among patients with allergic rhinitis. They observed that the urban extract provoked larger wheals, and more patients with rhinitis experienced a positive nasal challenge test than those administered the rural extract. The skin and nasal tests did not elicit reactions in healthy controls. The researchers reached the conclusion that growth of C. dactylon in an urban setting can produce alterations in the protein extract, with potential clinical ramifications for patients who experience allergic rhinitis.⁸

Conclusion

Regular readers of this column know of my interest in botanically sourced topical products. Such ingredients with an extensive history of traditional medical use are particularly compelling. Many of these compounds are found in the modern medical and dermatologic armamentaria. C. dactylon does boast a track record of use in Ayurvedic medicine. However, there is a paucity of modern research at the present time. While there are concerns about its allergenicity, some encouraging results have been seen in relation to RA and wound healing. Much more research is needed, though, before this botanical agent can be included feasibly for standard skin care.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems. Write to her at dermnews@mdedge.com.

References

1. Bhangale J, Acharya S. Pers. Indian J Exp Biol. 2014 Mar;52(3):215-22.

2. Sindhu G et al. Immunopharmacol Immunotoxicol. 2009;31(4):647-53.

3. Biswas TK et al. J Ethnopharmacol. 2017 Feb 2;197:128-37.

4. Reasor EH et al. Planta. 2016 Oct;244(4):761-73.

5. Perumal RK et al. Mater Sci Eng C Mater Biol Appl. 2018 Nov 1;92:297-306.

6. López-Matas MA et al. J Investig Allergol Clin Immunol. 2016;26(5):295-303.

7. Mehta D et al. Indian J Dermatol. 2018 Jul-Aug;63(4):311-6.

8. Sánchez J et al. Allergy Rhinol (Providence). 2018 Dec 17;9:2152656718815870.

Cynodon dactylon (also known as Indian doab, Bermuda grass, Bahama grass, and several other appellations) has been used in traditional Ayurvedic medicine to treat cutaneous diseases, fevers, and rheumatism,as well as a variety of chronic inflammatory conditions.^1,2 The Ayurvedic armamentarium is thought to be the most abundant source of botanically based drugs used to treat wounds.³ Unrelated to health concerns, with the possible exception of allergic reactions, C. dactylon – which originated in Africa, is widely dispersed in Europe, and became an invasive species in locations such as Bermuda – is also used on putting greens on golf courses in subtropical and tropical climates.⁴ This grass has been shown to be safe and effective for treating induced RA in rats.^1,2 Recent findings are encouraging in the area of wound healing.

Chemical constituents

Among the numerous ingredients contained in C. dactylon are proteins, carbohydrates, minerals, terpenoids, vitamin C, palmitic acid, and alkaloids.³ Other key phytoconstituents known to impart beneficial health effects that are present in the plant include flavonoids (such as apigenin and luteolin), carotenoids (such as beta-carotene and neoxanthin), phenolics, phytosterols, glycosides, saponins, and volatile oils.³ Given such components, it should not be surprising that C. dactylon has demonstrated antioxidant activity by scavenging the 2,2-diphenyl-1-picrylhydrazyl radical.³

Wound healing

Given the reputation of C. dactylon as an effective compound used in traditional medicine for wound healing as a hemostatic agent, Biswas et al. set out in 2017 to determine if they could provide scientific validation of the botanical as a viable wound-healing option. The investigators first undertook to compare a 15% ointment of the extract with a placebo control and the standard framycetin on full-thickness punch wounds in Wistar rats. Across all parameters, results for the C. dactylon–treated group far exceeded the control group and were comparable with the framycetin group. Subsequently, in a pilot clinical study, the researchers assessed the botanical ointment in a small cohort (n = 12) of men and women aged 65-75 years (n = 12) with chronic and complicated wounds. Half were treated with a topical C. dactylon ointment and half were treated with a topical framycetin sulfate ointment. Comparable effects were seen across the groups, with significant contraction of wounds and wound area noted, along with significant development of granulation and epithelial tissues. Hematologic parameters indicating improvement were comparable between the groups. The investigators concluded that all patients treated with C. dactylon healed successfully. They added that the antioxidant activity of the constituent phenolic acids and flavonoids in C. dactylon likely play a key role in conferring potent wound-healing effects by promoting collagenesis.³

