Pharmacology

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

MADRID – The serious adverse events faced by asthma patients taking maintenance or rescue oral corticosteroids (OCS) might be avoidable if data from a Dutch study presented at the annual congress of the European Respiratory Society are representative of practice elsewhere.

“The main message from our study is that OCS overuse is common and unnecessary in the majority of asthma patients,” reported Katrien A.B. Eger, MD, Amsterdam University Medical Centre.

In this study, 5,002 patients on high doses of inhaled corticosteroids (ICS), defined as at least 500 mcg/day, were identified in a pharmacy database in the Netherlands. These patients were asked to complete a questionnaire to determine how many had severe asthma and had received rescue or maintenance OCS in the past year.

Drawing from the pharmacy database, it could be determined that 29% of the 2,312 patients who responded to the questionnaire were taking harmfully high doses of OCS as well as high doses of ICS. For this study, harmful exposure was defined as a cumulative intake of 420 mg of prednisone-equivalent OCS over a 1-year period. The median cumulative 1-year exposure, according to Dr. Eger, was 750 mg of prednisone equivalent.

In this population, the investigators then calculated ICS medication adherence based on prescription refills. In addition, a subset of this population was evaluated for inhaler technique.

On the basis of these calculations, 47.4% of patients with harmful OCS exposure were found not to be adherent to their prescribed ICS. Of those who were adherent, 53.9% were found not be taking their inhaled steroids appropriately,

When these numbers are put together, the data suggest “78.1% of high OCS users are either nonadherent or using poor inhalation techniques, which means there is a big potential for treatment optimization,” Dr. Eger said.

Yet even among the 21.9% who were adherent and using good inhaler technique, identifying a group who presumably require OCS for exacerbations, the study found that only 46.1% had been prescribed a biologic, which Dr. Eger considers an important steroid-sparing option. She conceded that many of those not on a biologic might not be candidates, but she believes this is another missed opportunity for reducing OCS exposure.

“In the Netherlands, we have very good access to health care, and biologics are available to anyone who needs them,” said Dr. Eger, explaining that access to these drugs is not a barrier.

The evidence overall is that not enough is being done to ensure that asthma patients are being protected from the risks of OCS, according to Dr. Eger. Citing evidence that adverse events associated with OCS begin with a cumulative lifetime prednisone-equivalent exposure of only 500 mg, she believes that clinicians should be more aggressive in intervening.

“We know that there are both acute and chronic complications associated with OCS that involve a range of organ systems,” Dr. Eger said. She listed osteoporosis, diabetes mellitus, hypertension, and adrenal insufficiency as examples. Rescue OCS, even if used sparingly, can drive risk of OCS complications attributable to the importance of cumulative exposure.

In the session where these data were presented, the moderator, Guy Brusselle, MD, professor of asthma and immunology, Ghent (Belgium) University, labeled them “important.” However, he quibbled with Dr. Eger’s assertion that biologics represent a major opportunity to reduce OCS exposure.

“By suggesting that biologics are not being used often enough, there is an assumption that all of these patients have type 2 inflammatory asthma,” Dr. Brusselle said. “I think it makes more sense to emphasize steroid-sparing strategies, not just biologics.”

Dr. Eger did not disagree, but she emphasized that steroid-sparing alternatives are just one strategy to reduce OCS exposure, and ensuring that patients are adherent to prescribed ICS therapies and are using them correctly might have an even greater impact.

Dr. Eger reports no potential conflicts of interest.

MADRID – The serious adverse events faced by asthma patients taking maintenance or rescue oral corticosteroids (OCS) might be avoidable if data from a Dutch study presented at the annual congress of the European Respiratory Society are representative of practice elsewhere.

“The main message from our study is that OCS overuse is common and unnecessary in the majority of asthma patients,” reported Katrien A.B. Eger, MD, Amsterdam University Medical Centre.

In this study, 5,002 patients on high doses of inhaled corticosteroids (ICS), defined as at least 500 mcg/day, were identified in a pharmacy database in the Netherlands. These patients were asked to complete a questionnaire to determine how many had severe asthma and had received rescue or maintenance OCS in the past year.

Drawing from the pharmacy database, it could be determined that 29% of the 2,312 patients who responded to the questionnaire were taking harmfully high doses of OCS as well as high doses of ICS. For this study, harmful exposure was defined as a cumulative intake of 420 mg of prednisone-equivalent OCS over a 1-year period. The median cumulative 1-year exposure, according to Dr. Eger, was 750 mg of prednisone equivalent.

In this population, the investigators then calculated ICS medication adherence based on prescription refills. In addition, a subset of this population was evaluated for inhaler technique.

On the basis of these calculations, 47.4% of patients with harmful OCS exposure were found not to be adherent to their prescribed ICS. Of those who were adherent, 53.9% were found not be taking their inhaled steroids appropriately,

When these numbers are put together, the data suggest “78.1% of high OCS users are either nonadherent or using poor inhalation techniques, which means there is a big potential for treatment optimization,” Dr. Eger said.

Yet even among the 21.9% who were adherent and using good inhaler technique, identifying a group who presumably require OCS for exacerbations, the study found that only 46.1% had been prescribed a biologic, which Dr. Eger considers an important steroid-sparing option. She conceded that many of those not on a biologic might not be candidates, but she believes this is another missed opportunity for reducing OCS exposure.

“In the Netherlands, we have very good access to health care, and biologics are available to anyone who needs them,” said Dr. Eger, explaining that access to these drugs is not a barrier.

The evidence overall is that not enough is being done to ensure that asthma patients are being protected from the risks of OCS, according to Dr. Eger. Citing evidence that adverse events associated with OCS begin with a cumulative lifetime prednisone-equivalent exposure of only 500 mg, she believes that clinicians should be more aggressive in intervening.

“We know that there are both acute and chronic complications associated with OCS that involve a range of organ systems,” Dr. Eger said. She listed osteoporosis, diabetes mellitus, hypertension, and adrenal insufficiency as examples. Rescue OCS, even if used sparingly, can drive risk of OCS complications attributable to the importance of cumulative exposure.

In the session where these data were presented, the moderator, Guy Brusselle, MD, professor of asthma and immunology, Ghent (Belgium) University, labeled them “important.” However, he quibbled with Dr. Eger’s assertion that biologics represent a major opportunity to reduce OCS exposure.

“By suggesting that biologics are not being used often enough, there is an assumption that all of these patients have type 2 inflammatory asthma,” Dr. Brusselle said. “I think it makes more sense to emphasize steroid-sparing strategies, not just biologics.”

Dr. Eger did not disagree, but she emphasized that steroid-sparing alternatives are just one strategy to reduce OCS exposure, and ensuring that patients are adherent to prescribed ICS therapies and are using them correctly might have an even greater impact.

