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DMARDs may hamper pneumococcal vaccine response in systemic sclerosis patients
Patients taking disease-modifying antirheumatic medications for systemic sclerosis appear to have a decreased response to pneumococcal vaccines, a Swedish study has determined.
Those not taking disease-modifying antirheumatic medications (DMARDs), however, had a normal immune response, suggesting that it’s the immunomodulating medications, not the disease itself, that is affecting antibody levels, Roger Hesselstrand, MD, of Lund (Sweden) University and his colleagues reported online in Rheumatology.
“The currently recommended prime-boost vaccination strategy using a dose of PCV13 [13-valent pneumococcal conjugate vaccine] followed by a dose of PPV23 [23-valent pneumococcal polysaccharide vaccine] might be a possible way of enhancing the vaccine immunogenicity in immunosuppressed patients,” Dr. Hesselstrand and his coauthors wrote.
The study comprised 44 subjects with systemic sclerosis, 12 of whom were taking a DMARD (mycophenolate mofetil, azathioprine, or hydroxychloroquine), and 49 healthy controls; all underwent pneumococcal vaccination. The first 13 got a single dose of PPV23 intramuscularly. PCV13 was then licensed for adults in Sweden, and the remaining 31 patients received this vaccine. The primary outcome was 6-week change from baseline in the level of pneumococcal IgG to Streptococcus pneumoniae serotypes 23F and 6B.
Both vaccines were safe and well-tolerated by all patients, including those taking a DMARD.
Before vaccination, antibody levels to both serotypes were similar between the groups. After vaccination, antibody levels for both serotypes increased significantly in systemic sclerosis patients not taking a DMARD and in controls. However, patients taking a DMARD mounted only an adequate response to serotype 6B.
There were fewer responders among those taking DMARDs, whether they received the PCV13 or the PPV23 vaccine. An increase from prevaccination antibody levels of at least twofold occurred in fewer patients taking DMARDs than did in patients not taking DMARDs and in controls, regardless of vaccine type (PPV23, 50% vs. about 55% and 50%, respectively; PCV13, about 17% vs. 57% and 100%, respectively).
“We demonstrated that the antibody response ... as well as functionality of antibodies in [systemic sclerosis] patients not receiving DMARDs was as good as in controls regardless of vaccine type,” the investigators concluded. “Systemic sclerosis patients treated with DMARDs, however, had lower proportion of patients with positive antibody response, although the functionality of the antibodies was preserved. These results suggest that immunomodulating drugs but not systemic sclerosis itself and/or immunological disturbance as a part of this disease affect the ability to produce a sufficient amount of vaccine-specific antibodies, but not their function.”
None of the authors had conflicts of interest to disclose.
SOURCE: Hesselstrand R et al. Rheumatology [Oxford]. 2018 Jan 8. doi: 10.1093/rheumatology/kex471.
Patients taking disease-modifying antirheumatic medications for systemic sclerosis appear to have a decreased response to pneumococcal vaccines, a Swedish study has determined.
Those not taking disease-modifying antirheumatic medications (DMARDs), however, had a normal immune response, suggesting that it’s the immunomodulating medications, not the disease itself, that is affecting antibody levels, Roger Hesselstrand, MD, of Lund (Sweden) University and his colleagues reported online in Rheumatology.
“The currently recommended prime-boost vaccination strategy using a dose of PCV13 [13-valent pneumococcal conjugate vaccine] followed by a dose of PPV23 [23-valent pneumococcal polysaccharide vaccine] might be a possible way of enhancing the vaccine immunogenicity in immunosuppressed patients,” Dr. Hesselstrand and his coauthors wrote.
The study comprised 44 subjects with systemic sclerosis, 12 of whom were taking a DMARD (mycophenolate mofetil, azathioprine, or hydroxychloroquine), and 49 healthy controls; all underwent pneumococcal vaccination. The first 13 got a single dose of PPV23 intramuscularly. PCV13 was then licensed for adults in Sweden, and the remaining 31 patients received this vaccine. The primary outcome was 6-week change from baseline in the level of pneumococcal IgG to Streptococcus pneumoniae serotypes 23F and 6B.
Both vaccines were safe and well-tolerated by all patients, including those taking a DMARD.
Before vaccination, antibody levels to both serotypes were similar between the groups. After vaccination, antibody levels for both serotypes increased significantly in systemic sclerosis patients not taking a DMARD and in controls. However, patients taking a DMARD mounted only an adequate response to serotype 6B.