In 2018, Perumal et al. created a collagen-silica biocomposite enriched with C. dactylon extract and studied its wound-healing potential in vitro and in vivo in comparison with collagen as well as collagen-silica scaffold controls. The investigators found that the stability of the enriched product surpassed that of native collagen by virtue of the intermolecular interactions between the botanical ingredient and collagen. In a full-thickness excision wound model using Wistar rats, the biocomposite was associated with more rapid healing than wounds treated with collagen and the scaffold control.⁵

Arthritis

In 2009, Sindhu et al. orally administered C. dactylon to rats after intradermally inducing arthritis. The induction produced inflammation, and a marked rise in the levels of inflammatory mediators, C-reactive protein, myeloperoxidase, and nitrite. Resultant oxidative stress was noted with substantial declines in the activity of catalase, superoxide dismutase, and glutathione peroxidase, as well as levels of glutathione, vitamins C and E, and an increase in lipid peroxidation. Administration of C. dactylon yielded substantial changes, with mitigation of the inflammatory response and oxidative stress as well as diminution of the arthritic response nearly to the baseline condition. The investigators concluded that the botanical agent clearly demonstrates potential to protect against arthritis.²

A subsequent study in rats by Bhangale and Acharya supported the use of C. dactylon for RA, as its oral administration was found safe at all dose levels (100, 200 and 400 mg/kg), with 400 mg/kg as the most effective at ameliorating hemoglobin and red blood cell levels and C-reactive protein, as well as lowering tumor necrosis factor–alpha. The authors also noted that the ethanolic extract of C. dactylon contained alkaloids, flavonoids, and glycosides, all of which are known to confer health benefits.¹

Allergy

In 2016, López-Matas et al. studied the profiles of sensitization to C. dactylon (as well as Phragmites communis) in subjects sensitized to grasses and evaluated cross-reactivity between these grasses as well as temperate ones. Patients received skin prick tests with a grass mixture, and 24 patients (80%) were found to have had positive results for C. dactylon (and 90% to P. communis). The researchers concluded that sensitization to these species appears to be engendered by allergens other than those present in sweet grasses.⁶

Mehta et al. reported in 2018 on their investigation of common allergens in Ambala, India, using intradermal tests in patients with asthma, allergic rhinitis, and eczema. The study included 100 patients over an 8-year period, with 197 allergens (50 types of pollen, 19 fungi, 17 insects, 14 types of dust, 6 kinds of animal dander, 7 varieties of fabric and feathers, 82 foods, dust mites, and parthenium) tested. Pollens (51%) were the major allergens, followed by foods (28.9%), insects (26.9%), fungi (12.6%), and dusts (6.7%). C. dactylon (5%) was among two other species ranking fourth among pollen allergens.⁷

Also that year, Sánchez et al. investigated whether growing conditions (rural vs. urban) might influence the nasal inflammatory response to C. dactylon among patients with allergic rhinitis. They observed that the urban extract provoked larger wheals, and more patients with rhinitis experienced a positive nasal challenge test than those administered the rural extract. The skin and nasal tests did not elicit reactions in healthy controls. The researchers reached the conclusion that growth of C. dactylon in an urban setting can produce alterations in the protein extract, with potential clinical ramifications for patients who experience allergic rhinitis.⁸

Conclusion

Regular readers of this column know of my interest in botanically sourced topical products. Such ingredients with an extensive history of traditional medical use are particularly compelling. Many of these compounds are found in the modern medical and dermatologic armamentaria. C. dactylon does boast a track record of use in Ayurvedic medicine. However, there is a paucity of modern research at the present time. While there are concerns about its allergenicity, some encouraging results have been seen in relation to RA and wound healing. Much more research is needed, though, before this botanical agent can be included feasibly for standard skin care.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems. Write to her at dermnews@mdedge.com.

References

1. Bhangale J, Acharya S. Pers. Indian J Exp Biol. 2014 Mar;52(3):215-22.

2. Sindhu G et al. Immunopharmacol Immunotoxicol. 2009;31(4):647-53.

3. Biswas TK et al. J Ethnopharmacol. 2017 Feb 2;197:128-37.

4. Reasor EH et al. Planta. 2016 Oct;244(4):761-73.

5. Perumal RK et al. Mater Sci Eng C Mater Biol Appl. 2018 Nov 1;92:297-306.

6. López-Matas MA et al. J Investig Allergol Clin Immunol. 2016;26(5):295-303.

7. Mehta D et al. Indian J Dermatol. 2018 Jul-Aug;63(4):311-6.

8. Sánchez J et al. Allergy Rhinol (Providence). 2018 Dec 17;9:2152656718815870.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

A study using a new definition of early chronic obstructive pulmonary disease (COPD) has found that about 15% of Danish smokers under the age of 50 years meet the criteria.

