NEW ORLEANS – Ceftaroline fosamil reduced the median duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia by 2 days in Veterans Administration patients, a retrospective study showed.

Investigators identified 219 patients with MRSA within the Veterans Affairs (VA) medical system nationwide from 2011 to 2015. All patients received at least 48 hours of ceftaroline fosamil (Teflaro) therapy to treat MRSA bacteremia. “We know it has good activity against MRSA in vitro. We use it in bacteremia, but we don’t have a lot of clinical data to support or refute its use,” said Nicholas S. Britt, PharmD, a PGY2 infectious diseases resident at Barnes-Jewish Hospital in St. Louis.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

Treatment failures

A total of 88 of the 219 (40%) patients experienced treatment failure. This rate “seems kind of high, but, if you look at some of the other MRSA agents for bacteremia (vancomycin, for example), it usually has a treatment failure rate around 60%,” Dr. Britt said. “The outcomes were not as poor as I would expect with [patients] using it for second- and third-line therapy.”

Hospital-acquired infection (odds ratio, 2.11; P = .013), ICU admission (OR, 3.95; P less than .001) and infective endocarditis (OR, 4.77; P = .002) were significantly associated with treatment failure in a univariate analysis. “Admissions to the ICU and endocarditis were the big ones, factors you would associate with failure for most antibiotics,” Dr. Britt said. In a multivariate analysis, only ICU admission remained significantly associated with treatment failure (adjusted OR, 2.24; P = .028).

The investigators also looked at treatment failure with ceftaroline monotherapy, compared with its use in combination. There is in vitro data showing synergy when you add ceftaroline to daptomycin, vancomycin, or some of these other agents,” Dr. Britt said. However, he added, “We didn’t find any significant difference in outcomes when you added another agent.” Treatment failure with monotherapy was 35%, versus 46%, with combination treatment (P = .107).

“This could be because the sicker patients are the ones getting combination therapy.”

No observed differences by dosing

Dr. Britt and his colleagues also looked for any differences by dosing interval, “which hasn’t been evaluated extensively.”

The Food and Drug Administration labeled it for use every 12 hours, but treatment of MRSA bacteremia is an off-label use, Dr. Britt explained. Dosing every 8 hours instead improves the achievement of pharmacokinetic and pharmacodynamic parameters in in vitro studies. “Clinically, we’re almost always using it q8. They’re sick patients, so you don’t want to under-dose them. And ceftaroline is pretty well tolerated overall.”

“But, we didn’t really see any difference between the q8 and the q12” in terms of treatment failure. The rates were 36% and 42%, respectively, and not significantly different (P = .440). “Granted, patients who are sicker are probably going to get treated more aggressively,” Dr. Britt added.

The current research only focused on outcomes associated with ceftaroline. Going forward, Dr. Britt said, “We’re hoping to use this data to compare ceftaroline to other agents as well, probably as second-line therapy, since that’s how it’s used most often.”

Dr. Britt had no relevant financial disclosures.

NEW ORLEANS – Ceftaroline fosamil reduced the median duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia by 2 days in Veterans Administration patients, a retrospective study showed.

Investigators identified 219 patients with MRSA within the Veterans Affairs (VA) medical system nationwide from 2011 to 2015. All patients received at least 48 hours of ceftaroline fosamil (Teflaro) therapy to treat MRSA bacteremia. “We know it has good activity against MRSA in vitro. We use it in bacteremia, but we don’t have a lot of clinical data to support or refute its use,” said Nicholas S. Britt, PharmD, a PGY2 infectious diseases resident at Barnes-Jewish Hospital in St. Louis.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

Treatment failures

A total of 88 of the 219 (40%) patients experienced treatment failure. This rate “seems kind of high, but, if you look at some of the other MRSA agents for bacteremia (vancomycin, for example), it usually has a treatment failure rate around 60%,” Dr. Britt said. “The outcomes were not as poor as I would expect with [patients] using it for second- and third-line therapy.”

Hospital-acquired infection (odds ratio, 2.11; P = .013), ICU admission (OR, 3.95; P less than .001) and infective endocarditis (OR, 4.77; P = .002) were significantly associated with treatment failure in a univariate analysis. “Admissions to the ICU and endocarditis were the big ones, factors you would associate with failure for most antibiotics,” Dr. Britt said. In a multivariate analysis, only ICU admission remained significantly associated with treatment failure (adjusted OR, 2.24; P = .028).

The investigators also looked at treatment failure with ceftaroline monotherapy, compared with its use in combination. There is in vitro data showing synergy when you add ceftaroline to daptomycin, vancomycin, or some of these other agents,” Dr. Britt said. However, he added, “We didn’t find any significant difference in outcomes when you added another agent.” Treatment failure with monotherapy was 35%, versus 46%, with combination treatment (P = .107).

“This could be because the sicker patients are the ones getting combination therapy.”

No observed differences by dosing

Dr. Britt and his colleagues also looked for any differences by dosing interval, “which hasn’t been evaluated extensively.”

The Food and Drug Administration labeled it for use every 12 hours, but treatment of MRSA bacteremia is an off-label use, Dr. Britt explained. Dosing every 8 hours instead improves the achievement of pharmacokinetic and pharmacodynamic parameters in in vitro studies. “Clinically, we’re almost always using it q8. They’re sick patients, so you don’t want to under-dose them. And ceftaroline is pretty well tolerated overall.”

“But, we didn’t really see any difference between the q8 and the q12” in terms of treatment failure. The rates were 36% and 42%, respectively, and not significantly different (P = .440). “Granted, patients who are sicker are probably going to get treated more aggressively,” Dr. Britt added.

The current research only focused on outcomes associated with ceftaroline. Going forward, Dr. Britt said, “We’re hoping to use this data to compare ceftaroline to other agents as well, probably as second-line therapy, since that’s how it’s used most often.”

Dr. Britt had no relevant financial disclosures.

NEW ORLEANS – Ceftaroline fosamil reduced the median duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia by 2 days in Veterans Administration patients, a retrospective study showed.

Investigators identified 219 patients with MRSA within the Veterans Affairs (VA) medical system nationwide from 2011 to 2015. All patients received at least 48 hours of ceftaroline fosamil (Teflaro) therapy to treat MRSA bacteremia. “We know it has good activity against MRSA in vitro. We use it in bacteremia, but we don’t have a lot of clinical data to support or refute its use,” said Nicholas S. Britt, PharmD, a PGY2 infectious diseases resident at Barnes-Jewish Hospital in St. Louis.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

Treatment failures

A total of 88 of the 219 (40%) patients experienced treatment failure. This rate “seems kind of high, but, if you look at some of the other MRSA agents for bacteremia (vancomycin, for example), it usually has a treatment failure rate around 60%,” Dr. Britt said. “The outcomes were not as poor as I would expect with [patients] using it for second- and third-line therapy.”

Hospital-acquired infection (odds ratio, 2.11; P = .013), ICU admission (OR, 3.95; P less than .001) and infective endocarditis (OR, 4.77; P = .002) were significantly associated with treatment failure in a univariate analysis. “Admissions to the ICU and endocarditis were the big ones, factors you would associate with failure for most antibiotics,” Dr. Britt said. In a multivariate analysis, only ICU admission remained significantly associated with treatment failure (adjusted OR, 2.24; P = .028).

The investigators also looked at treatment failure with ceftaroline monotherapy, compared with its use in combination. There is in vitro data showing synergy when you add ceftaroline to daptomycin, vancomycin, or some of these other agents,” Dr. Britt said. However, he added, “We didn’t find any significant difference in outcomes when you added another agent.” Treatment failure with monotherapy was 35%, versus 46%, with combination treatment (P = .107).

“This could be because the sicker patients are the ones getting combination therapy.”

No observed differences by dosing

Dr. Britt and his colleagues also looked for any differences by dosing interval, “which hasn’t been evaluated extensively.”

The Food and Drug Administration labeled it for use every 12 hours, but treatment of MRSA bacteremia is an off-label use, Dr. Britt explained. Dosing every 8 hours instead improves the achievement of pharmacokinetic and pharmacodynamic parameters in in vitro studies. “Clinically, we’re almost always using it q8. They’re sick patients, so you don’t want to under-dose them. And ceftaroline is pretty well tolerated overall.”

“But, we didn’t really see any difference between the q8 and the q12” in terms of treatment failure. The rates were 36% and 42%, respectively, and not significantly different (P = .440). “Granted, patients who are sicker are probably going to get treated more aggressively,” Dr. Britt added.

The current research only focused on outcomes associated with ceftaroline. Going forward, Dr. Britt said, “We’re hoping to use this data to compare ceftaroline to other agents as well, probably as second-line therapy, since that’s how it’s used most often.”

Dr. Britt had no relevant financial disclosures.

NEW ORLEANS – Investigators discovered significant differences in risk factors when comparing 603 people hospitalized with carbapenem-resistant Gram-negative sepsis with either Enterobacteriaceae-caused or non-Enterobacteriaceae–caused infection.

“We know some of the virulence factors and the resistance mechanisms can differ between those two groups. We really wanted to see if that would influence outcomes,” said Nicholas S. Britt, PharmD, a PGY2 infectious disease resident at Barnes-Jewish Hospital in St. Louis. Mortality rates, however, did not differ significantly.

©CDC/ Melissa Brower

NEW ORLEANS – Investigators discovered significant differences in risk factors when comparing 603 people hospitalized with carbapenem-resistant Gram-negative sepsis with either Enterobacteriaceae-caused or non-Enterobacteriaceae–caused infection.

“We know some of the virulence factors and the resistance mechanisms can differ between those two groups. We really wanted to see if that would influence outcomes,” said Nicholas S. Britt, PharmD, a PGY2 infectious disease resident at Barnes-Jewish Hospital in St. Louis. Mortality rates, however, did not differ significantly.

©CDC/ Melissa Brower

NEW ORLEANS – Investigators discovered significant differences in risk factors when comparing 603 people hospitalized with carbapenem-resistant Gram-negative sepsis with either Enterobacteriaceae-caused or non-Enterobacteriaceae–caused infection.

“We know some of the virulence factors and the resistance mechanisms can differ between those two groups. We really wanted to see if that would influence outcomes,” said Nicholas S. Britt, PharmD, a PGY2 infectious disease resident at Barnes-Jewish Hospital in St. Louis. Mortality rates, however, did not differ significantly.

©CDC/ Melissa Brower

MADRID – The risk of osteoporotic fracture associated with hematopoietic stem cell transplantation (HSCT) could be assessed using the Fracture Risk Assessment Tool (FRAX), researchers from the University of Texas MD Anderson Cancer Center have found.

In a retrospective cohort study, Huifang Lu, MD, and her collaborators found that FRAX could predict the risk of fracture with reasonable accuracy. The area under the receiver operating characteristic curve was 0.66 for predicting a fracture 10 years after HSCT.

“Current guidelines recommend the evaluation of bone health at 1 year following the transplant, but we recommend that this needs to happen at a much earlier time,” Dr. Lu said at the European Congress of Rheumatology.

Determining how to assess risk earlier and prevent bone loss remains a challenge, however. FRAX is an easy and quick tool to use, but its predictive ability is modest, she said.

As the finding comes from a retrospective study, prospective evaluation of FRAX is needed in HSCT patients. If shown predictive in this setting, bone health could be assessed earlier using FRAX, ideally at or before the time of the transplant, to allow appropriate action to be taken, such as prescribing bisphosphonates to those identified to be at high risk.