Dr. Eger reports no potential conflicts of interest.

MADRID – The serious adverse events faced by asthma patients taking maintenance or rescue oral corticosteroids (OCS) might be avoidable if data from a Dutch study presented at the annual congress of the European Respiratory Society are representative of practice elsewhere.

“The main message from our study is that OCS overuse is common and unnecessary in the majority of asthma patients,” reported Katrien A.B. Eger, MD, Amsterdam University Medical Centre.

In this study, 5,002 patients on high doses of inhaled corticosteroids (ICS), defined as at least 500 mcg/day, were identified in a pharmacy database in the Netherlands. These patients were asked to complete a questionnaire to determine how many had severe asthma and had received rescue or maintenance OCS in the past year.

Drawing from the pharmacy database, it could be determined that 29% of the 2,312 patients who responded to the questionnaire were taking harmfully high doses of OCS as well as high doses of ICS. For this study, harmful exposure was defined as a cumulative intake of 420 mg of prednisone-equivalent OCS over a 1-year period. The median cumulative 1-year exposure, according to Dr. Eger, was 750 mg of prednisone equivalent.

In this population, the investigators then calculated ICS medication adherence based on prescription refills. In addition, a subset of this population was evaluated for inhaler technique.

On the basis of these calculations, 47.4% of patients with harmful OCS exposure were found not to be adherent to their prescribed ICS. Of those who were adherent, 53.9% were found not be taking their inhaled steroids appropriately,

When these numbers are put together, the data suggest “78.1% of high OCS users are either nonadherent or using poor inhalation techniques, which means there is a big potential for treatment optimization,” Dr. Eger said.

Yet even among the 21.9% who were adherent and using good inhaler technique, identifying a group who presumably require OCS for exacerbations, the study found that only 46.1% had been prescribed a biologic, which Dr. Eger considers an important steroid-sparing option. She conceded that many of those not on a biologic might not be candidates, but she believes this is another missed opportunity for reducing OCS exposure.

“In the Netherlands, we have very good access to health care, and biologics are available to anyone who needs them,” said Dr. Eger, explaining that access to these drugs is not a barrier.

The evidence overall is that not enough is being done to ensure that asthma patients are being protected from the risks of OCS, according to Dr. Eger. Citing evidence that adverse events associated with OCS begin with a cumulative lifetime prednisone-equivalent exposure of only 500 mg, she believes that clinicians should be more aggressive in intervening.

“We know that there are both acute and chronic complications associated with OCS that involve a range of organ systems,” Dr. Eger said. She listed osteoporosis, diabetes mellitus, hypertension, and adrenal insufficiency as examples. Rescue OCS, even if used sparingly, can drive risk of OCS complications attributable to the importance of cumulative exposure.

In the session where these data were presented, the moderator, Guy Brusselle, MD, professor of asthma and immunology, Ghent (Belgium) University, labeled them “important.” However, he quibbled with Dr. Eger’s assertion that biologics represent a major opportunity to reduce OCS exposure.

“By suggesting that biologics are not being used often enough, there is an assumption that all of these patients have type 2 inflammatory asthma,” Dr. Brusselle said. “I think it makes more sense to emphasize steroid-sparing strategies, not just biologics.”

Dr. Eger did not disagree, but she emphasized that steroid-sparing alternatives are just one strategy to reduce OCS exposure, and ensuring that patients are adherent to prescribed ICS therapies and are using them correctly might have an even greater impact.

Dr. Eger reports no potential conflicts of interest.

Gilead Sciences announced that the U.S. Food and Drug Administration approved a new drug combination, Descovy, for HIV preexposure prophylaxis (PrEP). The decision, backing the earlier recommendation of the FDA’s Antimicrobial Drugs Advisory Committee, was based upon results from DISCOVER, a pivotal, multiyear, global phase 3 clinical trial that evaluated the safety and efficacy of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25-mg tablets for PrEP, compared with Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300-mg tablets).

Olivier Le Moal/Getty Images

DISCOVER included more than 5,300 adult cisgender men who have sex with men or transgender women who have sex with men.

In the trial, Descovy achieved noninferiority to Truvada.

Descovy has a Boxed Warning in its U.S. product label regarding the risk of posttreatment acute exacerbation of hepatitis B, according to the company.

The Descovy label also includes a Boxed Warning regarding the risk of drug resistance with PrEP use in undiagnosed early HIV-1 infection. The effectiveness of Descovy for PrEP in individuals at risk of HIV-1 from receptive vaginal sex was not tested, and thus cisgender women at risk for infection from vaginal sex were not included in the population for which the drug was approved.

The Descovy label and safety information is available here.

The FDA version of the announcement is available here.

[email protected]

Gilead Sciences announced that the U.S. Food and Drug Administration approved a new drug combination, Descovy, for HIV preexposure prophylaxis (PrEP). The decision, backing the earlier recommendation of the FDA’s Antimicrobial Drugs Advisory Committee, was based upon results from DISCOVER, a pivotal, multiyear, global phase 3 clinical trial that evaluated the safety and efficacy of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25-mg tablets for PrEP, compared with Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300-mg tablets).

Olivier Le Moal/Getty Images

DISCOVER included more than 5,300 adult cisgender men who have sex with men or transgender women who have sex with men.

In the trial, Descovy achieved noninferiority to Truvada.

Descovy has a Boxed Warning in its U.S. product label regarding the risk of posttreatment acute exacerbation of hepatitis B, according to the company.

The Descovy label also includes a Boxed Warning regarding the risk of drug resistance with PrEP use in undiagnosed early HIV-1 infection. The effectiveness of Descovy for PrEP in individuals at risk of HIV-1 from receptive vaginal sex was not tested, and thus cisgender women at risk for infection from vaginal sex were not included in the population for which the drug was approved.

The Descovy label and safety information is available here.

The FDA version of the announcement is available here.

[email protected]

Gilead Sciences announced that the U.S. Food and Drug Administration approved a new drug combination, Descovy, for HIV preexposure prophylaxis (PrEP). The decision, backing the earlier recommendation of the FDA’s Antimicrobial Drugs Advisory Committee, was based upon results from DISCOVER, a pivotal, multiyear, global phase 3 clinical trial that evaluated the safety and efficacy of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25-mg tablets for PrEP, compared with Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300-mg tablets).

Olivier Le Moal/Getty Images

DISCOVER included more than 5,300 adult cisgender men who have sex with men or transgender women who have sex with men.

In the trial, Descovy achieved noninferiority to Truvada.

Descovy has a Boxed Warning in its U.S. product label regarding the risk of posttreatment acute exacerbation of hepatitis B, according to the company.