The population-based cohort looked at individuals who had been exposed to at least 10 pack-years, and defined early COPD as the ratio of forced expiratory volume to forced vital capacity being less than the lower limit of normal (FEV₁/FVC less than LLN). The definition of early COPD, published in 2018 (Am J Resp and Crit Care Med. 2018;197:1540-51), also included the presence of abnormalities on a CT scan or a decline in FEV₁ (greater than 60 mL/year) that is accelerated relative to FVC, but the new population study did not include the latter two criteria.

The researchers, under corresponding author Peter Lange, MD, of the University of Copenhagen found that those with early COPD were more likely to have chronic respiratory symptoms, severe impairment of lung function, acute respirator hospitalization, and early mortality at baseline and at follow-up. The work was published in the American Journal of Respiratory and Critical Care Medicine.

“To dig through the smokers and try to figure out which smokers are more at risk than other smokers is probably the best way to summarize what they’ve done here,” said Robert Reed, MD, from the University of Maryland, Baltimore, in an interview. However, he added that he would like to see the research extended to an even younger population, as well as nonsmokers. “We don’t need all of this information to tell us that smoking is bad. I think nonsmokers would be really interesting – creating a definition of COPD that excludes patients that meet the usual definition for COPD would be of potential interest,” added Dr. Reed, who was not involved in the study.

Using a cohort of 105,630 randomly selected individuals from Danish nationwide health registries, the study identified 8,064 individuals aged under 50 years with 10 or more pack-years of tobacco exposure. In this group, 1,175 (15%) had early COPD, of whom 58% were current smokers. The cohort of smokers was followed for up to 14.4 years. Multivariate analyses found that those with early COPD, compared with smokers without COPD, were at substantially greater risk of acute obstructive lung disease hospitalization (hazard ratio, 6.42; 95% confidence interval, 3.39-12.2), acute pneumonia hospitalization (HR, 2.03; 95% CI, 1.43-2.88), and all-cause mortality (HR, 1.79; 95% CI, 1.28-2.52).

There is value in gaining a better understanding of which smokers are at greatest risk of COPD down the line, but data on younger people, even 30-year-olds, could guide therapeutic decisions when and if new drugs that can alter the state of the disease become available. Focusing more on younger, high-risk patients could also be used to create greater incentives to quit smoking, though Dr. Reed has mixed feelings even about that. “What if we identified 15% of smokers that are at risk of COPD, and the other 85% say, ‘I’ll keep smoking,’ and they fall over dead from a heart attack?” said Dr. Reed, noting that smoking has a wide range of known risks. “They should all stop,” he added.

The study also captures a wide range of patients, from some with early disease that will likely progress to COPD later in life along with some who already developed full-blown COPD in, for example, their early 40s. “Those are very different patients and to lump them together is potentially problematic,” said Dr. Reed. More granulated data could potentially inform more personalized medicine, and the discovery and verification of genetic risk factors.

Nevertheless, Dr. Reed expects the data to move the field forward. “They created a nice, rich database that I think will generate a lot more analysis and discussion.”

The study was funded by the Lundbeck Foundation. One of the authors has received support from the National Institute for Health Research Manchester (England) Biomedical Research Centre. Dr. Reed has no relevant financial disclosures.

SOURCE: Colak Y et al. Am J Resp Crit Care Med. 2019 Nov 26. doi: 10.1164/rccm.201908-1644OC

A study using a new definition of early chronic obstructive pulmonary disease (COPD) has found that about 15% of Danish smokers under the age of 50 years meet the criteria.

The population-based cohort looked at individuals who had been exposed to at least 10 pack-years, and defined early COPD as the ratio of forced expiratory volume to forced vital capacity being less than the lower limit of normal (FEV₁/FVC less than LLN). The definition of early COPD, published in 2018 (Am J Resp and Crit Care Med. 2018;197:1540-51), also included the presence of abnormalities on a CT scan or a decline in FEV₁ (greater than 60 mL/year) that is accelerated relative to FVC, but the new population study did not include the latter two criteria.

The researchers, under corresponding author Peter Lange, MD, of the University of Copenhagen found that those with early COPD were more likely to have chronic respiratory symptoms, severe impairment of lung function, acute respirator hospitalization, and early mortality at baseline and at follow-up. The work was published in the American Journal of Respiratory and Critical Care Medicine.