There is no consensus on preventing and treating bone loss following HSCT, said Dr. Lu. In a meta-analysis performed by Dr. Lu and her associates (Bone Marrow Transplant. 2017;52[5]:663-70), less bone loss was seen in patients who received a bisphosphonate.

As the use of HSCT has expanded over the past two decades, there is an expanding population of survivors with potential long-term effects such as bone loss and a higher risk of fractures, compared with the general population, Dr. Lu explained.

The FRAX tool takes into account pre-HSCT factors such as age, smoking status, alcohol use, prior fracture, body mass index, and corticosteroid use. This can be considered in association with the fracture risk related to the various conditioning and supporting regimens that patients receive around the time of their transplants.

The study included 5,170 adult patients who had undergone HSCT at the University of Texas MD Anderson Cancer Center over a 10-year period. Patients were considered to have entered the cohort at the time of their transplants, Dr. Lu said. Their history of osteoporotic fractures up to 3.3 years later was obtained and verified by radiology and physician assessment. FRAX probabilities were then derived from baseline information.

The mean age of patients included was 52 years, 57% were male and 75% were white. One-quarter had experienced a prior fracture. Of note, 26% of the cohort underwent HSCT for multiple myeloma, 70% of whom had already had a fracture, compared with 9% of those who underwent HSCT for another reason such as leukemia or lymphoma.

Multivariate analyses were performed with and without considering death as a competing risk, and similar results were obtained. Higher FRAX scores (20 or greater) were more likely to be recorded in individuals who sustained a fracture than in those who did not. Patients who had an allogeneic HSCT were 15% more likely to have a fracture as those who received an autologous transplant. Perhaps not surprisingly, patients with multiple myeloma were more likely than those who had HSCT for other reasons to sustain a fracture by 10 years based on FRAX results (hazard ratio, 3.16).

Future research needs to look at the optimal cut offs for FRAX scores predictive of events and see if there is any association between the loss of bone and fracture risk. There also needs to be an evaluation of the use of concomitant medications and health economic analyses performed.

Dr. Lu had no conflicts of interest. The study was funded by the Rolanette and Berdon Lawrence Bone Disease Program of Texas and via Cancer Survivorship Research Seed Monday Grants from the University Cancer Foundation and Duncan Family Institute for Cancer Prevention and Risk Assessment to the University of Texas MD Anderson Cancer Center.

MADRID – The risk of osteoporotic fracture associated with hematopoietic stem cell transplantation (HSCT) could be assessed using the Fracture Risk Assessment Tool (FRAX), researchers from the University of Texas MD Anderson Cancer Center have found.

In a retrospective cohort study, Huifang Lu, MD, and her collaborators found that FRAX could predict the risk of fracture with reasonable accuracy. The area under the receiver operating characteristic curve was 0.66 for predicting a fracture 10 years after HSCT.

“Current guidelines recommend the evaluation of bone health at 1 year following the transplant, but we recommend that this needs to happen at a much earlier time,” Dr. Lu said at the European Congress of Rheumatology.

Determining how to assess risk earlier and prevent bone loss remains a challenge, however. FRAX is an easy and quick tool to use, but its predictive ability is modest, she said.

As the finding comes from a retrospective study, prospective evaluation of FRAX is needed in HSCT patients. If shown predictive in this setting, bone health could be assessed earlier using FRAX, ideally at or before the time of the transplant, to allow appropriate action to be taken, such as prescribing bisphosphonates to those identified to be at high risk.

There is no consensus on preventing and treating bone loss following HSCT, said Dr. Lu. In a meta-analysis performed by Dr. Lu and her associates (Bone Marrow Transplant. 2017;52[5]:663-70), less bone loss was seen in patients who received a bisphosphonate.

As the use of HSCT has expanded over the past two decades, there is an expanding population of survivors with potential long-term effects such as bone loss and a higher risk of fractures, compared with the general population, Dr. Lu explained.

The FRAX tool takes into account pre-HSCT factors such as age, smoking status, alcohol use, prior fracture, body mass index, and corticosteroid use. This can be considered in association with the fracture risk related to the various conditioning and supporting regimens that patients receive around the time of their transplants.

The study included 5,170 adult patients who had undergone HSCT at the University of Texas MD Anderson Cancer Center over a 10-year period. Patients were considered to have entered the cohort at the time of their transplants, Dr. Lu said. Their history of osteoporotic fractures up to 3.3 years later was obtained and verified by radiology and physician assessment. FRAX probabilities were then derived from baseline information.

The mean age of patients included was 52 years, 57% were male and 75% were white. One-quarter had experienced a prior fracture. Of note, 26% of the cohort underwent HSCT for multiple myeloma, 70% of whom had already had a fracture, compared with 9% of those who underwent HSCT for another reason such as leukemia or lymphoma.

Multivariate analyses were performed with and without considering death as a competing risk, and similar results were obtained. Higher FRAX scores (20 or greater) were more likely to be recorded in individuals who sustained a fracture than in those who did not. Patients who had an allogeneic HSCT were 15% more likely to have a fracture as those who received an autologous transplant. Perhaps not surprisingly, patients with multiple myeloma were more likely than those who had HSCT for other reasons to sustain a fracture by 10 years based on FRAX results (hazard ratio, 3.16).

Future research needs to look at the optimal cut offs for FRAX scores predictive of events and see if there is any association between the loss of bone and fracture risk. There also needs to be an evaluation of the use of concomitant medications and health economic analyses performed.

Dr. Lu had no conflicts of interest. The study was funded by the Rolanette and Berdon Lawrence Bone Disease Program of Texas and via Cancer Survivorship Research Seed Monday Grants from the University Cancer Foundation and Duncan Family Institute for Cancer Prevention and Risk Assessment to the University of Texas MD Anderson Cancer Center.

MADRID – The risk of osteoporotic fracture associated with hematopoietic stem cell transplantation (HSCT) could be assessed using the Fracture Risk Assessment Tool (FRAX), researchers from the University of Texas MD Anderson Cancer Center have found.

In a retrospective cohort study, Huifang Lu, MD, and her collaborators found that FRAX could predict the risk of fracture with reasonable accuracy. The area under the receiver operating characteristic curve was 0.66 for predicting a fracture 10 years after HSCT.

“Current guidelines recommend the evaluation of bone health at 1 year following the transplant, but we recommend that this needs to happen at a much earlier time,” Dr. Lu said at the European Congress of Rheumatology.

Determining how to assess risk earlier and prevent bone loss remains a challenge, however. FRAX is an easy and quick tool to use, but its predictive ability is modest, she said.

As the finding comes from a retrospective study, prospective evaluation of FRAX is needed in HSCT patients. If shown predictive in this setting, bone health could be assessed earlier using FRAX, ideally at or before the time of the transplant, to allow appropriate action to be taken, such as prescribing bisphosphonates to those identified to be at high risk.

There is no consensus on preventing and treating bone loss following HSCT, said Dr. Lu. In a meta-analysis performed by Dr. Lu and her associates (Bone Marrow Transplant. 2017;52[5]:663-70), less bone loss was seen in patients who received a bisphosphonate.

As the use of HSCT has expanded over the past two decades, there is an expanding population of survivors with potential long-term effects such as bone loss and a higher risk of fractures, compared with the general population, Dr. Lu explained.

The FRAX tool takes into account pre-HSCT factors such as age, smoking status, alcohol use, prior fracture, body mass index, and corticosteroid use. This can be considered in association with the fracture risk related to the various conditioning and supporting regimens that patients receive around the time of their transplants.

The study included 5,170 adult patients who had undergone HSCT at the University of Texas MD Anderson Cancer Center over a 10-year period. Patients were considered to have entered the cohort at the time of their transplants, Dr. Lu said. Their history of osteoporotic fractures up to 3.3 years later was obtained and verified by radiology and physician assessment. FRAX probabilities were then derived from baseline information.

The mean age of patients included was 52 years, 57% were male and 75% were white. One-quarter had experienced a prior fracture. Of note, 26% of the cohort underwent HSCT for multiple myeloma, 70% of whom had already had a fracture, compared with 9% of those who underwent HSCT for another reason such as leukemia or lymphoma.

Multivariate analyses were performed with and without considering death as a competing risk, and similar results were obtained. Higher FRAX scores (20 or greater) were more likely to be recorded in individuals who sustained a fracture than in those who did not. Patients who had an allogeneic HSCT were 15% more likely to have a fracture as those who received an autologous transplant. Perhaps not surprisingly, patients with multiple myeloma were more likely than those who had HSCT for other reasons to sustain a fracture by 10 years based on FRAX results (hazard ratio, 3.16).

Future research needs to look at the optimal cut offs for FRAX scores predictive of events and see if there is any association between the loss of bone and fracture risk. There also needs to be an evaluation of the use of concomitant medications and health economic analyses performed.

Dr. Lu had no conflicts of interest. The study was funded by the Rolanette and Berdon Lawrence Bone Disease Program of Texas and via Cancer Survivorship Research Seed Monday Grants from the University Cancer Foundation and Duncan Family Institute for Cancer Prevention and Risk Assessment to the University of Texas MD Anderson Cancer Center.

Non–cystic fibrosis–related Burkholderia cepacia complex infections occurred almost exclusively in older hospitalized patients with serious comorbidities – and the majority were acquired in a health care setting, a large U.S. Veterans Health Administration database study has determined.

Despite the bacteria’s tendency to be multidrug-resistant, both fluoroquinolones and trimethoprim-sulfamethoxazole were equally effective, as long as they were promptly initiated, Nadim G. El Chakhtoura, MD, and colleagues reported (Clin Infect Dis, 2017. doi: 10.1093/cid/cix559).

“We consider that the approach to improve survival in B. cepacia complex (Bcc) bloodstream infections … should include controlling the source of infection and prompt initiation of effective antibiotic therapy,” wrote Dr. El Chakhtoura of Cleveland Hospitals University Medical Center, and associates.

copyright claudiobaba/iStockPhoto.com

[email protected]

On Twitter @Alz_gal

Non–cystic fibrosis–related Burkholderia cepacia complex infections occurred almost exclusively in older hospitalized patients with serious comorbidities – and the majority were acquired in a health care setting, a large U.S. Veterans Health Administration database study has determined.

Despite the bacteria’s tendency to be multidrug-resistant, both fluoroquinolones and trimethoprim-sulfamethoxazole were equally effective, as long as they were promptly initiated, Nadim G. El Chakhtoura, MD, and colleagues reported (Clin Infect Dis, 2017. doi: 10.1093/cid/cix559).

“We consider that the approach to improve survival in B. cepacia complex (Bcc) bloodstream infections … should include controlling the source of infection and prompt initiation of effective antibiotic therapy,” wrote Dr. El Chakhtoura of Cleveland Hospitals University Medical Center, and associates.

copyright claudiobaba/iStockPhoto.com

[email protected]

On Twitter @Alz_gal

Non–cystic fibrosis–related Burkholderia cepacia complex infections occurred almost exclusively in older hospitalized patients with serious comorbidities – and the majority were acquired in a health care setting, a large U.S. Veterans Health Administration database study has determined.

Despite the bacteria’s tendency to be multidrug-resistant, both fluoroquinolones and trimethoprim-sulfamethoxazole were equally effective, as long as they were promptly initiated, Nadim G. El Chakhtoura, MD, and colleagues reported (Clin Infect Dis, 2017. doi: 10.1093/cid/cix559).