The Descovy label also includes a Boxed Warning regarding the risk of drug resistance with PrEP use in undiagnosed early HIV-1 infection. The effectiveness of Descovy for PrEP in individuals at risk of HIV-1 from receptive vaginal sex was not tested, and thus cisgender women at risk for infection from vaginal sex were not included in the population for which the drug was approved.

The Descovy label and safety information is available here.

The FDA version of the announcement is available here.

[email protected]

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.¹ Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.²

The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.

It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.³ A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.

Background

The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.

Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.

Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.

Methods

The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.

These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.

Results

The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.⁴ Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.

DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A_1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.

In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.

HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.

Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. ⁵ Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.

Discussion

These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.

Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.

Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.

Conclusion

The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.² The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.

Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.

The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.¹ Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.²

The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.

It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.³ A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.

Background

The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.

Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.

Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.

Methods

The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.

These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.

Results

The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.⁴ Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.

DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A_1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.

In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.

HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.

Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. ⁵ Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.

Discussion

These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.

Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.

Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.

Conclusion

The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.² The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.

Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.

The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.¹ Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.²

The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.

It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.³ A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.

Background

The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.

Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.

Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.

Methods

The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.

These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.

Results

The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.⁴ Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.

DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A_1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.

In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.

HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.

Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. ⁵ Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.

Discussion

These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.

Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.

Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.

Conclusion

The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.² The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.

Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.

Relatively few of the adverse health outcomes attributed to antidepressants are supported by convincing evidence, reported the authors of a systematic review of 45 meta-analyses.

The authors did find convincing evidence linking the use of antidepressants and suicide attempt or completion among people under age 19 years and use of the medication and autism risk among offspring. “However, the few [studies] with convincing evidence associations did not reflect causality, and none of them remained at the convincing evidence level after accounting for confounding by indication,” wrote Elena Dragioti, PhD, of the Pain and Rehabilitation Centre at Linköping (Sweden) University and coauthors. The study was published in JAMA Psychiatry.

Dr. Dragioti and coauthors undertook a systematic “umbrella review” grading the evidence from the 45 meta-analyses of 695 observational studies into the association between antidepressant use and the risk of adverse health outcomes. All the meta-analyses included a control group not exposed to antidepressants, with the exception of one that compared the risk of gastrointestinal bleeding between two classes of antidepressants.

They found 120 possible adverse health associations described in the meta-analyses, 61.7% of which related to maternal and pregnancy-related adverse health outcomes. Two-thirds of the adverse health outcome associations involved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

However, among the 120 adverse health associations, only three (2.5%) were supported by “convincing” evidence. One was the association between SSRIs and increased risk of suicide attempts and completion in children and adolescents. Convincing evidence also was found between any antidepressant use before pregnancy and autism spectrum disorder and between SSRI use during pregnancy and autism spectrum disorder. The evidence for the association with suicide risk was deemed high quality, but the two associations with autism spectrum disorder were only of moderate quality.

The authors commented that these findings needed to be considered when prescribing antidepressants in adolescents and children, particularly as another networked meta-analysis had found fluoxetine was the only antidepressant that worked better than placebo in children and adolescents. “In addition, the increased suicidality in children and adolescents who use antidepressants may be associated with the unsuccessful reduction of depressive symptoms in suicidal individuals rather than a direct result of antidepressant use,” they wrote.

The review found that 11 adverse health outcomes (9.2%) had “highly suggestive” evidence linking them to antidepressant use. These were ADHD in children, cataract development, severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fracture, and hip fracture.

Seven of those – ADHD in children, lower Apgar score, severe bleeding at any site, cataract development, osteoporotic features, preterm birth, and upper GI bleeding – had moderate-quality evidence. However, the authors noted that the effect sizes were small and had low prevalence.

The study also found highly suggestive evidence linking antidepressant use to a decreased risk of suicide attempts or completion in adults.

The authors said several of those adverse events in adults, such as GI bleeding and osteoporotic fractures, could be prevented with medication, so the advantages of antidepressant use in adults could outweigh the disadvantage of those preventable safety issues.

Twenty-one adverse health outcomes showed either suggestive, weak, or no evidence for their association with antidepressant use.

They also conducted a sensitivity analysis that limited the analysis to cohort studies, prospective cohort studies, studies that controlled for confounding by the treatment indication, and studies from North America. This showed that none of the associations for which there was originally deemed to be convincing evidence retained that same rank.

“Overall, the results showed that the association between antidepressant use and adverse health outcomes was not supported by robust evidence and that the underlying disease likely inflated the findings in a relevant way,” the authors wrote.

However, when they looked solely at prospective cohort studies, the association between preterm birth and use of any antidepressant was upgraded to having convincing evidence.

When the analysis focused on SSRIs only, the association with lower Apgar scores at 5 minutes also was upgraded to having convincing evidence. Similarly, the evidence for an association with preterm birth also was found to be convincing when the analysis was limited to other or mixed antidepressants.

Dr. Dragioti and coauthors cited several limitations, including the inability of some randomized, controlled trials to address adverse outcomes.

“Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases,” the authors wrote.

The study was funded by several entities, including the National Institute for Health Research’s Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Dr. Dragioti reported no disclosures. Four authors declared funding, consultancies, personal fees, royalties, or shares in the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Dragioti E et al. JAMA Psychiatry. 2019 Oct 2. doi: 10.1001/jamapsychiatry.2019.2859.

Relatively few of the adverse health outcomes attributed to antidepressants are supported by convincing evidence, reported the authors of a systematic review of 45 meta-analyses.

The authors did find convincing evidence linking the use of antidepressants and suicide attempt or completion among people under age 19 years and use of the medication and autism risk among offspring. “However, the few [studies] with convincing evidence associations did not reflect causality, and none of them remained at the convincing evidence level after accounting for confounding by indication,” wrote Elena Dragioti, PhD, of the Pain and Rehabilitation Centre at Linköping (Sweden) University and coauthors. The study was published in JAMA Psychiatry.

Dr. Dragioti and coauthors undertook a systematic “umbrella review” grading the evidence from the 45 meta-analyses of 695 observational studies into the association between antidepressant use and the risk of adverse health outcomes. All the meta-analyses included a control group not exposed to antidepressants, with the exception of one that compared the risk of gastrointestinal bleeding between two classes of antidepressants.

They found 120 possible adverse health associations described in the meta-analyses, 61.7% of which related to maternal and pregnancy-related adverse health outcomes. Two-thirds of the adverse health outcome associations involved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

However, among the 120 adverse health associations, only three (2.5%) were supported by “convincing” evidence. One was the association between SSRIs and increased risk of suicide attempts and completion in children and adolescents. Convincing evidence also was found between any antidepressant use before pregnancy and autism spectrum disorder and between SSRI use during pregnancy and autism spectrum disorder. The evidence for the association with suicide risk was deemed high quality, but the two associations with autism spectrum disorder were only of moderate quality.