“To dig through the smokers and try to figure out which smokers are more at risk than other smokers is probably the best way to summarize what they’ve done here,” said Robert Reed, MD, from the University of Maryland, Baltimore, in an interview. However, he added that he would like to see the research extended to an even younger population, as well as nonsmokers. “We don’t need all of this information to tell us that smoking is bad. I think nonsmokers would be really interesting – creating a definition of COPD that excludes patients that meet the usual definition for COPD would be of potential interest,” added Dr. Reed, who was not involved in the study.

Using a cohort of 105,630 randomly selected individuals from Danish nationwide health registries, the study identified 8,064 individuals aged under 50 years with 10 or more pack-years of tobacco exposure. In this group, 1,175 (15%) had early COPD, of whom 58% were current smokers. The cohort of smokers was followed for up to 14.4 years. Multivariate analyses found that those with early COPD, compared with smokers without COPD, were at substantially greater risk of acute obstructive lung disease hospitalization (hazard ratio, 6.42; 95% confidence interval, 3.39-12.2), acute pneumonia hospitalization (HR, 2.03; 95% CI, 1.43-2.88), and all-cause mortality (HR, 1.79; 95% CI, 1.28-2.52).

There is value in gaining a better understanding of which smokers are at greatest risk of COPD down the line, but data on younger people, even 30-year-olds, could guide therapeutic decisions when and if new drugs that can alter the state of the disease become available. Focusing more on younger, high-risk patients could also be used to create greater incentives to quit smoking, though Dr. Reed has mixed feelings even about that. “What if we identified 15% of smokers that are at risk of COPD, and the other 85% say, ‘I’ll keep smoking,’ and they fall over dead from a heart attack?” said Dr. Reed, noting that smoking has a wide range of known risks. “They should all stop,” he added.

The study also captures a wide range of patients, from some with early disease that will likely progress to COPD later in life along with some who already developed full-blown COPD in, for example, their early 40s. “Those are very different patients and to lump them together is potentially problematic,” said Dr. Reed. More granulated data could potentially inform more personalized medicine, and the discovery and verification of genetic risk factors.

Nevertheless, Dr. Reed expects the data to move the field forward. “They created a nice, rich database that I think will generate a lot more analysis and discussion.”

The study was funded by the Lundbeck Foundation. One of the authors has received support from the National Institute for Health Research Manchester (England) Biomedical Research Centre. Dr. Reed has no relevant financial disclosures.

SOURCE: Colak Y et al. Am J Resp Crit Care Med. 2019 Nov 26. doi: 10.1164/rccm.201908-1644OC

A study using a new definition of early chronic obstructive pulmonary disease (COPD) has found that about 15% of Danish smokers under the age of 50 years meet the criteria.

The population-based cohort looked at individuals who had been exposed to at least 10 pack-years, and defined early COPD as the ratio of forced expiratory volume to forced vital capacity being less than the lower limit of normal (FEV₁/FVC less than LLN). The definition of early COPD, published in 2018 (Am J Resp and Crit Care Med. 2018;197:1540-51), also included the presence of abnormalities on a CT scan or a decline in FEV₁ (greater than 60 mL/year) that is accelerated relative to FVC, but the new population study did not include the latter two criteria.

The researchers, under corresponding author Peter Lange, MD, of the University of Copenhagen found that those with early COPD were more likely to have chronic respiratory symptoms, severe impairment of lung function, acute respirator hospitalization, and early mortality at baseline and at follow-up. The work was published in the American Journal of Respiratory and Critical Care Medicine.

“To dig through the smokers and try to figure out which smokers are more at risk than other smokers is probably the best way to summarize what they’ve done here,” said Robert Reed, MD, from the University of Maryland, Baltimore, in an interview. However, he added that he would like to see the research extended to an even younger population, as well as nonsmokers. “We don’t need all of this information to tell us that smoking is bad. I think nonsmokers would be really interesting – creating a definition of COPD that excludes patients that meet the usual definition for COPD would be of potential interest,” added Dr. Reed, who was not involved in the study.

Using a cohort of 105,630 randomly selected individuals from Danish nationwide health registries, the study identified 8,064 individuals aged under 50 years with 10 or more pack-years of tobacco exposure. In this group, 1,175 (15%) had early COPD, of whom 58% were current smokers. The cohort of smokers was followed for up to 14.4 years. Multivariate analyses found that those with early COPD, compared with smokers without COPD, were at substantially greater risk of acute obstructive lung disease hospitalization (hazard ratio, 6.42; 95% confidence interval, 3.39-12.2), acute pneumonia hospitalization (HR, 2.03; 95% CI, 1.43-2.88), and all-cause mortality (HR, 1.79; 95% CI, 1.28-2.52).