“We consider that the approach to improve survival in B. cepacia complex (Bcc) bloodstream infections … should include controlling the source of infection and prompt initiation of effective antibiotic therapy,” wrote Dr. El Chakhtoura of Cleveland Hospitals University Medical Center, and associates.

copyright claudiobaba/iStockPhoto.com

[email protected]

On Twitter @Alz_gal

High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.

Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.

[email protected]

High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.

Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.

[email protected]

High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.

Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.

[email protected]

MADRID – Previous infection with nontuberculous mycobacteria was associated with an 11 times increased risk of later developing Sjögren’s syndrome in a large population-based study reported at the European Congress of Rheumatology.

Study investigator Hsin-Hua Chen, MD, and his colleagues at the Taichung (Taiwan) Veterans Hospital found that the adjusted odds ratio for having Sjögren’s syndrome after nontuberculous mycobacteria infection (NTM) was 11.24, with a 95% confidence interval of 2.37-53.24.

The risk for having Sjögren’s syndrome was found to be highest in those aged 40-65 years, versus those older than 65 (aOR, 39.24; P = .09) and in those with no prior history of bronchiectasis (aOR, 37.98; P = .09). Although, in both analyses, the 95% CIs were very wide (3.97-387.75 and 3.83-376.92, respectively), and the P values were not significant.

[email protected]

MADRID – Previous infection with nontuberculous mycobacteria was associated with an 11 times increased risk of later developing Sjögren’s syndrome in a large population-based study reported at the European Congress of Rheumatology.

Study investigator Hsin-Hua Chen, MD, and his colleagues at the Taichung (Taiwan) Veterans Hospital found that the adjusted odds ratio for having Sjögren’s syndrome after nontuberculous mycobacteria infection (NTM) was 11.24, with a 95% confidence interval of 2.37-53.24.

The risk for having Sjögren’s syndrome was found to be highest in those aged 40-65 years, versus those older than 65 (aOR, 39.24; P = .09) and in those with no prior history of bronchiectasis (aOR, 37.98; P = .09). Although, in both analyses, the 95% CIs were very wide (3.97-387.75 and 3.83-376.92, respectively), and the P values were not significant.

[email protected]

MADRID – Previous infection with nontuberculous mycobacteria was associated with an 11 times increased risk of later developing Sjögren’s syndrome in a large population-based study reported at the European Congress of Rheumatology.

Study investigator Hsin-Hua Chen, MD, and his colleagues at the Taichung (Taiwan) Veterans Hospital found that the adjusted odds ratio for having Sjögren’s syndrome after nontuberculous mycobacteria infection (NTM) was 11.24, with a 95% confidence interval of 2.37-53.24.

The risk for having Sjögren’s syndrome was found to be highest in those aged 40-65 years, versus those older than 65 (aOR, 39.24; P = .09) and in those with no prior history of bronchiectasis (aOR, 37.98; P = .09). Although, in both analyses, the 95% CIs were very wide (3.97-387.75 and 3.83-376.92, respectively), and the P values were not significant.

[email protected]

From the Mayo Clinic, Scottsdale, AZ.

Abstract

• Objective: To review the impact of migraine and explore the barriers to optimal migraine diagnosis and treatment.
• Methods: Review of the literature.
• Results: Several factors may play a role in the inadequate care of migraine patients, including issues related to poor access to care, diagnostic insight, misdiagnosis, adherence to treatment, and management of comorbidities. Both patient and physician factors play an important role and many be modifiable.
• Conclusions: A focus on education of both patients and physicians is of paramount importance to improve the care provided to migraine patients. Patient evaluations should be multisystemic and include addressing comorbid conditions as well as a discussion about appropriate use of prevention and avoidance of medication overuse.

Key words: migraine; triptans; medication overuse headache; medication adherence; primary care.

Migraine is a common, debilitating condition that is a significant source of reduced productivity and increased disability [1]. According to the latest government statistics, 14.2% of US adults have reported having migraine or severe headaches in the previous 3 months, with an overall age-adjusted 3-month prevalence of 19.1% in females and 9.0% in males [2]. In a self-administered headache questionnaire mailed to 120,000 representative US households, the 1-year period prevalence for migraine was 11.7% (17.1% in women and 5.6% in men). Prevalence peaked in middle life and was lower in adolescents and those older than age 60 years [3]. Migraine is an important cause of reduced health-related quality of life and has a very high economic burden [4]. This effect is even more marked in those with chronic migraine, who are even more likely to have professional and social absenteeism and experience more severe disability [4].

Migraine and headache are a common reason for primary care physician (PCP) visits. Some estimates suggest that as many as 10% of primary care consultations are due to headache [5]. Approximately 75% of all patients complaining of headache in primary care will eventually be diagnosed with migraine [6]. Of these, as many as 1% to 5% will have chronic migraine [6].

Despite the high frequency and social and economic impact of migraine, migraine is underrecognized and undertreated. A survey of US households revealed that only 13% of migraineurs were currently using a preventive thrapy while 43.3% had never used one [3]. This is despite the fact that 32.4% met expert criteria for consideration of a preventive medication [3]. The reasons for underrecognition and undertreatment are multifactorial and include both patient and physician factors.

Physician Factors

Although migraine and headache are a leading cause of physicians visits, most physicians have had little formal training in headache. In the United States, medical students spend an average of 1 hour of preclinical and 2 hours of clinical education in headache [7]. Furthermore, primary care physicians receive little formal training in headache during residency [8]. In addition to the lack of formal training, there is also a lack of substantial clinic time available to fully evaluate and treat a new headache patient in the primary care setting [8]. Headache consultations can often be timely and detail-driven in order to determine the correct diagnosis and treatment [9].

Misdiagnosis

Evidence suggests that misdiagnosis plays a large role in the suboptimal management of migraineurs. Studies have shown that as many as 59.7% of migraineurs were not given a diagnosis of migraine by their primary care provider [10]. Common mistaken diagnoses include tension-type headache [11], “sinus headache” [12], cervical pain syndrome or cervicogenic headache [13], and “stress headache” [14].

The reasons for these misdiagnoses is not certain. It may be that the patient and practitioner assume that location of the pain is suggestive of the cause [13]. This is even though more than half of those with migraine have associated neck pain [15]. A recent study suggests that 60% of migraineurs who self-reported a diagnosis of cervical pain have been subsequently diagnosed with cervicalgia by a physician [13]. If patients endorse stress as a precipitant or the presence of cervical pain, they are more likely to obtain a diagnosis other than migraine. The presence of aura in association with the headache appears to be protective against misdiagnosis [13].

Similarly, patients are often given a diagnosis of “sinus headache.” This diagnosis is often made without radiologic evidence of sinusitis and even in those with a more typical migraine headache [16]. In one survey, 40% of patients meeting criteria for migraine were given this diagnosis. Many of these patients did have nasal symptoms or facial pain without clear evidence or rhinosinusitis, and in some cases these symptoms would respond to migraine treatments [16]. This is a particularly important misdiagnosis to highlight, as attributing symptoms to sinus disease may lead to unnecessary consultations and even sinus instrumentation.

In addition to common misdiagnoses, many PCPs are unfamiliar with the “red flags” that may indicate a secondary headache disorder and are also unfamiliar with appropriate use of neuroimaging in headache patients [17].

Misuse of As-Needed Medications

Studies have suggested that a large proportion of PCPs will prescribe nonspecific analgesics for migraine rather than migraine-specific medications [18]. These treatments may include NSAIDs, acetaminophen, barbiturates, and even opiates. This appears to be the pattern even for those with severe attacks [18], suggesting that migraine-specific medications such as triptans may be underused in the primary care setting. Postulated reasons for this pattern include lack of physician knowledge regarding the specific recommendations for managing migraine, the cost of medications, as well as lack of insurance coverage for these medications [19]. Misuse of as-needed medications can lead to medication overuse headache (MOH), which is an underrecognized problem in the primary care setting [20]. In a survey of PCPs in Boston, only 54% of PCPs were aware that barbiturates can cause MOH and only 34% were aware that opiates can cause MOH [17]. The same survey revealed that approximately 20% of PCPs had never made the diagnosis of MOH [17].

Underuse of Preventive Medications

As many as 40% of migraineurs need preventive therapy, but only approximately 13% are currently receiving it [3]. Additionally, the average time from diagnosis of migraine to instituting preventive treatment is 4.3 years, and often there is only a single preventive medication trial if one is instituted [21]. The reasons for this appear to be complex. The physician factors contributing to the underuse of preventive medications include inadequate education, discomfort and inadequate time for assessments. Only 27.8% of surveyed PCPs were aware of the American Academy of Neurology guidelines for prescribing preventive medications [17].

There may be an underestimate of the disability experienced by migraineurs, which can explain some of the underuse of preventive medications. While many PCPs endorse inquiring about headache-related disability, many do not used validated scales such as the Migraine Disability Assessment Score (MIDAS) or the Headache Impact Test (HIT) [17]. In addition, patients often underreport their headache days and report only their severe exacerbations unless clearly asked about a daily headache [22]. This may be part of the reason why only 20% of migraineurs who meet criteria for chronic migraine are diagnosed as such and why preventatives may not be offered [23].

After preventatives are started, less than 25% of patients will be adherent to oral migraine preventive agents at 1 year [24]. Common reasons for discontinuing preventives include adverse effects and perceived inefficacy [22]. Preventive medications may need a 6- to 8-week trial before efficacy is determined, but in practice medications may be stopped before this threshold is reached. Inadequate follow-up and lack of detail with regard to medication trials may result in the perception of an intractable patient prematurely. It has been suggested that a systematic approach to documenting and choosing preventive agents is helpful in the treatment of migraine [25], although this is not always practical in the primary care setting.

Another contributor to underuse of effective prophylaxis is related to access. Treatment with onabotulinumtoxin A, an efficacious prophylactic treatment approved for select chronic migraine patients [26], will usually require referral to a headache specialist, which is not always available to PCPs in a timely manner [7].

Nonpharmacologic Approaches

Effective nonpharmacologic treatment modalities for migraine, such as cognitive-behavioral therapy and biofeedback [27], are not commonly recommended by PCPs [17]. Instead, there appears to be more focus on avoidance of triggers and referral to non–evidence-based resources, such as special diets and massage therapy [17]. While these methods are not always inappropriate, it should be noted that they often have little or no evidence for efficacy.

Patients often wish for non-medication approaches to migraine management, but for those with significant and severe disability, these are probably insufficient. In these patients, non-medication approaches may best be used as a supplement to pharmacological treatment, with education on pharmacologic prevention given. Neuromodulation is a promising, novel approach that is emerging as a new treatment for migraine, but likely will require referral to a headache specialist.

Suboptimal Management of Migraine Comorbidities

There are several disorders that are commonly comorbid with migraine. Among the most common are anxiety, depression, medication (and caffeine) overuse, obesity, and sleep disorders [22]. A survey of PCPs reveals that only 50.6% of PCPs screen for anxiety, 60.2% for depression, and 73.5% for sleep disorders [17]. They are, for the most part, modifiable or treatable conditions and their proper management may help ease migraine disability.