The authors commented that these findings needed to be considered when prescribing antidepressants in adolescents and children, particularly as another networked meta-analysis had found fluoxetine was the only antidepressant that worked better than placebo in children and adolescents. “In addition, the increased suicidality in children and adolescents who use antidepressants may be associated with the unsuccessful reduction of depressive symptoms in suicidal individuals rather than a direct result of antidepressant use,” they wrote.

The review found that 11 adverse health outcomes (9.2%) had “highly suggestive” evidence linking them to antidepressant use. These were ADHD in children, cataract development, severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fracture, and hip fracture.

Seven of those – ADHD in children, lower Apgar score, severe bleeding at any site, cataract development, osteoporotic features, preterm birth, and upper GI bleeding – had moderate-quality evidence. However, the authors noted that the effect sizes were small and had low prevalence.

The study also found highly suggestive evidence linking antidepressant use to a decreased risk of suicide attempts or completion in adults.

The authors said several of those adverse events in adults, such as GI bleeding and osteoporotic fractures, could be prevented with medication, so the advantages of antidepressant use in adults could outweigh the disadvantage of those preventable safety issues.

Twenty-one adverse health outcomes showed either suggestive, weak, or no evidence for their association with antidepressant use.

They also conducted a sensitivity analysis that limited the analysis to cohort studies, prospective cohort studies, studies that controlled for confounding by the treatment indication, and studies from North America. This showed that none of the associations for which there was originally deemed to be convincing evidence retained that same rank.

“Overall, the results showed that the association between antidepressant use and adverse health outcomes was not supported by robust evidence and that the underlying disease likely inflated the findings in a relevant way,” the authors wrote.

However, when they looked solely at prospective cohort studies, the association between preterm birth and use of any antidepressant was upgraded to having convincing evidence.

When the analysis focused on SSRIs only, the association with lower Apgar scores at 5 minutes also was upgraded to having convincing evidence. Similarly, the evidence for an association with preterm birth also was found to be convincing when the analysis was limited to other or mixed antidepressants.

Dr. Dragioti and coauthors cited several limitations, including the inability of some randomized, controlled trials to address adverse outcomes.

“Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases,” the authors wrote.

The study was funded by several entities, including the National Institute for Health Research’s Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Dr. Dragioti reported no disclosures. Four authors declared funding, consultancies, personal fees, royalties, or shares in the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Dragioti E et al. JAMA Psychiatry. 2019 Oct 2. doi: 10.1001/jamapsychiatry.2019.2859.

Relatively few of the adverse health outcomes attributed to antidepressants are supported by convincing evidence, reported the authors of a systematic review of 45 meta-analyses.

The authors did find convincing evidence linking the use of antidepressants and suicide attempt or completion among people under age 19 years and use of the medication and autism risk among offspring. “However, the few [studies] with convincing evidence associations did not reflect causality, and none of them remained at the convincing evidence level after accounting for confounding by indication,” wrote Elena Dragioti, PhD, of the Pain and Rehabilitation Centre at Linköping (Sweden) University and coauthors. The study was published in JAMA Psychiatry.

Dr. Dragioti and coauthors undertook a systematic “umbrella review” grading the evidence from the 45 meta-analyses of 695 observational studies into the association between antidepressant use and the risk of adverse health outcomes. All the meta-analyses included a control group not exposed to antidepressants, with the exception of one that compared the risk of gastrointestinal bleeding between two classes of antidepressants.

They found 120 possible adverse health associations described in the meta-analyses, 61.7% of which related to maternal and pregnancy-related adverse health outcomes. Two-thirds of the adverse health outcome associations involved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

However, among the 120 adverse health associations, only three (2.5%) were supported by “convincing” evidence. One was the association between SSRIs and increased risk of suicide attempts and completion in children and adolescents. Convincing evidence also was found between any antidepressant use before pregnancy and autism spectrum disorder and between SSRI use during pregnancy and autism spectrum disorder. The evidence for the association with suicide risk was deemed high quality, but the two associations with autism spectrum disorder were only of moderate quality.

The authors commented that these findings needed to be considered when prescribing antidepressants in adolescents and children, particularly as another networked meta-analysis had found fluoxetine was the only antidepressant that worked better than placebo in children and adolescents. “In addition, the increased suicidality in children and adolescents who use antidepressants may be associated with the unsuccessful reduction of depressive symptoms in suicidal individuals rather than a direct result of antidepressant use,” they wrote.

The review found that 11 adverse health outcomes (9.2%) had “highly suggestive” evidence linking them to antidepressant use. These were ADHD in children, cataract development, severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fracture, and hip fracture.

Seven of those – ADHD in children, lower Apgar score, severe bleeding at any site, cataract development, osteoporotic features, preterm birth, and upper GI bleeding – had moderate-quality evidence. However, the authors noted that the effect sizes were small and had low prevalence.

The study also found highly suggestive evidence linking antidepressant use to a decreased risk of suicide attempts or completion in adults.

The authors said several of those adverse events in adults, such as GI bleeding and osteoporotic fractures, could be prevented with medication, so the advantages of antidepressant use in adults could outweigh the disadvantage of those preventable safety issues.

Twenty-one adverse health outcomes showed either suggestive, weak, or no evidence for their association with antidepressant use.

They also conducted a sensitivity analysis that limited the analysis to cohort studies, prospective cohort studies, studies that controlled for confounding by the treatment indication, and studies from North America. This showed that none of the associations for which there was originally deemed to be convincing evidence retained that same rank.

“Overall, the results showed that the association between antidepressant use and adverse health outcomes was not supported by robust evidence and that the underlying disease likely inflated the findings in a relevant way,” the authors wrote.

However, when they looked solely at prospective cohort studies, the association between preterm birth and use of any antidepressant was upgraded to having convincing evidence.

When the analysis focused on SSRIs only, the association with lower Apgar scores at 5 minutes also was upgraded to having convincing evidence. Similarly, the evidence for an association with preterm birth also was found to be convincing when the analysis was limited to other or mixed antidepressants.

Dr. Dragioti and coauthors cited several limitations, including the inability of some randomized, controlled trials to address adverse outcomes.

“Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases,” the authors wrote.

The study was funded by several entities, including the National Institute for Health Research’s Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Dr. Dragioti reported no disclosures. Four authors declared funding, consultancies, personal fees, royalties, or shares in the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Dragioti E et al. JAMA Psychiatry. 2019 Oct 2. doi: 10.1001/jamapsychiatry.2019.2859.