There is value in gaining a better understanding of which smokers are at greatest risk of COPD down the line, but data on younger people, even 30-year-olds, could guide therapeutic decisions when and if new drugs that can alter the state of the disease become available. Focusing more on younger, high-risk patients could also be used to create greater incentives to quit smoking, though Dr. Reed has mixed feelings even about that. “What if we identified 15% of smokers that are at risk of COPD, and the other 85% say, ‘I’ll keep smoking,’ and they fall over dead from a heart attack?” said Dr. Reed, noting that smoking has a wide range of known risks. “They should all stop,” he added.

The study also captures a wide range of patients, from some with early disease that will likely progress to COPD later in life along with some who already developed full-blown COPD in, for example, their early 40s. “Those are very different patients and to lump them together is potentially problematic,” said Dr. Reed. More granulated data could potentially inform more personalized medicine, and the discovery and verification of genetic risk factors.

Nevertheless, Dr. Reed expects the data to move the field forward. “They created a nice, rich database that I think will generate a lot more analysis and discussion.”

The study was funded by the Lundbeck Foundation. One of the authors has received support from the National Institute for Health Research Manchester (England) Biomedical Research Centre. Dr. Reed has no relevant financial disclosures.

SOURCE: Colak Y et al. Am J Resp Crit Care Med. 2019 Nov 26. doi: 10.1164/rccm.201908-1644OC

Physicians treating transgender patients – in particular, transgender men who were born female – are faced with a confusing process when prescribing isotretinoin for severe acne.

A research letter published in the Journal of the American Academy of Dermatology reports that half of dermatologists surveyed reported having encountered difficulties classifying a transgender patient in iPLEDGE, the risk-management registry established to prevent female patients from starting isotretinoin therapy while pregnant or from becoming pregnant while exposed to the teratogenic medication.

Nearly 90% of respondents favored changing the current gender-specific categories in iPLEDGE to gender-neutral ones, classifying patients only by whether or not they have the ability to become pregnant.

For their research, Courtney Ensslin, MD, of the department of dermatology at Johns Hopkins University, Baltimore, and colleagues, distributed an 18-point questionnaire to 385 members of the Association of Professors of Dermatology that included questions assessing clinicians’ knowledge about the reproductive potential of transgender men and women. The recipients were asked to distribute it to faculty members and residents. The survey also described three clinical scenarios in which the physician needed to decide how to register a patient in iPLEDGE. The clinicians largely opted to class transgender men as women with childbearing potential, even if the category conflicted with the patient’s self-identified and legally recognized male gender.

Of the 136 clinicians who responded, 60% were women, almost half were aged 25-34 years. About 12% of respondents said the complexities of prescribing isotretinoin to a transgender patient led them to choose alternative therapies. And the survey revealed some gaps on providers’ general literacy on transgender patients and their reproductive potential. For example, fewer than a third of respondents answered correctly as to whether testosterone treatment decreases the quality and development of an immature ovum.

The researchers wrote that the survey results, while limited by a small sample of respondents that skewed toward younger women providers, suggest that “continued education on fertility in transgender patients is needed because prescribers must fully understand each patient’s reproductive potential to safely prescribe teratogenic medications.” Additionally, they pointed out, the results support ongoing efforts to reform iPLEDGE, as the current categories “do not offer an inclusive approach to care for transgender patients.”

Earlier this year the American Academy of Dermatology issued a position statement that described a number of ongoing initiatives aimed at improving treatment for patients who are members of gender and sexual minorities. These included the “revision of the AAD position statement on isotretinoin to support a gender-neutral categorization model for [iPLEDGE] … based on child-bearing potential rather than on gender identity,” the statement said.

Dr. Ensslin and colleagues reported conflicts of interest related to their research. The study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health.

SOURCE: Ensslin C et al. J Am Acad Dermatol. 2019 Dec;81(6):1426-9.

Physicians treating transgender patients – in particular, transgender men who were born female – are faced with a confusing process when prescribing isotretinoin for severe acne.

A research letter published in the Journal of the American Academy of Dermatology reports that half of dermatologists surveyed reported having encountered difficulties classifying a transgender patient in iPLEDGE, the risk-management registry established to prevent female patients from starting isotretinoin therapy while pregnant or from becoming pregnant while exposed to the teratogenic medication.