In addition, the presence of these comorbidities may alter choice of treatment, for example, favoring the use of an serotonin and norepinephrine reuptake inhibitor such as venlafaxine for treatment  in those with comorbid anxiety and depression. It is also worthwhile to have a high index of suspicion for obstructive sleep apnea in patients with headache, particularly in the obese and in those who endorse nonrestorative sleep or excessive daytime somnolence. It appears that patients who are adherent to the treatment of sleep apnea are more likely to report improvement in their headache [28].

Given the time constraints that often exist in the PCP office setting, addressing these comorbidities thoroughly is not always possible. It is reasonable, however, to have patients use screening tools while in the waiting room or prior to an appointment, to better identify those with modifiable comorbidities. Depression, anxiety, and excessive daytime sleepiness can all be screened for relatively easily with tools such as the PHQ-9 [29], GAD-7 [30] and Epworth Sleepiness Scale [31], respectively. A positive screen on any of these could lead the PCP to further investigate these entities as a possible contributor to migraine.

Patient Factors

In addition to the physician factors identified above, patient factors can contribute to the suboptimal management of migraine as well. These factors include a lack insight into diagnosis, poor compliance with treatment of migraine or its comorbidities, and overuse of abortive medications. There are also less modifiable patient factors such as socioeconomic status and the stigma that may be associated with migraine.

Poor Insight Into Diagnosis

Despite the high prevalence and burden of migraine in the general population, there is a staggering lack of awareness among migraineurs. Some estimates state that as many as 54% of patients were unaware that their headaches represented migraine [32]. The most common self-reported diagnoses in migraineurs are sinus headache (39%), tension-type headache (31%) and stress headache (29%) [14]. In addition, many patients believe they are suffering from cervical spine–related pain [13]. This is likely due to the common presence of posteriorly located pain, attacks triggered by poor sleep, or attacks associated with weather changes [13]. Patients presenting with aura are more likely to report and to receive a physician diagnosis of migraine [14]. Women are more likely to receive and report a diagnosis of migraine compared with men [32].

There are many factors that play a role in poor insight. Many patients appear to believe that the location of the pain is suggestive of the cause [13]. Many patients never seek out consultation for their headaches, and thus never receive a proper diagnosis [33]. Some patients may seek out medical care for their headaches, but fail to remember their diagnosis or receive an improper diagnosis [34].

Poor Adherence

The body of literature examining adherence with headache treatment is growing, but remains small [35]. In a recent systematic review of treatment adherence in pediatric and adult patients with headache, adherence rates in adults with headache ranged from 25% to 94% [35]. In this review, prescription claims data analyses found poor persistence in patients prescribed triptans for migraine treatment. In one large claims-based study, 53.8% of patients  receiving a new triptan prescription did not persistently refill their index triptan [36]. Although some of these patients switched to an alternative triptan, the majority switched to a non-triptan migraine medication, including opioids and nonsteroidal anti-inflammatory drugs [36].

Cady and colleagues’ study of lapsed and sustained triptan users found that sustained users were significantly more satisfied with their medication, confident in the medication’s ability to control headache, and reported control of migraine with fewer doses of medication [37]. The authors concluded that the findings suggest that lapsed users may not be receiving optimal treatment. In a review by Rains et al [38], the authors found that headache treatment adherence declines “with more frequent and complex dosing regimens, side effects, and costs, and is subject to a wide range of psychosocial influences.”

Adherence issues also exist for migraine prevention. Less than 25% of chronic migraine patients continue to take oral preventive therapies at 1 year [24]. The reasons for this nonadherence are not completely clear, but are likely multifactorial. Preventives may take several weeks to months to become effective, which may contribute to noncompliance. In addition, migraineurs appears to have inadequate follow-up for migraine. Studies from France suggest that only 18% of those aware of their migraine diagnosis received medical follow-up [39].

Medication Overuse

While the data is not entirely clear, it is likely that overuse of as-needed medication plays a role in migraine chronification [40]. The reasons for medication overuse in the migraine population include some of the issues already highlighted above, including inadequate patient education, poor insight into diagnosis, not seeking care, misdiagnosis, and treatment nonadherence. Patients should be educated on the proper use of as-needed medication. Limits to medication use should be set during the physician-patient encounter. Patients should be counselled to limit their as-needed medication to no more than 10 days per month to reduce the risk of medication overuse headache. Ideally, opiates and barbiturates should be avoided, and never used as first-line therapy in patients who lack contraindications to NSAIDs and triptans. If their use in unavoidable for other reasons, they should be used sparingly, as use on as few as 5 to 8 days per month can be problematic [41]. Furthermore it is important to note that if patients are using several different acute analgesics, the combined total use of all as-needed pain medications needs to be less than 10 days per month to reduce the potential for medication overuse headache.

Socioeconomic Factors

Low socioeconomic status has been associated with an increased prevalence for all headache forms and an increased migraine attack frequency [42], but there appear to be few studies looking at the impact of low socioeconomic status and treatment. Lipton et al found that health insurance status was an important predictor of persons with migraine consulting a health care professional [43]. Among consulters, women were far more likely to be diagnosed than men, suggesting that gender bias in diagnosis may be an important barrier for men. Higher household income appeared to be a predictor for receiving a correct diagnosis of migraine. These researchers also found economic barriers related to use of appropriate prescription medications [43]. Differences in diagnosis and treatment may indicate racial and ethnic disparities in access and quality of care for minority patients [44].

Stigma

At least 1 study has reported that migraine patients experience stigma. In Young et al’s study of  123 episodic migraine patients, 123 chronic migraine patients, and 62 epilepsy patients, adjusted stigma was similar for chronic migraine and epilepsy, which were greater than for episodic migraine [45]. Stigma correlated most strongly with inability to work. Migraine patients reported equally high stigma scores across age, income, and education. The stigma of migraine may pose a barrier to seeking consultation and treatment. Further, the perception that migraine is “just a headache” may lead to stigmatizing attitudes on the part of friends, family, and coworkers of patients with migraine.

Conclusions and Recommendations

Migraine is a prevalent and frequently disabling condition that is underrecognized and undertreated in the primary care setting. Both physician and patient factors pose barriers to the optimal diagnosis and treatment of migraine. Remedies to address these barriers include education of both patients and physicians first and foremost. Targeting physician education in medical school and during residency training, including in primary care subspecialties, could include additional didactic teaching, but also clinical encounters in headache subspecialty clinics to increase exposure. Patient advocacy groups and public campaigns to improve understanding of migraine in the community may be a means for improving patient education and reducing stigma. Patients should be encouraged to seek out consultations for headache to reduce long-term headache disability. Management of comorbidities is paramount, and screening tools for migraine-associated disability, anxiety, depression, and medication use may be helpful to implement in the primary care setting as they are easy to use and time saving.

Recent surveys of PCPs suggest that the resource that is most desired is ready access to subspecialists for advice and “curb-side” consultation [17]. While this solution is not always practical, it may be worthwhile exploring closer relationships between primary care and subspecialty headache clinics, or perhaps more access to e-consultation or telephone consultation for more rural areas. Recently, Minen et al examined education strategies for PCPs. While in-person education sessions with PCPs were poorly attended, multiple possibilities for further education were identified. It was suggested that PCPs having real-time access to resources during the patient encounter would improve their comfort in managing patients. This includes online databases, simple algorithms for treatment, and directions for when to refer to a neurologist [46]. In addition, it may be worthwhile to train not only PCPs but also nursing and allied health staff so that they can provide headache education to patients. This may help ease some of the time burden on PCPs as well as provide a collaborative environment in which headache can be managed [46].

Corresponding author: William S. Kingston, MD, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ 85259.

Financial disclosures: None.

From the Mayo Clinic, Scottsdale, AZ.

Abstract

• Objective: To review the impact of migraine and explore the barriers to optimal migraine diagnosis and treatment.
• Methods: Review of the literature.
• Results: Several factors may play a role in the inadequate care of migraine patients, including issues related to poor access to care, diagnostic insight, misdiagnosis, adherence to treatment, and management of comorbidities. Both patient and physician factors play an important role and many be modifiable.
• Conclusions: A focus on education of both patients and physicians is of paramount importance to improve the care provided to migraine patients. Patient evaluations should be multisystemic and include addressing comorbid conditions as well as a discussion about appropriate use of prevention and avoidance of medication overuse.

Key words: migraine; triptans; medication overuse headache; medication adherence; primary care.

Migraine is a common, debilitating condition that is a significant source of reduced productivity and increased disability [1]. According to the latest government statistics, 14.2% of US adults have reported having migraine or severe headaches in the previous 3 months, with an overall age-adjusted 3-month prevalence of 19.1% in females and 9.0% in males [2]. In a self-administered headache questionnaire mailed to 120,000 representative US households, the 1-year period prevalence for migraine was 11.7% (17.1% in women and 5.6% in men). Prevalence peaked in middle life and was lower in adolescents and those older than age 60 years [3]. Migraine is an important cause of reduced health-related quality of life and has a very high economic burden [4]. This effect is even more marked in those with chronic migraine, who are even more likely to have professional and social absenteeism and experience more severe disability [4].

Migraine and headache are a common reason for primary care physician (PCP) visits. Some estimates suggest that as many as 10% of primary care consultations are due to headache [5]. Approximately 75% of all patients complaining of headache in primary care will eventually be diagnosed with migraine [6]. Of these, as many as 1% to 5% will have chronic migraine [6].

Despite the high frequency and social and economic impact of migraine, migraine is underrecognized and undertreated. A survey of US households revealed that only 13% of migraineurs were currently using a preventive thrapy while 43.3% had never used one [3]. This is despite the fact that 32.4% met expert criteria for consideration of a preventive medication [3]. The reasons for underrecognition and undertreatment are multifactorial and include both patient and physician factors.

Physician Factors

Although migraine and headache are a leading cause of physicians visits, most physicians have had little formal training in headache. In the United States, medical students spend an average of 1 hour of preclinical and 2 hours of clinical education in headache [7]. Furthermore, primary care physicians receive little formal training in headache during residency [8]. In addition to the lack of formal training, there is also a lack of substantial clinic time available to fully evaluate and treat a new headache patient in the primary care setting [8]. Headache consultations can often be timely and detail-driven in order to determine the correct diagnosis and treatment [9].

Misdiagnosis

Evidence suggests that misdiagnosis plays a large role in the suboptimal management of migraineurs. Studies have shown that as many as 59.7% of migraineurs were not given a diagnosis of migraine by their primary care provider [10]. Common mistaken diagnoses include tension-type headache [11], “sinus headache” [12], cervical pain syndrome or cervicogenic headache [13], and “stress headache” [14].

The reasons for these misdiagnoses is not certain. It may be that the patient and practitioner assume that location of the pain is suggestive of the cause [13]. This is even though more than half of those with migraine have associated neck pain [15]. A recent study suggests that 60% of migraineurs who self-reported a diagnosis of cervical pain have been subsequently diagnosed with cervicalgia by a physician [13]. If patients endorse stress as a precipitant or the presence of cervical pain, they are more likely to obtain a diagnosis other than migraine. The presence of aura in association with the headache appears to be protective against misdiagnosis [13].

Similarly, patients are often given a diagnosis of “sinus headache.” This diagnosis is often made without radiologic evidence of sinusitis and even in those with a more typical migraine headache [16]. In one survey, 40% of patients meeting criteria for migraine were given this diagnosis. Many of these patients did have nasal symptoms or facial pain without clear evidence or rhinosinusitis, and in some cases these symptoms would respond to migraine treatments [16]. This is a particularly important misdiagnosis to highlight, as attributing symptoms to sinus disease may lead to unnecessary consultations and even sinus instrumentation.