Heparin is the anticoagulant of choice when a rapid anticoagulant is indicated: Onset of action is immediate when administered IV as a bolus.¹ The major anticoagulant effect of heparin is mediated by heparin/antithrombin (AT) interaction. Heparin/AT inactivates factor IIa (thrombin) and factors Xa, IXa, XIa, and XIIa. Heparin is approved for multiple indications, such as venous thromboembolism (VTE) treatment and prophylaxis of medical and surgical patients; stroke prevention in atrial fibrillation (AF); acute coronary syndrome (ACS); vascular and cardiac surgeries; and various interventional procedures (eg, diagnostic angiography and percutaneous coronary intervention [PCI]). It also is used as an anticoagulant in blood transfusions, extracorporeal circulation, and for maintaining patency of central vascular access devices (CVADs).

About 60% of the crude heparin used to manufacture heparin in the US originates in China, derived from porcine mucosa. African swine fever, a contagious virus with no cure, has eliminated about 25% to 35% of China’s pig population, or about 150 million pigs. In July 2019, members of the US House of Representatives Committee on Energy and Commerce sent a letter to the US Food and Drug Administration asking for details on the potential impact of African swine fever on the supply of heparin.²

The US Department of Veterans Affairs (VA) heath care system is currently experiencing a shortage of heparin vials and syringes. It is unclear when resolution of this shortage will occur as it could resolve within several weeks or as late as January 2020.³ Although vials and syringes are the current products that are affected, it is possible the shortage may eventually include IV heparin bags as well.

Since the foremost objective of VA health care providers is to provide timely access to medications for veterans, strategies to conserve unfractionated heparin (UfH) must be used since it is a first-line therapy where few evidence-based alternatives exist. Conservation strategies may include drug rationing, therapeutic substitution, and compounding of needed products using the limited stock available in the pharmacy.⁴ It is important that all staff are educated on facility strategies in order to be familiar with alternatives and limit the potential for near misses, adverse events, and provider frustration.

In shortage situations, the VA-Pharmacy Benefits Management (PBM) defers decisions regarding drug preservation, processes to shift to viable alternatives, and the best practice for safe transitions to local facilities and their subject matter experts.⁵ At the VA Tennessee Valley Healthcare System, a 1A, tertiary, dual campus health care system, a pharmacy task force has formed to track drug shortages impacting the facility’s efficiencies and budgets. This group communicates with the Pharmacy and Therapeutics committee about potential risks to patient care and develops shortage briefs (following an SBAR [situation, background, assessment, recommendation] design) generally authored and championed by at least 1 clinical pharmacy specialist and supervising physicians who are field experts. Prior to dissemination, the SBAR undergoes a rapid peer-review process.

To date, VA PBM has not issued specific guidance on how pharmacists should proceed in case of a shortage. However, we recommend strategies that may be considered for implementation during a potential UfH shortage. For example, pharmacists can use therapeutic alternatives for which best available evidence suggests no disadvantage.⁴ The Table lists alternative agents according to indication and patient-specific considerations that may preclude use. Existing UfH products may also be used for drug compounding (eg, use current stock to provide an indicated aliquot) to meet the need of prioritized patients.⁴ In addition, we suggest prioritizing current UfH/heparinized saline for use for the following groups of patients⁴:

• Emergent/urgent cardiac surgery^1,6;
• Hemodialysis patients^1,7-9 for which the low-molecular-weight heparin (LMWH) dalteparin is deemed inappropriate or the patient is not monitored in the intensive care unit for regional citrate administration;
• VTE prophylaxis for patients with epidurals or chest tubes for which urgent invasive management may occur, recent cardiac or neurosurgery, or for patients with a creatine clearance < 15 mL/min or receiving hemodialysis^10-12;
• Vascular surgery (eg, limb ischemia) and interventions (eg, carotid stenting, endarterectomy)^13,14;
• Mesenteric ischemia (venous thrombosis) with a potential to proceed to laparotomy¹⁵;
• Critically ill patients with arterial lines for which normal saline is deemed inappropriate for line flushing¹⁶;
• Electrophysiology procedures (eg, AF ablation)¹⁷; and
• Contraindication to use of a long-acting alternative listed in the table or a medical necessity exists for using a rapidly reversible agent. Examples for this category include but are not limited to recent gastrointestinal bleeding, central nervous system lesion, and select neurologic diagnoses (eg, cerebral venous sinus thrombosis with hemorrhage, thrombus in vertebral basilar system or anterior circulation, intraparenchymal hemorrhage plus mechanical valve, medium to large cardioembolic stroke with intracardiac thrombus).

Conclusion

The UfH drug shortage represents a significant threat to public health and is a major challenge for US health care systems, including the Veterans Health Administration. Overreliance on a predominant source of crude heparin has affected multiple UfH manufacturers and products. Current alternatives to UfH include low-molecular-weight heparins, IV direct thrombin inhibitors, and SC fondaparinux, with selection supported by guidelines or evolving literature. However, the shortage has the potential to expand to other injectables, such as dalteparin and enoxaparin, and severely limit care for veterans. It is vital that clinicians rapidly address the current shortage by creating a plan to develop efficient and equitable access to UfH, continue to assess supply and update stakeholders, and select evidence-based alternatives while maintaining focus on efficacy and safety.

Acknowledgments

The authors thank Ashley Yost, PharmD, for her coordination of the multidisciplinary task force assigned to efficiently manage the heparin drug shortage. This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville, Tennessee.

Heparin is the anticoagulant of choice when a rapid anticoagulant is indicated: Onset of action is immediate when administered IV as a bolus.¹ The major anticoagulant effect of heparin is mediated by heparin/antithrombin (AT) interaction. Heparin/AT inactivates factor IIa (thrombin) and factors Xa, IXa, XIa, and XIIa. Heparin is approved for multiple indications, such as venous thromboembolism (VTE) treatment and prophylaxis of medical and surgical patients; stroke prevention in atrial fibrillation (AF); acute coronary syndrome (ACS); vascular and cardiac surgeries; and various interventional procedures (eg, diagnostic angiography and percutaneous coronary intervention [PCI]). It also is used as an anticoagulant in blood transfusions, extracorporeal circulation, and for maintaining patency of central vascular access devices (CVADs).

About 60% of the crude heparin used to manufacture heparin in the US originates in China, derived from porcine mucosa. African swine fever, a contagious virus with no cure, has eliminated about 25% to 35% of China’s pig population, or about 150 million pigs. In July 2019, members of the US House of Representatives Committee on Energy and Commerce sent a letter to the US Food and Drug Administration asking for details on the potential impact of African swine fever on the supply of heparin.²

The US Department of Veterans Affairs (VA) heath care system is currently experiencing a shortage of heparin vials and syringes. It is unclear when resolution of this shortage will occur as it could resolve within several weeks or as late as January 2020.³ Although vials and syringes are the current products that are affected, it is possible the shortage may eventually include IV heparin bags as well.