There were fewer responders among those taking DMARDs, whether they received the PCV13 or the PPV23 vaccine. An increase from prevaccination antibody levels of at least twofold occurred in fewer patients taking DMARDs than did in patients not taking DMARDs and in controls, regardless of vaccine type (PPV23, 50% vs. about 55% and 50%, respectively; PCV13, about 17% vs. 57% and 100%, respectively).
“We demonstrated that the antibody response ... as well as functionality of antibodies in [systemic sclerosis] patients not receiving DMARDs was as good as in controls regardless of vaccine type,” the investigators concluded. “Systemic sclerosis patients treated with DMARDs, however, had lower proportion of patients with positive antibody response, although the functionality of the antibodies was preserved. These results suggest that immunomodulating drugs but not systemic sclerosis itself and/or immunological disturbance as a part of this disease affect the ability to produce a sufficient amount of vaccine-specific antibodies, but not their function.”
None of the authors had conflicts of interest to disclose.
SOURCE: Hesselstrand R et al. Rheumatology [Oxford]. 2018 Jan 8. doi: 10.1093/rheumatology/kex471.
Patients taking disease-modifying antirheumatic medications for systemic sclerosis appear to have a decreased response to pneumococcal vaccines, a Swedish study has determined.
Those not taking disease-modifying antirheumatic medications (DMARDs), however, had a normal immune response, suggesting that it’s the immunomodulating medications, not the disease itself, that is affecting antibody levels, Roger Hesselstrand, MD, of Lund (Sweden) University and his colleagues reported online in Rheumatology.
“The currently recommended prime-boost vaccination strategy using a dose of PCV13 [13-valent pneumococcal conjugate vaccine] followed by a dose of PPV23 [23-valent pneumococcal polysaccharide vaccine] might be a possible way of enhancing the vaccine immunogenicity in immunosuppressed patients,” Dr. Hesselstrand and his coauthors wrote.
The study comprised 44 subjects with systemic sclerosis, 12 of whom were taking a DMARD (mycophenolate mofetil, azathioprine, or hydroxychloroquine), and 49 healthy controls; all underwent pneumococcal vaccination. The first 13 got a single dose of PPV23 intramuscularly. PCV13 was then licensed for adults in Sweden, and the remaining 31 patients received this vaccine. The primary outcome was 6-week change from baseline in the level of pneumococcal IgG to Streptococcus pneumoniae serotypes 23F and 6B.
Both vaccines were safe and well-tolerated by all patients, including those taking a DMARD.
Before vaccination, antibody levels to both serotypes were similar between the groups. After vaccination, antibody levels for both serotypes increased significantly in systemic sclerosis patients not taking a DMARD and in controls. However, patients taking a DMARD mounted only an adequate response to serotype 6B.
There were fewer responders among those taking DMARDs, whether they received the PCV13 or the PPV23 vaccine. An increase from prevaccination antibody levels of at least twofold occurred in fewer patients taking DMARDs than did in patients not taking DMARDs and in controls, regardless of vaccine type (PPV23, 50% vs. about 55% and 50%, respectively; PCV13, about 17% vs. 57% and 100%, respectively).
“We demonstrated that the antibody response ... as well as functionality of antibodies in [systemic sclerosis] patients not receiving DMARDs was as good as in controls regardless of vaccine type,” the investigators concluded. “Systemic sclerosis patients treated with DMARDs, however, had lower proportion of patients with positive antibody response, although the functionality of the antibodies was preserved. These results suggest that immunomodulating drugs but not systemic sclerosis itself and/or immunological disturbance as a part of this disease affect the ability to produce a sufficient amount of vaccine-specific antibodies, but not their function.”
None of the authors had conflicts of interest to disclose.
SOURCE: Hesselstrand R et al. Rheumatology [Oxford]. 2018 Jan 8. doi: 10.1093/rheumatology/kex471.
FROM RHEUMATOLOGY
Key clinical point:
Major finding: An increase in prevaccination antibody levels of at least twofold occurred in significantly fewer patients taking DMARDs than in patients not taking DMARDs and controls, regardless of vaccine type (PPV23, 50% vs. about 55% and 50%, respectively; PCV13, about 17% vs. 57% and 100%, respectively).
Study details: The prospective study comprised 44 systemic sclerosis patients and 49 healthy controls.
Disclosures: None of the authors had conflicts of interest to disclose.
Source: Hesselstrand R et al. Rheumatology [Oxford]. 2018 Jan 8. doi: 10.1093/rheumatology/kex471
Tracheobronchial tree size changes may predict IPF outcomes
Changes in tracheobronchial tree size may serve as a practical and noninvasive method for predicting disease severity in patients diagnosed with idiopathic pulmonary fibrosis, according to data from 150 adults.