In addition to common misdiagnoses, many PCPs are unfamiliar with the “red flags” that may indicate a secondary headache disorder and are also unfamiliar with appropriate use of neuroimaging in headache patients [17].

Misuse of As-Needed Medications

Studies have suggested that a large proportion of PCPs will prescribe nonspecific analgesics for migraine rather than migraine-specific medications [18]. These treatments may include NSAIDs, acetaminophen, barbiturates, and even opiates. This appears to be the pattern even for those with severe attacks [18], suggesting that migraine-specific medications such as triptans may be underused in the primary care setting. Postulated reasons for this pattern include lack of physician knowledge regarding the specific recommendations for managing migraine, the cost of medications, as well as lack of insurance coverage for these medications [19]. Misuse of as-needed medications can lead to medication overuse headache (MOH), which is an underrecognized problem in the primary care setting [20]. In a survey of PCPs in Boston, only 54% of PCPs were aware that barbiturates can cause MOH and only 34% were aware that opiates can cause MOH [17]. The same survey revealed that approximately 20% of PCPs had never made the diagnosis of MOH [17].

Underuse of Preventive Medications

As many as 40% of migraineurs need preventive therapy, but only approximately 13% are currently receiving it [3]. Additionally, the average time from diagnosis of migraine to instituting preventive treatment is 4.3 years, and often there is only a single preventive medication trial if one is instituted [21]. The reasons for this appear to be complex. The physician factors contributing to the underuse of preventive medications include inadequate education, discomfort and inadequate time for assessments. Only 27.8% of surveyed PCPs were aware of the American Academy of Neurology guidelines for prescribing preventive medications [17].

There may be an underestimate of the disability experienced by migraineurs, which can explain some of the underuse of preventive medications. While many PCPs endorse inquiring about headache-related disability, many do not used validated scales such as the Migraine Disability Assessment Score (MIDAS) or the Headache Impact Test (HIT) [17]. In addition, patients often underreport their headache days and report only their severe exacerbations unless clearly asked about a daily headache [22]. This may be part of the reason why only 20% of migraineurs who meet criteria for chronic migraine are diagnosed as such and why preventatives may not be offered [23].

After preventatives are started, less than 25% of patients will be adherent to oral migraine preventive agents at 1 year [24]. Common reasons for discontinuing preventives include adverse effects and perceived inefficacy [22]. Preventive medications may need a 6- to 8-week trial before efficacy is determined, but in practice medications may be stopped before this threshold is reached. Inadequate follow-up and lack of detail with regard to medication trials may result in the perception of an intractable patient prematurely. It has been suggested that a systematic approach to documenting and choosing preventive agents is helpful in the treatment of migraine [25], although this is not always practical in the primary care setting.

Another contributor to underuse of effective prophylaxis is related to access. Treatment with onabotulinumtoxin A, an efficacious prophylactic treatment approved for select chronic migraine patients [26], will usually require referral to a headache specialist, which is not always available to PCPs in a timely manner [7].

Nonpharmacologic Approaches

Effective nonpharmacologic treatment modalities for migraine, such as cognitive-behavioral therapy and biofeedback [27], are not commonly recommended by PCPs [17]. Instead, there appears to be more focus on avoidance of triggers and referral to non–evidence-based resources, such as special diets and massage therapy [17]. While these methods are not always inappropriate, it should be noted that they often have little or no evidence for efficacy.

Patients often wish for non-medication approaches to migraine management, but for those with significant and severe disability, these are probably insufficient. In these patients, non-medication approaches may best be used as a supplement to pharmacological treatment, with education on pharmacologic prevention given. Neuromodulation is a promising, novel approach that is emerging as a new treatment for migraine, but likely will require referral to a headache specialist.

Suboptimal Management of Migraine Comorbidities

There are several disorders that are commonly comorbid with migraine. Among the most common are anxiety, depression, medication (and caffeine) overuse, obesity, and sleep disorders [22]. A survey of PCPs reveals that only 50.6% of PCPs screen for anxiety, 60.2% for depression, and 73.5% for sleep disorders [17]. They are, for the most part, modifiable or treatable conditions and their proper management may help ease migraine disability.

In addition, the presence of these comorbidities may alter choice of treatment, for example, favoring the use of an serotonin and norepinephrine reuptake inhibitor such as venlafaxine for treatment  in those with comorbid anxiety and depression. It is also worthwhile to have a high index of suspicion for obstructive sleep apnea in patients with headache, particularly in the obese and in those who endorse nonrestorative sleep or excessive daytime somnolence. It appears that patients who are adherent to the treatment of sleep apnea are more likely to report improvement in their headache [28].

Given the time constraints that often exist in the PCP office setting, addressing these comorbidities thoroughly is not always possible. It is reasonable, however, to have patients use screening tools while in the waiting room or prior to an appointment, to better identify those with modifiable comorbidities. Depression, anxiety, and excessive daytime sleepiness can all be screened for relatively easily with tools such as the PHQ-9 [29], GAD-7 [30] and Epworth Sleepiness Scale [31], respectively. A positive screen on any of these could lead the PCP to further investigate these entities as a possible contributor to migraine.

Patient Factors

In addition to the physician factors identified above, patient factors can contribute to the suboptimal management of migraine as well. These factors include a lack insight into diagnosis, poor compliance with treatment of migraine or its comorbidities, and overuse of abortive medications. There are also less modifiable patient factors such as socioeconomic status and the stigma that may be associated with migraine.

Poor Insight Into Diagnosis

Despite the high prevalence and burden of migraine in the general population, there is a staggering lack of awareness among migraineurs. Some estimates state that as many as 54% of patients were unaware that their headaches represented migraine [32]. The most common self-reported diagnoses in migraineurs are sinus headache (39%), tension-type headache (31%) and stress headache (29%) [14]. In addition, many patients believe they are suffering from cervical spine–related pain [13]. This is likely due to the common presence of posteriorly located pain, attacks triggered by poor sleep, or attacks associated with weather changes [13]. Patients presenting with aura are more likely to report and to receive a physician diagnosis of migraine [14]. Women are more likely to receive and report a diagnosis of migraine compared with men [32].

There are many factors that play a role in poor insight. Many patients appear to believe that the location of the pain is suggestive of the cause [13]. Many patients never seek out consultation for their headaches, and thus never receive a proper diagnosis [33]. Some patients may seek out medical care for their headaches, but fail to remember their diagnosis or receive an improper diagnosis [34].

Poor Adherence

The body of literature examining adherence with headache treatment is growing, but remains small [35]. In a recent systematic review of treatment adherence in pediatric and adult patients with headache, adherence rates in adults with headache ranged from 25% to 94% [35]. In this review, prescription claims data analyses found poor persistence in patients prescribed triptans for migraine treatment. In one large claims-based study, 53.8% of patients  receiving a new triptan prescription did not persistently refill their index triptan [36]. Although some of these patients switched to an alternative triptan, the majority switched to a non-triptan migraine medication, including opioids and nonsteroidal anti-inflammatory drugs [36].

Cady and colleagues’ study of lapsed and sustained triptan users found that sustained users were significantly more satisfied with their medication, confident in the medication’s ability to control headache, and reported control of migraine with fewer doses of medication [37]. The authors concluded that the findings suggest that lapsed users may not be receiving optimal treatment. In a review by Rains et al [38], the authors found that headache treatment adherence declines “with more frequent and complex dosing regimens, side effects, and costs, and is subject to a wide range of psychosocial influences.”

Adherence issues also exist for migraine prevention. Less than 25% of chronic migraine patients continue to take oral preventive therapies at 1 year [24]. The reasons for this nonadherence are not completely clear, but are likely multifactorial. Preventives may take several weeks to months to become effective, which may contribute to noncompliance. In addition, migraineurs appears to have inadequate follow-up for migraine. Studies from France suggest that only 18% of those aware of their migraine diagnosis received medical follow-up [39].

Medication Overuse

While the data is not entirely clear, it is likely that overuse of as-needed medication plays a role in migraine chronification [40]. The reasons for medication overuse in the migraine population include some of the issues already highlighted above, including inadequate patient education, poor insight into diagnosis, not seeking care, misdiagnosis, and treatment nonadherence. Patients should be educated on the proper use of as-needed medication. Limits to medication use should be set during the physician-patient encounter. Patients should be counselled to limit their as-needed medication to no more than 10 days per month to reduce the risk of medication overuse headache. Ideally, opiates and barbiturates should be avoided, and never used as first-line therapy in patients who lack contraindications to NSAIDs and triptans. If their use in unavoidable for other reasons, they should be used sparingly, as use on as few as 5 to 8 days per month can be problematic [41]. Furthermore it is important to note that if patients are using several different acute analgesics, the combined total use of all as-needed pain medications needs to be less than 10 days per month to reduce the potential for medication overuse headache.

Socioeconomic Factors

Low socioeconomic status has been associated with an increased prevalence for all headache forms and an increased migraine attack frequency [42], but there appear to be few studies looking at the impact of low socioeconomic status and treatment. Lipton et al found that health insurance status was an important predictor of persons with migraine consulting a health care professional [43]. Among consulters, women were far more likely to be diagnosed than men, suggesting that gender bias in diagnosis may be an important barrier for men. Higher household income appeared to be a predictor for receiving a correct diagnosis of migraine. These researchers also found economic barriers related to use of appropriate prescription medications [43]. Differences in diagnosis and treatment may indicate racial and ethnic disparities in access and quality of care for minority patients [44].

Stigma

At least 1 study has reported that migraine patients experience stigma. In Young et al’s study of  123 episodic migraine patients, 123 chronic migraine patients, and 62 epilepsy patients, adjusted stigma was similar for chronic migraine and epilepsy, which were greater than for episodic migraine [45]. Stigma correlated most strongly with inability to work. Migraine patients reported equally high stigma scores across age, income, and education. The stigma of migraine may pose a barrier to seeking consultation and treatment. Further, the perception that migraine is “just a headache” may lead to stigmatizing attitudes on the part of friends, family, and coworkers of patients with migraine.

Conclusions and Recommendations

Migraine is a prevalent and frequently disabling condition that is underrecognized and undertreated in the primary care setting. Both physician and patient factors pose barriers to the optimal diagnosis and treatment of migraine. Remedies to address these barriers include education of both patients and physicians first and foremost. Targeting physician education in medical school and during residency training, including in primary care subspecialties, could include additional didactic teaching, but also clinical encounters in headache subspecialty clinics to increase exposure. Patient advocacy groups and public campaigns to improve understanding of migraine in the community may be a means for improving patient education and reducing stigma. Patients should be encouraged to seek out consultations for headache to reduce long-term headache disability. Management of comorbidities is paramount, and screening tools for migraine-associated disability, anxiety, depression, and medication use may be helpful to implement in the primary care setting as they are easy to use and time saving.

Recent surveys of PCPs suggest that the resource that is most desired is ready access to subspecialists for advice and “curb-side” consultation [17]. While this solution is not always practical, it may be worthwhile exploring closer relationships between primary care and subspecialty headache clinics, or perhaps more access to e-consultation or telephone consultation for more rural areas. Recently, Minen et al examined education strategies for PCPs. While in-person education sessions with PCPs were poorly attended, multiple possibilities for further education were identified. It was suggested that PCPs having real-time access to resources during the patient encounter would improve their comfort in managing patients. This includes online databases, simple algorithms for treatment, and directions for when to refer to a neurologist [46]. In addition, it may be worthwhile to train not only PCPs but also nursing and allied health staff so that they can provide headache education to patients. This may help ease some of the time burden on PCPs as well as provide a collaborative environment in which headache can be managed [46].