Nearly 90% of respondents favored changing the current gender-specific categories in iPLEDGE to gender-neutral ones, classifying patients only by whether or not they have the ability to become pregnant.

For their research, Courtney Ensslin, MD, of the department of dermatology at Johns Hopkins University, Baltimore, and colleagues, distributed an 18-point questionnaire to 385 members of the Association of Professors of Dermatology that included questions assessing clinicians’ knowledge about the reproductive potential of transgender men and women. The recipients were asked to distribute it to faculty members and residents. The survey also described three clinical scenarios in which the physician needed to decide how to register a patient in iPLEDGE. The clinicians largely opted to class transgender men as women with childbearing potential, even if the category conflicted with the patient’s self-identified and legally recognized male gender.

Of the 136 clinicians who responded, 60% were women, almost half were aged 25-34 years. About 12% of respondents said the complexities of prescribing isotretinoin to a transgender patient led them to choose alternative therapies. And the survey revealed some gaps on providers’ general literacy on transgender patients and their reproductive potential. For example, fewer than a third of respondents answered correctly as to whether testosterone treatment decreases the quality and development of an immature ovum.

The researchers wrote that the survey results, while limited by a small sample of respondents that skewed toward younger women providers, suggest that “continued education on fertility in transgender patients is needed because prescribers must fully understand each patient’s reproductive potential to safely prescribe teratogenic medications.” Additionally, they pointed out, the results support ongoing efforts to reform iPLEDGE, as the current categories “do not offer an inclusive approach to care for transgender patients.”

Earlier this year the American Academy of Dermatology issued a position statement that described a number of ongoing initiatives aimed at improving treatment for patients who are members of gender and sexual minorities. These included the “revision of the AAD position statement on isotretinoin to support a gender-neutral categorization model for [iPLEDGE] … based on child-bearing potential rather than on gender identity,” the statement said.

Dr. Ensslin and colleagues reported conflicts of interest related to their research. The study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health.

SOURCE: Ensslin C et al. J Am Acad Dermatol. 2019 Dec;81(6):1426-9.

Physicians treating transgender patients – in particular, transgender men who were born female – are faced with a confusing process when prescribing isotretinoin for severe acne.

A research letter published in the Journal of the American Academy of Dermatology reports that half of dermatologists surveyed reported having encountered difficulties classifying a transgender patient in iPLEDGE, the risk-management registry established to prevent female patients from starting isotretinoin therapy while pregnant or from becoming pregnant while exposed to the teratogenic medication.

Nearly 90% of respondents favored changing the current gender-specific categories in iPLEDGE to gender-neutral ones, classifying patients only by whether or not they have the ability to become pregnant.

For their research, Courtney Ensslin, MD, of the department of dermatology at Johns Hopkins University, Baltimore, and colleagues, distributed an 18-point questionnaire to 385 members of the Association of Professors of Dermatology that included questions assessing clinicians’ knowledge about the reproductive potential of transgender men and women. The recipients were asked to distribute it to faculty members and residents. The survey also described three clinical scenarios in which the physician needed to decide how to register a patient in iPLEDGE. The clinicians largely opted to class transgender men as women with childbearing potential, even if the category conflicted with the patient’s self-identified and legally recognized male gender.

Of the 136 clinicians who responded, 60% were women, almost half were aged 25-34 years. About 12% of respondents said the complexities of prescribing isotretinoin to a transgender patient led them to choose alternative therapies. And the survey revealed some gaps on providers’ general literacy on transgender patients and their reproductive potential. For example, fewer than a third of respondents answered correctly as to whether testosterone treatment decreases the quality and development of an immature ovum.

The researchers wrote that the survey results, while limited by a small sample of respondents that skewed toward younger women providers, suggest that “continued education on fertility in transgender patients is needed because prescribers must fully understand each patient’s reproductive potential to safely prescribe teratogenic medications.” Additionally, they pointed out, the results support ongoing efforts to reform iPLEDGE, as the current categories “do not offer an inclusive approach to care for transgender patients.”

Earlier this year the American Academy of Dermatology issued a position statement that described a number of ongoing initiatives aimed at improving treatment for patients who are members of gender and sexual minorities. These included the “revision of the AAD position statement on isotretinoin to support a gender-neutral categorization model for [iPLEDGE] … based on child-bearing potential rather than on gender identity,” the statement said.

Dr. Ensslin and colleagues reported conflicts of interest related to their research. The study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health.

SOURCE: Ensslin C et al. J Am Acad Dermatol. 2019 Dec;81(6):1426-9.