Since the foremost objective of VA health care providers is to provide timely access to medications for veterans, strategies to conserve unfractionated heparin (UfH) must be used since it is a first-line therapy where few evidence-based alternatives exist. Conservation strategies may include drug rationing, therapeutic substitution, and compounding of needed products using the limited stock available in the pharmacy.⁴ It is important that all staff are educated on facility strategies in order to be familiar with alternatives and limit the potential for near misses, adverse events, and provider frustration.

In shortage situations, the VA-Pharmacy Benefits Management (PBM) defers decisions regarding drug preservation, processes to shift to viable alternatives, and the best practice for safe transitions to local facilities and their subject matter experts.⁵ At the VA Tennessee Valley Healthcare System, a 1A, tertiary, dual campus health care system, a pharmacy task force has formed to track drug shortages impacting the facility’s efficiencies and budgets. This group communicates with the Pharmacy and Therapeutics committee about potential risks to patient care and develops shortage briefs (following an SBAR [situation, background, assessment, recommendation] design) generally authored and championed by at least 1 clinical pharmacy specialist and supervising physicians who are field experts. Prior to dissemination, the SBAR undergoes a rapid peer-review process.

To date, VA PBM has not issued specific guidance on how pharmacists should proceed in case of a shortage. However, we recommend strategies that may be considered for implementation during a potential UfH shortage. For example, pharmacists can use therapeutic alternatives for which best available evidence suggests no disadvantage.⁴ The Table lists alternative agents according to indication and patient-specific considerations that may preclude use. Existing UfH products may also be used for drug compounding (eg, use current stock to provide an indicated aliquot) to meet the need of prioritized patients.⁴ In addition, we suggest prioritizing current UfH/heparinized saline for use for the following groups of patients⁴:

• Emergent/urgent cardiac surgery^1,6;
• Hemodialysis patients^1,7-9 for which the low-molecular-weight heparin (LMWH) dalteparin is deemed inappropriate or the patient is not monitored in the intensive care unit for regional citrate administration;
• VTE prophylaxis for patients with epidurals or chest tubes for which urgent invasive management may occur, recent cardiac or neurosurgery, or for patients with a creatine clearance < 15 mL/min or receiving hemodialysis^10-12;
• Vascular surgery (eg, limb ischemia) and interventions (eg, carotid stenting, endarterectomy)^13,14;
• Mesenteric ischemia (venous thrombosis) with a potential to proceed to laparotomy¹⁵;
• Critically ill patients with arterial lines for which normal saline is deemed inappropriate for line flushing¹⁶;
• Electrophysiology procedures (eg, AF ablation)¹⁷; and
• Contraindication to use of a long-acting alternative listed in the table or a medical necessity exists for using a rapidly reversible agent. Examples for this category include but are not limited to recent gastrointestinal bleeding, central nervous system lesion, and select neurologic diagnoses (eg, cerebral venous sinus thrombosis with hemorrhage, thrombus in vertebral basilar system or anterior circulation, intraparenchymal hemorrhage plus mechanical valve, medium to large cardioembolic stroke with intracardiac thrombus).

Conclusion

The UfH drug shortage represents a significant threat to public health and is a major challenge for US health care systems, including the Veterans Health Administration. Overreliance on a predominant source of crude heparin has affected multiple UfH manufacturers and products. Current alternatives to UfH include low-molecular-weight heparins, IV direct thrombin inhibitors, and SC fondaparinux, with selection supported by guidelines or evolving literature. However, the shortage has the potential to expand to other injectables, such as dalteparin and enoxaparin, and severely limit care for veterans. It is vital that clinicians rapidly address the current shortage by creating a plan to develop efficient and equitable access to UfH, continue to assess supply and update stakeholders, and select evidence-based alternatives while maintaining focus on efficacy and safety.

Acknowledgments

The authors thank Ashley Yost, PharmD, for her coordination of the multidisciplinary task force assigned to efficiently manage the heparin drug shortage. This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville, Tennessee.

Heparin is the anticoagulant of choice when a rapid anticoagulant is indicated: Onset of action is immediate when administered IV as a bolus.¹ The major anticoagulant effect of heparin is mediated by heparin/antithrombin (AT) interaction. Heparin/AT inactivates factor IIa (thrombin) and factors Xa, IXa, XIa, and XIIa. Heparin is approved for multiple indications, such as venous thromboembolism (VTE) treatment and prophylaxis of medical and surgical patients; stroke prevention in atrial fibrillation (AF); acute coronary syndrome (ACS); vascular and cardiac surgeries; and various interventional procedures (eg, diagnostic angiography and percutaneous coronary intervention [PCI]). It also is used as an anticoagulant in blood transfusions, extracorporeal circulation, and for maintaining patency of central vascular access devices (CVADs).

About 60% of the crude heparin used to manufacture heparin in the US originates in China, derived from porcine mucosa. African swine fever, a contagious virus with no cure, has eliminated about 25% to 35% of China’s pig population, or about 150 million pigs. In July 2019, members of the US House of Representatives Committee on Energy and Commerce sent a letter to the US Food and Drug Administration asking for details on the potential impact of African swine fever on the supply of heparin.²

The US Department of Veterans Affairs (VA) heath care system is currently experiencing a shortage of heparin vials and syringes. It is unclear when resolution of this shortage will occur as it could resolve within several weeks or as late as January 2020.³ Although vials and syringes are the current products that are affected, it is possible the shortage may eventually include IV heparin bags as well.

Since the foremost objective of VA health care providers is to provide timely access to medications for veterans, strategies to conserve unfractionated heparin (UfH) must be used since it is a first-line therapy where few evidence-based alternatives exist. Conservation strategies may include drug rationing, therapeutic substitution, and compounding of needed products using the limited stock available in the pharmacy.⁴ It is important that all staff are educated on facility strategies in order to be familiar with alternatives and limit the potential for near misses, adverse events, and provider frustration.

In shortage situations, the VA-Pharmacy Benefits Management (PBM) defers decisions regarding drug preservation, processes to shift to viable alternatives, and the best practice for safe transitions to local facilities and their subject matter experts.⁵ At the VA Tennessee Valley Healthcare System, a 1A, tertiary, dual campus health care system, a pharmacy task force has formed to track drug shortages impacting the facility’s efficiencies and budgets. This group communicates with the Pharmacy and Therapeutics committee about potential risks to patient care and develops shortage briefs (following an SBAR [situation, background, assessment, recommendation] design) generally authored and championed by at least 1 clinical pharmacy specialist and supervising physicians who are field experts. Prior to dissemination, the SBAR undergoes a rapid peer-review process.