Corresponding author: William S. Kingston, MD, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ 85259.

Financial disclosures: None.

From the Mayo Clinic, Scottsdale, AZ.

Abstract

• Objective: To review the impact of migraine and explore the barriers to optimal migraine diagnosis and treatment.
• Methods: Review of the literature.
• Results: Several factors may play a role in the inadequate care of migraine patients, including issues related to poor access to care, diagnostic insight, misdiagnosis, adherence to treatment, and management of comorbidities. Both patient and physician factors play an important role and many be modifiable.
• Conclusions: A focus on education of both patients and physicians is of paramount importance to improve the care provided to migraine patients. Patient evaluations should be multisystemic and include addressing comorbid conditions as well as a discussion about appropriate use of prevention and avoidance of medication overuse.

Key words: migraine; triptans; medication overuse headache; medication adherence; primary care.

Migraine is a common, debilitating condition that is a significant source of reduced productivity and increased disability [1]. According to the latest government statistics, 14.2% of US adults have reported having migraine or severe headaches in the previous 3 months, with an overall age-adjusted 3-month prevalence of 19.1% in females and 9.0% in males [2]. In a self-administered headache questionnaire mailed to 120,000 representative US households, the 1-year period prevalence for migraine was 11.7% (17.1% in women and 5.6% in men). Prevalence peaked in middle life and was lower in adolescents and those older than age 60 years [3]. Migraine is an important cause of reduced health-related quality of life and has a very high economic burden [4]. This effect is even more marked in those with chronic migraine, who are even more likely to have professional and social absenteeism and experience more severe disability [4].

Migraine and headache are a common reason for primary care physician (PCP) visits. Some estimates suggest that as many as 10% of primary care consultations are due to headache [5]. Approximately 75% of all patients complaining of headache in primary care will eventually be diagnosed with migraine [6]. Of these, as many as 1% to 5% will have chronic migraine [6].

Despite the high frequency and social and economic impact of migraine, migraine is underrecognized and undertreated. A survey of US households revealed that only 13% of migraineurs were currently using a preventive thrapy while 43.3% had never used one [3]. This is despite the fact that 32.4% met expert criteria for consideration of a preventive medication [3]. The reasons for underrecognition and undertreatment are multifactorial and include both patient and physician factors.

Physician Factors

Although migraine and headache are a leading cause of physicians visits, most physicians have had little formal training in headache. In the United States, medical students spend an average of 1 hour of preclinical and 2 hours of clinical education in headache [7]. Furthermore, primary care physicians receive little formal training in headache during residency [8]. In addition to the lack of formal training, there is also a lack of substantial clinic time available to fully evaluate and treat a new headache patient in the primary care setting [8]. Headache consultations can often be timely and detail-driven in order to determine the correct diagnosis and treatment [9].

Misdiagnosis

Evidence suggests that misdiagnosis plays a large role in the suboptimal management of migraineurs. Studies have shown that as many as 59.7% of migraineurs were not given a diagnosis of migraine by their primary care provider [10]. Common mistaken diagnoses include tension-type headache [11], “sinus headache” [12], cervical pain syndrome or cervicogenic headache [13], and “stress headache” [14].

The reasons for these misdiagnoses is not certain. It may be that the patient and practitioner assume that location of the pain is suggestive of the cause [13]. This is even though more than half of those with migraine have associated neck pain [15]. A recent study suggests that 60% of migraineurs who self-reported a diagnosis of cervical pain have been subsequently diagnosed with cervicalgia by a physician [13]. If patients endorse stress as a precipitant or the presence of cervical pain, they are more likely to obtain a diagnosis other than migraine. The presence of aura in association with the headache appears to be protective against misdiagnosis [13].

Similarly, patients are often given a diagnosis of “sinus headache.” This diagnosis is often made without radiologic evidence of sinusitis and even in those with a more typical migraine headache [16]. In one survey, 40% of patients meeting criteria for migraine were given this diagnosis. Many of these patients did have nasal symptoms or facial pain without clear evidence or rhinosinusitis, and in some cases these symptoms would respond to migraine treatments [16]. This is a particularly important misdiagnosis to highlight, as attributing symptoms to sinus disease may lead to unnecessary consultations and even sinus instrumentation.

In addition to common misdiagnoses, many PCPs are unfamiliar with the “red flags” that may indicate a secondary headache disorder and are also unfamiliar with appropriate use of neuroimaging in headache patients [17].

Misuse of As-Needed Medications

Studies have suggested that a large proportion of PCPs will prescribe nonspecific analgesics for migraine rather than migraine-specific medications [18]. These treatments may include NSAIDs, acetaminophen, barbiturates, and even opiates. This appears to be the pattern even for those with severe attacks [18], suggesting that migraine-specific medications such as triptans may be underused in the primary care setting. Postulated reasons for this pattern include lack of physician knowledge regarding the specific recommendations for managing migraine, the cost of medications, as well as lack of insurance coverage for these medications [19]. Misuse of as-needed medications can lead to medication overuse headache (MOH), which is an underrecognized problem in the primary care setting [20]. In a survey of PCPs in Boston, only 54% of PCPs were aware that barbiturates can cause MOH and only 34% were aware that opiates can cause MOH [17]. The same survey revealed that approximately 20% of PCPs had never made the diagnosis of MOH [17].

Underuse of Preventive Medications

As many as 40% of migraineurs need preventive therapy, but only approximately 13% are currently receiving it [3]. Additionally, the average time from diagnosis of migraine to instituting preventive treatment is 4.3 years, and often there is only a single preventive medication trial if one is instituted [21]. The reasons for this appear to be complex. The physician factors contributing to the underuse of preventive medications include inadequate education, discomfort and inadequate time for assessments. Only 27.8% of surveyed PCPs were aware of the American Academy of Neurology guidelines for prescribing preventive medications [17].

There may be an underestimate of the disability experienced by migraineurs, which can explain some of the underuse of preventive medications. While many PCPs endorse inquiring about headache-related disability, many do not used validated scales such as the Migraine Disability Assessment Score (MIDAS) or the Headache Impact Test (HIT) [17]. In addition, patients often underreport their headache days and report only their severe exacerbations unless clearly asked about a daily headache [22]. This may be part of the reason why only 20% of migraineurs who meet criteria for chronic migraine are diagnosed as such and why preventatives may not be offered [23].

After preventatives are started, less than 25% of patients will be adherent to oral migraine preventive agents at 1 year [24]. Common reasons for discontinuing preventives include adverse effects and perceived inefficacy [22]. Preventive medications may need a 6- to 8-week trial before efficacy is determined, but in practice medications may be stopped before this threshold is reached. Inadequate follow-up and lack of detail with regard to medication trials may result in the perception of an intractable patient prematurely. It has been suggested that a systematic approach to documenting and choosing preventive agents is helpful in the treatment of migraine [25], although this is not always practical in the primary care setting.

Another contributor to underuse of effective prophylaxis is related to access. Treatment with onabotulinumtoxin A, an efficacious prophylactic treatment approved for select chronic migraine patients [26], will usually require referral to a headache specialist, which is not always available to PCPs in a timely manner [7].

Nonpharmacologic Approaches

Effective nonpharmacologic treatment modalities for migraine, such as cognitive-behavioral therapy and biofeedback [27], are not commonly recommended by PCPs [17]. Instead, there appears to be more focus on avoidance of triggers and referral to non–evidence-based resources, such as special diets and massage therapy [17]. While these methods are not always inappropriate, it should be noted that they often have little or no evidence for efficacy.

Patients often wish for non-medication approaches to migraine management, but for those with significant and severe disability, these are probably insufficient. In these patients, non-medication approaches may best be used as a supplement to pharmacological treatment, with education on pharmacologic prevention given. Neuromodulation is a promising, novel approach that is emerging as a new treatment for migraine, but likely will require referral to a headache specialist.

Suboptimal Management of Migraine Comorbidities

There are several disorders that are commonly comorbid with migraine. Among the most common are anxiety, depression, medication (and caffeine) overuse, obesity, and sleep disorders [22]. A survey of PCPs reveals that only 50.6% of PCPs screen for anxiety, 60.2% for depression, and 73.5% for sleep disorders [17]. They are, for the most part, modifiable or treatable conditions and their proper management may help ease migraine disability.

In addition, the presence of these comorbidities may alter choice of treatment, for example, favoring the use of an serotonin and norepinephrine reuptake inhibitor such as venlafaxine for treatment  in those with comorbid anxiety and depression. It is also worthwhile to have a high index of suspicion for obstructive sleep apnea in patients with headache, particularly in the obese and in those who endorse nonrestorative sleep or excessive daytime somnolence. It appears that patients who are adherent to the treatment of sleep apnea are more likely to report improvement in their headache [28].

Given the time constraints that often exist in the PCP office setting, addressing these comorbidities thoroughly is not always possible. It is reasonable, however, to have patients use screening tools while in the waiting room or prior to an appointment, to better identify those with modifiable comorbidities. Depression, anxiety, and excessive daytime sleepiness can all be screened for relatively easily with tools such as the PHQ-9 [29], GAD-7 [30] and Epworth Sleepiness Scale [31], respectively. A positive screen on any of these could lead the PCP to further investigate these entities as a possible contributor to migraine.

Patient Factors

In addition to the physician factors identified above, patient factors can contribute to the suboptimal management of migraine as well. These factors include a lack insight into diagnosis, poor compliance with treatment of migraine or its comorbidities, and overuse of abortive medications. There are also less modifiable patient factors such as socioeconomic status and the stigma that may be associated with migraine.

Poor Insight Into Diagnosis

Despite the high prevalence and burden of migraine in the general population, there is a staggering lack of awareness among migraineurs. Some estimates state that as many as 54% of patients were unaware that their headaches represented migraine [32]. The most common self-reported diagnoses in migraineurs are sinus headache (39%), tension-type headache (31%) and stress headache (29%) [14]. In addition, many patients believe they are suffering from cervical spine–related pain [13]. This is likely due to the common presence of posteriorly located pain, attacks triggered by poor sleep, or attacks associated with weather changes [13]. Patients presenting with aura are more likely to report and to receive a physician diagnosis of migraine [14]. Women are more likely to receive and report a diagnosis of migraine compared with men [32].

There are many factors that play a role in poor insight. Many patients appear to believe that the location of the pain is suggestive of the cause [13]. Many patients never seek out consultation for their headaches, and thus never receive a proper diagnosis [33]. Some patients may seek out medical care for their headaches, but fail to remember their diagnosis or receive an improper diagnosis [34].

Poor Adherence

The body of literature examining adherence with headache treatment is growing, but remains small [35]. In a recent systematic review of treatment adherence in pediatric and adult patients with headache, adherence rates in adults with headache ranged from 25% to 94% [35]. In this review, prescription claims data analyses found poor persistence in patients prescribed triptans for migraine treatment. In one large claims-based study, 53.8% of patients  receiving a new triptan prescription did not persistently refill their index triptan [36]. Although some of these patients switched to an alternative triptan, the majority switched to a non-triptan migraine medication, including opioids and nonsteroidal anti-inflammatory drugs [36].