To determine the potential predictive value of tracheobronchial tree changes on mortality, Ankush Ratwani, MD, of Georgetown University, Washington, and colleagues reviewed data from adults with IPF seen at a single center between March 2012 and December 2016. The findings were presented at the CHEST annual meeting.
The researchers measured the tracheal diameters of the patients and used the GAP index, an established system for predicting mortality in IPF patients, to determine a relationship. Overall, they found a significant correlation between GAP index scores and increasing tracheobronchial tree size across eight measurements of different levels along the tracheobronchial tree “with an increase in GAP index stage for every level of increase in tracheal measurements (P less than .005),” they noted.
Measurements included the anterior-posterior diameter at the subglottic level, aortic arch, carina, right main stem bronchus, and left main stem bronchus, as well as transverse diameter assessment at the subglottis, aortic arch, and carina. The average anterior-posterior tracheal diameters were 21.77 mm for the subglottis, 21.84 mm for the aortic arch, 20.47 mm for the carina, 15.19 for the right main stem bronchus, and 14.21 mm for the left main stem bronchus.
No correlation appeared between tracheal size and lung volume, which suggests that enlargement of the trachea is likely caused by other factors beyond fibrosis, and next steps for research should determine whether tracheal size is an independent predictor of mortality in IPF patients, the investigators noted.
“With the field of treatment and management changing for IPF over the last few years, it has becoming increasingly important to prognose these patients in order to find where they fit in the spectrum for treatment or lung transplant,” Dr. Ratwani said in an interview. “Additionally, there needs to be a noninvasive measure to show disease progression, such as with using CT scans, and correlate with other prognostic indicators to hopefully create a regression formula that encompasses multiple parameters,” he explained.
“The results were surprising in that there was a correlation of a radiographic measure that has not been looked at previously with a validated measure of prognostication in IPF (GAP Index),” Dr. Ratwani said.
Although the findings do not imply more than a correlation, the results serve as “a good start to validate the theory that as the distal airways enlarge (traction bronchiectasis) in later stages of IPF, so may the proximal airways, which may be used to easily measure disease progression and guide the conversation for transplant or treatment,” Dr. Ratwani noted. His next steps for research include studying transplant-free survival in correlation with tracheal size, as well as serial changes between CT scans with correlations of lung volumes and survival.
Changes in tracheobronchial tree size may serve as a practical and noninvasive method for predicting disease severity in patients diagnosed with idiopathic pulmonary fibrosis, according to data from 150 adults.
To determine the potential predictive value of tracheobronchial tree changes on mortality, Ankush Ratwani, MD, of Georgetown University, Washington, and colleagues reviewed data from adults with IPF seen at a single center between March 2012 and December 2016. The findings were presented at the CHEST annual meeting.
The researchers measured the tracheal diameters of the patients and used the GAP index, an established system for predicting mortality in IPF patients, to determine a relationship. Overall, they found a significant correlation between GAP index scores and increasing tracheobronchial tree size across eight measurements of different levels along the tracheobronchial tree “with an increase in GAP index stage for every level of increase in tracheal measurements (P less than .005),” they noted.
Measurements included the anterior-posterior diameter at the subglottic level, aortic arch, carina, right main stem bronchus, and left main stem bronchus, as well as transverse diameter assessment at the subglottis, aortic arch, and carina. The average anterior-posterior tracheal diameters were 21.77 mm for the subglottis, 21.84 mm for the aortic arch, 20.47 mm for the carina, 15.19 for the right main stem bronchus, and 14.21 mm for the left main stem bronchus.
No correlation appeared between tracheal size and lung volume, which suggests that enlargement of the trachea is likely caused by other factors beyond fibrosis, and next steps for research should determine whether tracheal size is an independent predictor of mortality in IPF patients, the investigators noted.
“With the field of treatment and management changing for IPF over the last few years, it has becoming increasingly important to prognose these patients in order to find where they fit in the spectrum for treatment or lung transplant,” Dr. Ratwani said in an interview. “Additionally, there needs to be a noninvasive measure to show disease progression, such as with using CT scans, and correlate with other prognostic indicators to hopefully create a regression formula that encompasses multiple parameters,” he explained.
“The results were surprising in that there was a correlation of a radiographic measure that has not been looked at previously with a validated measure of prognostication in IPF (GAP Index),” Dr. Ratwani said.