To date, VA PBM has not issued specific guidance on how pharmacists should proceed in case of a shortage. However, we recommend strategies that may be considered for implementation during a potential UfH shortage. For example, pharmacists can use therapeutic alternatives for which best available evidence suggests no disadvantage.⁴ The Table lists alternative agents according to indication and patient-specific considerations that may preclude use. Existing UfH products may also be used for drug compounding (eg, use current stock to provide an indicated aliquot) to meet the need of prioritized patients.⁴ In addition, we suggest prioritizing current UfH/heparinized saline for use for the following groups of patients⁴:

• Emergent/urgent cardiac surgery^1,6;
• Hemodialysis patients^1,7-9 for which the low-molecular-weight heparin (LMWH) dalteparin is deemed inappropriate or the patient is not monitored in the intensive care unit for regional citrate administration;
• VTE prophylaxis for patients with epidurals or chest tubes for which urgent invasive management may occur, recent cardiac or neurosurgery, or for patients with a creatine clearance < 15 mL/min or receiving hemodialysis^10-12;
• Vascular surgery (eg, limb ischemia) and interventions (eg, carotid stenting, endarterectomy)^13,14;
• Mesenteric ischemia (venous thrombosis) with a potential to proceed to laparotomy¹⁵;
• Critically ill patients with arterial lines for which normal saline is deemed inappropriate for line flushing¹⁶;
• Electrophysiology procedures (eg, AF ablation)¹⁷; and
• Contraindication to use of a long-acting alternative listed in the table or a medical necessity exists for using a rapidly reversible agent. Examples for this category include but are not limited to recent gastrointestinal bleeding, central nervous system lesion, and select neurologic diagnoses (eg, cerebral venous sinus thrombosis with hemorrhage, thrombus in vertebral basilar system or anterior circulation, intraparenchymal hemorrhage plus mechanical valve, medium to large cardioembolic stroke with intracardiac thrombus).

Conclusion

The UfH drug shortage represents a significant threat to public health and is a major challenge for US health care systems, including the Veterans Health Administration. Overreliance on a predominant source of crude heparin has affected multiple UfH manufacturers and products. Current alternatives to UfH include low-molecular-weight heparins, IV direct thrombin inhibitors, and SC fondaparinux, with selection supported by guidelines or evolving literature. However, the shortage has the potential to expand to other injectables, such as dalteparin and enoxaparin, and severely limit care for veterans. It is vital that clinicians rapidly address the current shortage by creating a plan to develop efficient and equitable access to UfH, continue to assess supply and update stakeholders, and select evidence-based alternatives while maintaining focus on efficacy and safety.

Acknowledgments

The authors thank Ashley Yost, PharmD, for her coordination of the multidisciplinary task force assigned to efficiently manage the heparin drug shortage. This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville, Tennessee.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – A similar overall risk of symptomatic hypoglycemia was observed with insulin degludec (Tresiba) and insulin glargine U300 (Toujeo) in the phase 3 CONCLUDE study data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

During a 36-week maintenance treatment period, the rate ratio (RR) for the primary endpoint of the study – severe or confirmed symptomatic hypoglycemia, defined as a blood-glucose level of less than 3.1 mmol/L (56 mg/dL) – was 0.88 (95% confidence interval, 0.73-1.06; P = .17) in a comparison the two long-acting insulins.

There were some differences that favored insulin degludec over insulin glargine when other endpoints were considered, but because a statistical testing hierarchy was used, “no confirmatory results can be made from CONCLUDE,” one of the study investigators, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, San Diego, said during a special symposium at the meeting.

“If the primary endpoint was not achieved, the testing hierarchy stopped after the first occurrence of nonsignificance,” she explained. Although that occurred, the other endpoints could still be analyzed as they were all prespecified, she argued. These showed that during the maintenance treatment period, there were lower rates of nocturnal symptomatic hypoglycemic episodes (RR, 0.63; 95% CI, 0.48-0.84; P = .0014) and severe episodes (those requiring third-party assistance; RR, 0.20; 95% CI, 0.07-0.57; P = .0027) with insulin degludec, compared with insulin glargine.

The trial came under fire, however, from Stefano Del Prato, MD, professor of endocrinology in the department of endocrinology metabolism and chief of the section of diabetes at the University of Pisa, Italy, who provided the EASD-invited independent commentary on the study’s findings. “This is the CONCLUDE trial. You’d could expect a CONCLUDE trial to be conclusive in its conclusions!” he said, noting that there were “too many uncertainties” in the trial.

CONCLUDE was a randomized, open-label, head-to-head study of insulin degludec versus insulin glargine in 1,609 adult patients with type 2 diabetes who were inadequately treated with basal insulin with or without oral antidiabetic drugs. The aim of the trial was to evaluate the risk of hypoglycemia associated with the two long-acting insulins.

“Hypoglycemia is a very common event in both type 1 and type 2 diabetes,” Thomas Pieber, MD, Medical University Graz, Austria, reminded the audience. Severe hypoglycemia is associated with insulin use, and data show that patients with type 2 diabetes are at as much risk as are those with type 1 diabetes in the longer term (Diabetologia. 2007;50:1140-7).

Sara Freeman/MDedge News

Sara Freeman/MDedge News

He said that it was not clear from the findings why there might be a lower risk of hypoglycemia with insulin degludec. He noted that the rate of diurnal hypoglycemia should be considered, and that the statistical interpretation of the data may be “a matter of uncertainty as well.”

Dr. Del Prato agreed that “prevention of hypoglycemia remained a major task in treating type 2 diabetic patients, particularly those on insulin therapy.” He proposed that differentiating between new basal insulin analogs may need “better tools for characterization of PK/PD, rigorous interpretation of the results, careful assessment of the generalizability of results from randomized controlled trials performed in selected study populations, and independent research and careful real-world studies to be performed.”

Furthermore, he said translating the potential benefit of new insulin analogs “cannot just rely on their properties, rather it requires validation over the time of the accuracy of glucose meters, and adequate patient education, and even more, education reinforcement.”

All of the speakers disclosed ties with Novo Nordisk, which funded the study, as well as other pharmaceutical companies.
 

SOURCES: Philis-Tsimikas A. EASD 2019, Oral Presentation 90; Pieber T. EASD 2019, Oral Presentation S38.1; Philis-Tsimikas A. EASD 2019, Oral Presentation S38.2; Del Prato S. EASD 2019. Oral Presentation S38.3.

BARCELONA – A similar overall risk of symptomatic hypoglycemia was observed with insulin degludec (Tresiba) and insulin glargine U300 (Toujeo) in the phase 3 CONCLUDE study data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

During a 36-week maintenance treatment period, the rate ratio (RR) for the primary endpoint of the study – severe or confirmed symptomatic hypoglycemia, defined as a blood-glucose level of less than 3.1 mmol/L (56 mg/dL) – was 0.88 (95% confidence interval, 0.73-1.06; P = .17) in a comparison the two long-acting insulins.