Cady and colleagues’ study of lapsed and sustained triptan users found that sustained users were significantly more satisfied with their medication, confident in the medication’s ability to control headache, and reported control of migraine with fewer doses of medication [37]. The authors concluded that the findings suggest that lapsed users may not be receiving optimal treatment. In a review by Rains et al [38], the authors found that headache treatment adherence declines “with more frequent and complex dosing regimens, side effects, and costs, and is subject to a wide range of psychosocial influences.”

Adherence issues also exist for migraine prevention. Less than 25% of chronic migraine patients continue to take oral preventive therapies at 1 year [24]. The reasons for this nonadherence are not completely clear, but are likely multifactorial. Preventives may take several weeks to months to become effective, which may contribute to noncompliance. In addition, migraineurs appears to have inadequate follow-up for migraine. Studies from France suggest that only 18% of those aware of their migraine diagnosis received medical follow-up [39].

Medication Overuse

While the data is not entirely clear, it is likely that overuse of as-needed medication plays a role in migraine chronification [40]. The reasons for medication overuse in the migraine population include some of the issues already highlighted above, including inadequate patient education, poor insight into diagnosis, not seeking care, misdiagnosis, and treatment nonadherence. Patients should be educated on the proper use of as-needed medication. Limits to medication use should be set during the physician-patient encounter. Patients should be counselled to limit their as-needed medication to no more than 10 days per month to reduce the risk of medication overuse headache. Ideally, opiates and barbiturates should be avoided, and never used as first-line therapy in patients who lack contraindications to NSAIDs and triptans. If their use in unavoidable for other reasons, they should be used sparingly, as use on as few as 5 to 8 days per month can be problematic [41]. Furthermore it is important to note that if patients are using several different acute analgesics, the combined total use of all as-needed pain medications needs to be less than 10 days per month to reduce the potential for medication overuse headache.

Socioeconomic Factors

Low socioeconomic status has been associated with an increased prevalence for all headache forms and an increased migraine attack frequency [42], but there appear to be few studies looking at the impact of low socioeconomic status and treatment. Lipton et al found that health insurance status was an important predictor of persons with migraine consulting a health care professional [43]. Among consulters, women were far more likely to be diagnosed than men, suggesting that gender bias in diagnosis may be an important barrier for men. Higher household income appeared to be a predictor for receiving a correct diagnosis of migraine. These researchers also found economic barriers related to use of appropriate prescription medications [43]. Differences in diagnosis and treatment may indicate racial and ethnic disparities in access and quality of care for minority patients [44].

Stigma

At least 1 study has reported that migraine patients experience stigma. In Young et al’s study of  123 episodic migraine patients, 123 chronic migraine patients, and 62 epilepsy patients, adjusted stigma was similar for chronic migraine and epilepsy, which were greater than for episodic migraine [45]. Stigma correlated most strongly with inability to work. Migraine patients reported equally high stigma scores across age, income, and education. The stigma of migraine may pose a barrier to seeking consultation and treatment. Further, the perception that migraine is “just a headache” may lead to stigmatizing attitudes on the part of friends, family, and coworkers of patients with migraine.

Conclusions and Recommendations

Migraine is a prevalent and frequently disabling condition that is underrecognized and undertreated in the primary care setting. Both physician and patient factors pose barriers to the optimal diagnosis and treatment of migraine. Remedies to address these barriers include education of both patients and physicians first and foremost. Targeting physician education in medical school and during residency training, including in primary care subspecialties, could include additional didactic teaching, but also clinical encounters in headache subspecialty clinics to increase exposure. Patient advocacy groups and public campaigns to improve understanding of migraine in the community may be a means for improving patient education and reducing stigma. Patients should be encouraged to seek out consultations for headache to reduce long-term headache disability. Management of comorbidities is paramount, and screening tools for migraine-associated disability, anxiety, depression, and medication use may be helpful to implement in the primary care setting as they are easy to use and time saving.

Recent surveys of PCPs suggest that the resource that is most desired is ready access to subspecialists for advice and “curb-side” consultation [17]. While this solution is not always practical, it may be worthwhile exploring closer relationships between primary care and subspecialty headache clinics, or perhaps more access to e-consultation or telephone consultation for more rural areas. Recently, Minen et al examined education strategies for PCPs. While in-person education sessions with PCPs were poorly attended, multiple possibilities for further education were identified. It was suggested that PCPs having real-time access to resources during the patient encounter would improve their comfort in managing patients. This includes online databases, simple algorithms for treatment, and directions for when to refer to a neurologist [46]. In addition, it may be worthwhile to train not only PCPs but also nursing and allied health staff so that they can provide headache education to patients. This may help ease some of the time burden on PCPs as well as provide a collaborative environment in which headache can be managed [46].

Corresponding author: William S. Kingston, MD, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ 85259.

Financial disclosures: None.

MIAMI – Expert clinicians endorsed long-acting injectables as a preferred treatment for bipolar I disorder on the basis of patient characteristics and treatment history, rather than on an assumed level of treatment adherence, according to a small survey.

“Just over three-quarters of the experts we surveyed said they were ‘somewhat’ or ‘not very’ confident about their ability to assess their patients’ adherence,” said Martha Sajatovic, MD, who presented the data during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation Unit meeting.

The finding reflects a shift, according to Dr. Sajatovic, professor of psychiatry and neurology, and the Willard Brown Chair in Neurological Outcomes Research, at Case Western University in Cleveland.

Whitney McKnight/Frontline Medical News

[email protected]

On Twitter @whitneymcknight

MIAMI – Expert clinicians endorsed long-acting injectables as a preferred treatment for bipolar I disorder on the basis of patient characteristics and treatment history, rather than on an assumed level of treatment adherence, according to a small survey.

“Just over three-quarters of the experts we surveyed said they were ‘somewhat’ or ‘not very’ confident about their ability to assess their patients’ adherence,” said Martha Sajatovic, MD, who presented the data during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation Unit meeting.

The finding reflects a shift, according to Dr. Sajatovic, professor of psychiatry and neurology, and the Willard Brown Chair in Neurological Outcomes Research, at Case Western University in Cleveland.

Whitney McKnight/Frontline Medical News

[email protected]

On Twitter @whitneymcknight

MIAMI – Expert clinicians endorsed long-acting injectables as a preferred treatment for bipolar I disorder on the basis of patient characteristics and treatment history, rather than on an assumed level of treatment adherence, according to a small survey.

“Just over three-quarters of the experts we surveyed said they were ‘somewhat’ or ‘not very’ confident about their ability to assess their patients’ adherence,” said Martha Sajatovic, MD, who presented the data during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation Unit meeting.

The finding reflects a shift, according to Dr. Sajatovic, professor of psychiatry and neurology, and the Willard Brown Chair in Neurological Outcomes Research, at Case Western University in Cleveland.

Whitney McKnight/Frontline Medical News

[email protected]

On Twitter @whitneymcknight

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine the effect of navigation for older cancer patients by lay persons on health care use and Medicare costs.

Design. Observational cohort study using propensity score–matched controls.

Setting and participants. The study was conducted at the University of Alabama at Birmingham Health System Cancer Community Network, which consists of 2 academic and 10 community cancer centers across Alabama, Georgia, Florida, Mississippi and Tennessee. Participants were Medicare beneficiaries who received care at these facilities from 1 Jan 2012 to 31 Dec 2015. The patient population includes Medicare beneficiaries age 65 years or older with primary Medicare Part A and B insurance and a cancer diagnosis from 2012 to 2015, and excludes those with Medicare health maintenance organization coverage. Only patients with 1 quarter of observation prior to receiving patient navigation and those with 2 quarters of observation after initiation of navigation services were included in the sample. Propensity score matching method was used to establish a matched group of patients without patient navigation. Covariates included in the propensity score matching include age at diagnosis, race, sex, cancer acuity, phase of care, comorbidity score, cost of care, treatment with chemotherapy and emergency department (ED) and intensive care unit use at baseline.

Patients were identified to receive patient navigation through review of patient census in the ED and hospital, clinical referral, and self-referral. High-risk patients were prioritized to receive navigation; this included patients with metastatic disease, cancers that have high morbidity, chronic diseases that have high morbidity, or a history of recent acute care utilization.

Navigation program. The patient navigation program was started in 2013 as an innovation project funded by the Center for Medicare and Medicaid Services. Implementation began in March 2013 and all sites started to enroll patients for patient navigation by October 2013. Patient navigation was conducted by lay navigators who were hired from within the community. Navigators were required to have a bachelor’s degree but were not licensed clinicians such as a nurse or social worker. Patient navigators aimed to proactively identify patient needs, connect patient with resources, coordinate patient care, and empower patients to take an active role in their own care. Navigators performed distress screenings that assessed patients’ practical, information, financial, familial, emotional, spiritual and physical concerns. Assistance was given to patients at patients’ request and algorithms were used to guide frequency of contact.

Main outcome measures. The main outcome measure was Medicare costs per beneficiary per quarter; these costs include all amounts paid by Medicare for all care received but exclude Medicare Part D prescription drug costs. Other outcomes included source of costs and resource utilization defined by number of ED visits, hospitalizations, and intensive care unit admissions per quarter. The return on investment was also examined with the investment defined by salaries for the patient navigators, including fringe benefits; each navigator had a mean caseload of 152 patients per quarter. The return on investment was calculated as reduced Medicare costs of navigated patients compared with non-navigated patients multiplied by the number of patients served.

Main results. A total of 6214 matched pairs of navigated and non-navigated patients were included in the analysis. The mean age of the patients was 75 (SD ± 7) and 12% were African American. Medicare costs declined faster among those with navigation compared to the control group by $781 more per quarter per navigated patient. Inpatient and outpatient costs had the largest decline at $294 and $275 respectively. Resource use decreased in the navigated group more so than the non-navigated group, with a 6% more decrease per quarter in ED visits, 8% more decrease in hospitalization, and 11% more decrease in intensive care unit admissions. The return on investment was estimated at 1:10 with a $475,024 reduction in Medicare cost per navigator annually.

Conclusion. Navigation by lay persons among older Medicare beneficiaries with cancer is associated with a decrease in Medicare costs and resource utilization. There is substantial return on investment when considering the salaries of navigator staff against the Medicare savings associated with care navigation. Lay navigation appears to have benefits of reducing health care costs and resource use.

Commentary

The U.S. health care system is often difficult to navigate for older persons, particularly those with complex health care needs. Older adults with chronic disease, including cancer, may utilize care in multiple settings and with multiple providers and teams, making it challenging to organize and obtain needed care. In this study, the authors examined the impact of a patient navigation program on older patients with cancer and found that the use of lay navigation is associated with reduced costs and resource use for the health care system. Prior studies have examined the use of care navigation in complex chronic disease management, such as HIV infection and cancer [1,2] and have often found positive impacts on patient satisfaction, adherence to treatments, and reducing care disparities in vulnerable populations [3]. Care navigation has been performed using clinical staff, such as nursing, but with lay persons as well [4]. Lay persons offer the benefit of reduced costs, and if they are able to perform the care navigation tasks well with training, clinical staff use may not be necessary.

This study uses alternative methods to randomization to generate a balanced non-navigated control group for comparison to determine the impact of care navigation. The limitation is that the propensity score method used may balance potential confounders that are specified but unmeasured confounders were not accounted for in the analysis [5]. Another limitation is that the comparison group may not be concurrent, because non-navigated patients prior to the initiation of the navigation program were included in the control group. As care delivery often changes over time, non-concurrent comparison may introduce bias in the study. Nonetheless, the effect that is found on costs and resource utilization appear to be a strong one and is consistent with prior studies on the effects of care navigation.

Although this study spanned several clinical settings across a large geographic area, it is unclear if the program will offer similar benefits at other institutions. Additional studies that examine the impact of lay navigation on other patient outcomes such as satisfaction will be useful, as will studying the model at other institutions and in other settings to examine whether the program’s effects can be generalized.

Applications for Clinical Practice

In general, evidence suggests that patient navigation is an effective intervention for use in health care. Clinicians should consider assigning team members to help their patients with cancer navigate the health care system.

—William W. Hung, MD, MPH

Study Overview

Objective. To determine the effect of navigation for older cancer patients by lay persons on health care use and Medicare costs.

Design. Observational cohort study using propensity score–matched controls.

Setting and participants. The study was conducted at the University of Alabama at Birmingham Health System Cancer Community Network, which consists of 2 academic and 10 community cancer centers across Alabama, Georgia, Florida, Mississippi and Tennessee. Participants were Medicare beneficiaries who received care at these facilities from 1 Jan 2012 to 31 Dec 2015. The patient population includes Medicare beneficiaries age 65 years or older with primary Medicare Part A and B insurance and a cancer diagnosis from 2012 to 2015, and excludes those with Medicare health maintenance organization coverage. Only patients with 1 quarter of observation prior to receiving patient navigation and those with 2 quarters of observation after initiation of navigation services were included in the sample. Propensity score matching method was used to establish a matched group of patients without patient navigation. Covariates included in the propensity score matching include age at diagnosis, race, sex, cancer acuity, phase of care, comorbidity score, cost of care, treatment with chemotherapy and emergency department (ED) and intensive care unit use at baseline.

Patients were identified to receive patient navigation through review of patient census in the ED and hospital, clinical referral, and self-referral. High-risk patients were prioritized to receive navigation; this included patients with metastatic disease, cancers that have high morbidity, chronic diseases that have high morbidity, or a history of recent acute care utilization.

Navigation program. The patient navigation program was started in 2013 as an innovation project funded by the Center for Medicare and Medicaid Services. Implementation began in March 2013 and all sites started to enroll patients for patient navigation by October 2013. Patient navigation was conducted by lay navigators who were hired from within the community. Navigators were required to have a bachelor’s degree but were not licensed clinicians such as a nurse or social worker. Patient navigators aimed to proactively identify patient needs, connect patient with resources, coordinate patient care, and empower patients to take an active role in their own care. Navigators performed distress screenings that assessed patients’ practical, information, financial, familial, emotional, spiritual and physical concerns. Assistance was given to patients at patients’ request and algorithms were used to guide frequency of contact.

Main outcome measures. The main outcome measure was Medicare costs per beneficiary per quarter; these costs include all amounts paid by Medicare for all care received but exclude Medicare Part D prescription drug costs. Other outcomes included source of costs and resource utilization defined by number of ED visits, hospitalizations, and intensive care unit admissions per quarter. The return on investment was also examined with the investment defined by salaries for the patient navigators, including fringe benefits; each navigator had a mean caseload of 152 patients per quarter. The return on investment was calculated as reduced Medicare costs of navigated patients compared with non-navigated patients multiplied by the number of patients served.

Main results. A total of 6214 matched pairs of navigated and non-navigated patients were included in the analysis. The mean age of the patients was 75 (SD ± 7) and 12% were African American. Medicare costs declined faster among those with navigation compared to the control group by $781 more per quarter per navigated patient. Inpatient and outpatient costs had the largest decline at $294 and $275 respectively. Resource use decreased in the navigated group more so than the non-navigated group, with a 6% more decrease per quarter in ED visits, 8% more decrease in hospitalization, and 11% more decrease in intensive care unit admissions. The return on investment was estimated at 1:10 with a $475,024 reduction in Medicare cost per navigator annually.

Conclusion. Navigation by lay persons among older Medicare beneficiaries with cancer is associated with a decrease in Medicare costs and resource utilization. There is substantial return on investment when considering the salaries of navigator staff against the Medicare savings associated with care navigation. Lay navigation appears to have benefits of reducing health care costs and resource use.

Commentary

The U.S. health care system is often difficult to navigate for older persons, particularly those with complex health care needs. Older adults with chronic disease, including cancer, may utilize care in multiple settings and with multiple providers and teams, making it challenging to organize and obtain needed care. In this study, the authors examined the impact of a patient navigation program on older patients with cancer and found that the use of lay navigation is associated with reduced costs and resource use for the health care system. Prior studies have examined the use of care navigation in complex chronic disease management, such as HIV infection and cancer [1,2] and have often found positive impacts on patient satisfaction, adherence to treatments, and reducing care disparities in vulnerable populations [3]. Care navigation has been performed using clinical staff, such as nursing, but with lay persons as well [4]. Lay persons offer the benefit of reduced costs, and if they are able to perform the care navigation tasks well with training, clinical staff use may not be necessary.

This study uses alternative methods to randomization to generate a balanced non-navigated control group for comparison to determine the impact of care navigation. The limitation is that the propensity score method used may balance potential confounders that are specified but unmeasured confounders were not accounted for in the analysis [5]. Another limitation is that the comparison group may not be concurrent, because non-navigated patients prior to the initiation of the navigation program were included in the control group. As care delivery often changes over time, non-concurrent comparison may introduce bias in the study. Nonetheless, the effect that is found on costs and resource utilization appear to be a strong one and is consistent with prior studies on the effects of care navigation.

Although this study spanned several clinical settings across a large geographic area, it is unclear if the program will offer similar benefits at other institutions. Additional studies that examine the impact of lay navigation on other patient outcomes such as satisfaction will be useful, as will studying the model at other institutions and in other settings to examine whether the program’s effects can be generalized.

Applications for Clinical Practice

In general, evidence suggests that patient navigation is an effective intervention for use in health care. Clinicians should consider assigning team members to help their patients with cancer navigate the health care system.

—William W. Hung, MD, MPH

Study Overview

Objective. To determine the effect of navigation for older cancer patients by lay persons on health care use and Medicare costs.

Design. Observational cohort study using propensity score–matched controls.

Setting and participants. The study was conducted at the University of Alabama at Birmingham Health System Cancer Community Network, which consists of 2 academic and 10 community cancer centers across Alabama, Georgia, Florida, Mississippi and Tennessee. Participants were Medicare beneficiaries who received care at these facilities from 1 Jan 2012 to 31 Dec 2015. The patient population includes Medicare beneficiaries age 65 years or older with primary Medicare Part A and B insurance and a cancer diagnosis from 2012 to 2015, and excludes those with Medicare health maintenance organization coverage. Only patients with 1 quarter of observation prior to receiving patient navigation and those with 2 quarters of observation after initiation of navigation services were included in the sample. Propensity score matching method was used to establish a matched group of patients without patient navigation. Covariates included in the propensity score matching include age at diagnosis, race, sex, cancer acuity, phase of care, comorbidity score, cost of care, treatment with chemotherapy and emergency department (ED) and intensive care unit use at baseline.

Patients were identified to receive patient navigation through review of patient census in the ED and hospital, clinical referral, and self-referral. High-risk patients were prioritized to receive navigation; this included patients with metastatic disease, cancers that have high morbidity, chronic diseases that have high morbidity, or a history of recent acute care utilization.

Navigation program. The patient navigation program was started in 2013 as an innovation project funded by the Center for Medicare and Medicaid Services. Implementation began in March 2013 and all sites started to enroll patients for patient navigation by October 2013. Patient navigation was conducted by lay navigators who were hired from within the community. Navigators were required to have a bachelor’s degree but were not licensed clinicians such as a nurse or social worker. Patient navigators aimed to proactively identify patient needs, connect patient with resources, coordinate patient care, and empower patients to take an active role in their own care. Navigators performed distress screenings that assessed patients’ practical, information, financial, familial, emotional, spiritual and physical concerns. Assistance was given to patients at patients’ request and algorithms were used to guide frequency of contact.

Main outcome measures. The main outcome measure was Medicare costs per beneficiary per quarter; these costs include all amounts paid by Medicare for all care received but exclude Medicare Part D prescription drug costs. Other outcomes included source of costs and resource utilization defined by number of ED visits, hospitalizations, and intensive care unit admissions per quarter. The return on investment was also examined with the investment defined by salaries for the patient navigators, including fringe benefits; each navigator had a mean caseload of 152 patients per quarter. The return on investment was calculated as reduced Medicare costs of navigated patients compared with non-navigated patients multiplied by the number of patients served.

Main results. A total of 6214 matched pairs of navigated and non-navigated patients were included in the analysis. The mean age of the patients was 75 (SD ± 7) and 12% were African American. Medicare costs declined faster among those with navigation compared to the control group by $781 more per quarter per navigated patient. Inpatient and outpatient costs had the largest decline at $294 and $275 respectively. Resource use decreased in the navigated group more so than the non-navigated group, with a 6% more decrease per quarter in ED visits, 8% more decrease in hospitalization, and 11% more decrease in intensive care unit admissions. The return on investment was estimated at 1:10 with a $475,024 reduction in Medicare cost per navigator annually.

Conclusion. Navigation by lay persons among older Medicare beneficiaries with cancer is associated with a decrease in Medicare costs and resource utilization. There is substantial return on investment when considering the salaries of navigator staff against the Medicare savings associated with care navigation. Lay navigation appears to have benefits of reducing health care costs and resource use.

Commentary

The U.S. health care system is often difficult to navigate for older persons, particularly those with complex health care needs. Older adults with chronic disease, including cancer, may utilize care in multiple settings and with multiple providers and teams, making it challenging to organize and obtain needed care. In this study, the authors examined the impact of a patient navigation program on older patients with cancer and found that the use of lay navigation is associated with reduced costs and resource use for the health care system. Prior studies have examined the use of care navigation in complex chronic disease management, such as HIV infection and cancer [1,2] and have often found positive impacts on patient satisfaction, adherence to treatments, and reducing care disparities in vulnerable populations [3]. Care navigation has been performed using clinical staff, such as nursing, but with lay persons as well [4]. Lay persons offer the benefit of reduced costs, and if they are able to perform the care navigation tasks well with training, clinical staff use may not be necessary.

This study uses alternative methods to randomization to generate a balanced non-navigated control group for comparison to determine the impact of care navigation. The limitation is that the propensity score method used may balance potential confounders that are specified but unmeasured confounders were not accounted for in the analysis [5]. Another limitation is that the comparison group may not be concurrent, because non-navigated patients prior to the initiation of the navigation program were included in the control group. As care delivery often changes over time, non-concurrent comparison may introduce bias in the study. Nonetheless, the effect that is found on costs and resource utilization appear to be a strong one and is consistent with prior studies on the effects of care navigation.

Although this study spanned several clinical settings across a large geographic area, it is unclear if the program will offer similar benefits at other institutions. Additional studies that examine the impact of lay navigation on other patient outcomes such as satisfaction will be useful, as will studying the model at other institutions and in other settings to examine whether the program’s effects can be generalized.

Applications for Clinical Practice

In general, evidence suggests that patient navigation is an effective intervention for use in health care. Clinicians should consider assigning team members to help their patients with cancer navigate the health care system.

—William W. Hung, MD, MPH