There were some differences that favored insulin degludec over insulin glargine when other endpoints were considered, but because a statistical testing hierarchy was used, “no confirmatory results can be made from CONCLUDE,” one of the study investigators, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, San Diego, said during a special symposium at the meeting.

“If the primary endpoint was not achieved, the testing hierarchy stopped after the first occurrence of nonsignificance,” she explained. Although that occurred, the other endpoints could still be analyzed as they were all prespecified, she argued. These showed that during the maintenance treatment period, there were lower rates of nocturnal symptomatic hypoglycemic episodes (RR, 0.63; 95% CI, 0.48-0.84; P = .0014) and severe episodes (those requiring third-party assistance; RR, 0.20; 95% CI, 0.07-0.57; P = .0027) with insulin degludec, compared with insulin glargine.

The trial came under fire, however, from Stefano Del Prato, MD, professor of endocrinology in the department of endocrinology metabolism and chief of the section of diabetes at the University of Pisa, Italy, who provided the EASD-invited independent commentary on the study’s findings. “This is the CONCLUDE trial. You’d could expect a CONCLUDE trial to be conclusive in its conclusions!” he said, noting that there were “too many uncertainties” in the trial.

CONCLUDE was a randomized, open-label, head-to-head study of insulin degludec versus insulin glargine in 1,609 adult patients with type 2 diabetes who were inadequately treated with basal insulin with or without oral antidiabetic drugs. The aim of the trial was to evaluate the risk of hypoglycemia associated with the two long-acting insulins.

“Hypoglycemia is a very common event in both type 1 and type 2 diabetes,” Thomas Pieber, MD, Medical University Graz, Austria, reminded the audience. Severe hypoglycemia is associated with insulin use, and data show that patients with type 2 diabetes are at as much risk as are those with type 1 diabetes in the longer term (Diabetologia. 2007;50:1140-7).

Sara Freeman/MDedge News

Sara Freeman/MDedge News

He said that it was not clear from the findings why there might be a lower risk of hypoglycemia with insulin degludec. He noted that the rate of diurnal hypoglycemia should be considered, and that the statistical interpretation of the data may be “a matter of uncertainty as well.”

Dr. Del Prato agreed that “prevention of hypoglycemia remained a major task in treating type 2 diabetic patients, particularly those on insulin therapy.” He proposed that differentiating between new basal insulin analogs may need “better tools for characterization of PK/PD, rigorous interpretation of the results, careful assessment of the generalizability of results from randomized controlled trials performed in selected study populations, and independent research and careful real-world studies to be performed.”

Furthermore, he said translating the potential benefit of new insulin analogs “cannot just rely on their properties, rather it requires validation over the time of the accuracy of glucose meters, and adequate patient education, and even more, education reinforcement.”

All of the speakers disclosed ties with Novo Nordisk, which funded the study, as well as other pharmaceutical companies.
 

SOURCES: Philis-Tsimikas A. EASD 2019, Oral Presentation 90; Pieber T. EASD 2019, Oral Presentation S38.1; Philis-Tsimikas A. EASD 2019, Oral Presentation S38.2; Del Prato S. EASD 2019. Oral Presentation S38.3.

BARCELONA – A similar overall risk of symptomatic hypoglycemia was observed with insulin degludec (Tresiba) and insulin glargine U300 (Toujeo) in the phase 3 CONCLUDE study data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

During a 36-week maintenance treatment period, the rate ratio (RR) for the primary endpoint of the study – severe or confirmed symptomatic hypoglycemia, defined as a blood-glucose level of less than 3.1 mmol/L (56 mg/dL) – was 0.88 (95% confidence interval, 0.73-1.06; P = .17) in a comparison the two long-acting insulins.

There were some differences that favored insulin degludec over insulin glargine when other endpoints were considered, but because a statistical testing hierarchy was used, “no confirmatory results can be made from CONCLUDE,” one of the study investigators, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, San Diego, said during a special symposium at the meeting.

“If the primary endpoint was not achieved, the testing hierarchy stopped after the first occurrence of nonsignificance,” she explained. Although that occurred, the other endpoints could still be analyzed as they were all prespecified, she argued. These showed that during the maintenance treatment period, there were lower rates of nocturnal symptomatic hypoglycemic episodes (RR, 0.63; 95% CI, 0.48-0.84; P = .0014) and severe episodes (those requiring third-party assistance; RR, 0.20; 95% CI, 0.07-0.57; P = .0027) with insulin degludec, compared with insulin glargine.

The trial came under fire, however, from Stefano Del Prato, MD, professor of endocrinology in the department of endocrinology metabolism and chief of the section of diabetes at the University of Pisa, Italy, who provided the EASD-invited independent commentary on the study’s findings. “This is the CONCLUDE trial. You’d could expect a CONCLUDE trial to be conclusive in its conclusions!” he said, noting that there were “too many uncertainties” in the trial.

CONCLUDE was a randomized, open-label, head-to-head study of insulin degludec versus insulin glargine in 1,609 adult patients with type 2 diabetes who were inadequately treated with basal insulin with or without oral antidiabetic drugs. The aim of the trial was to evaluate the risk of hypoglycemia associated with the two long-acting insulins.

“Hypoglycemia is a very common event in both type 1 and type 2 diabetes,” Thomas Pieber, MD, Medical University Graz, Austria, reminded the audience. Severe hypoglycemia is associated with insulin use, and data show that patients with type 2 diabetes are at as much risk as are those with type 1 diabetes in the longer term (Diabetologia. 2007;50:1140-7).

Sara Freeman/MDedge News

Sara Freeman/MDedge News

He said that it was not clear from the findings why there might be a lower risk of hypoglycemia with insulin degludec. He noted that the rate of diurnal hypoglycemia should be considered, and that the statistical interpretation of the data may be “a matter of uncertainty as well.”

Dr. Del Prato agreed that “prevention of hypoglycemia remained a major task in treating type 2 diabetic patients, particularly those on insulin therapy.” He proposed that differentiating between new basal insulin analogs may need “better tools for characterization of PK/PD, rigorous interpretation of the results, careful assessment of the generalizability of results from randomized controlled trials performed in selected study populations, and independent research and careful real-world studies to be performed.”

Furthermore, he said translating the potential benefit of new insulin analogs “cannot just rely on their properties, rather it requires validation over the time of the accuracy of glucose meters, and adequate patient education, and even more, education reinforcement.”

All of the speakers disclosed ties with Novo Nordisk, which funded the study, as well as other pharmaceutical companies.
 

SOURCES: Philis-Tsimikas A. EASD 2019, Oral Presentation 90; Pieber T. EASD 2019, Oral Presentation S38.1; Philis-Tsimikas A. EASD 2019, Oral Presentation S38.2; Del Prato S. EASD 2019. Oral Presentation S38.3.