Although the findings do not imply more than a correlation, the results serve as “a good start to validate the theory that as the distal airways enlarge (traction bronchiectasis) in later stages of IPF, so may the proximal airways, which may be used to easily measure disease progression and guide the conversation for transplant or treatment,” Dr. Ratwani noted. His next steps for research include studying transplant-free survival in correlation with tracheal size, as well as serial changes between CT scans with correlations of lung volumes and survival.
Changes in tracheobronchial tree size may serve as a practical and noninvasive method for predicting disease severity in patients diagnosed with idiopathic pulmonary fibrosis, according to data from 150 adults.
To determine the potential predictive value of tracheobronchial tree changes on mortality, Ankush Ratwani, MD, of Georgetown University, Washington, and colleagues reviewed data from adults with IPF seen at a single center between March 2012 and December 2016. The findings were presented at the CHEST annual meeting.
The researchers measured the tracheal diameters of the patients and used the GAP index, an established system for predicting mortality in IPF patients, to determine a relationship. Overall, they found a significant correlation between GAP index scores and increasing tracheobronchial tree size across eight measurements of different levels along the tracheobronchial tree “with an increase in GAP index stage for every level of increase in tracheal measurements (P less than .005),” they noted.
Measurements included the anterior-posterior diameter at the subglottic level, aortic arch, carina, right main stem bronchus, and left main stem bronchus, as well as transverse diameter assessment at the subglottis, aortic arch, and carina. The average anterior-posterior tracheal diameters were 21.77 mm for the subglottis, 21.84 mm for the aortic arch, 20.47 mm for the carina, 15.19 for the right main stem bronchus, and 14.21 mm for the left main stem bronchus.
No correlation appeared between tracheal size and lung volume, which suggests that enlargement of the trachea is likely caused by other factors beyond fibrosis, and next steps for research should determine whether tracheal size is an independent predictor of mortality in IPF patients, the investigators noted.
“With the field of treatment and management changing for IPF over the last few years, it has becoming increasingly important to prognose these patients in order to find where they fit in the spectrum for treatment or lung transplant,” Dr. Ratwani said in an interview. “Additionally, there needs to be a noninvasive measure to show disease progression, such as with using CT scans, and correlate with other prognostic indicators to hopefully create a regression formula that encompasses multiple parameters,” he explained.
“The results were surprising in that there was a correlation of a radiographic measure that has not been looked at previously with a validated measure of prognostication in IPF (GAP Index),” Dr. Ratwani said.
Although the findings do not imply more than a correlation, the results serve as “a good start to validate the theory that as the distal airways enlarge (traction bronchiectasis) in later stages of IPF, so may the proximal airways, which may be used to easily measure disease progression and guide the conversation for transplant or treatment,” Dr. Ratwani noted. His next steps for research include studying transplant-free survival in correlation with tracheal size, as well as serial changes between CT scans with correlations of lung volumes and survival.
FROM CHEST 2017
U.S. influenza activity widespread to start 2018
As far as the influenza virus is concerned, the new year started in the same way as the old one ended: with almost half of the states at the highest level of flu activity, according to the Centers for Disease Control and Prevention.
For the week ending Jan. 6, 2018, there were 23 states – including California, Illinois, and Texas – at level 10 on the CDC’s 1-10 scale for influenza-like illness (ILI) activity, which was up from 22 for the last full week of 2017. Joining the 23 states in the “high” range were New Jersey and Ohio at level 9 and Colorado at level 8, the CDC’s influenza division reported Jan. 12.
Seven flu-related pediatric deaths were reported during the week ending Jan. 6, although one occurred during the week ending Dec. 16 and two were during the week ending Dec. 23. There have been a total of 20 pediatric deaths related to influenza so far for the 2017-2018 season, the CDC said. In 2016-2017, there were 110 pediatric deaths from the flu.
As far as the influenza virus is concerned, the new year started in the same way as the old one ended: with almost half of the states at the highest level of flu activity, according to the Centers for Disease Control and Prevention.
For the week ending Jan. 6, 2018, there were 23 states – including California, Illinois, and Texas – at level 10 on the CDC’s 1-10 scale for influenza-like illness (ILI) activity, which was up from 22 for the last full week of 2017. Joining the 23 states in the “high” range were New Jersey and Ohio at level 9 and Colorado at level 8, the CDC’s influenza division reported Jan. 12.
Seven flu-related pediatric deaths were reported during the week ending Jan. 6, although one occurred during the week ending Dec. 16 and two were during the week ending Dec. 23. There have been a total of 20 pediatric deaths related to influenza so far for the 2017-2018 season, the CDC said. In 2016-2017, there were 110 pediatric deaths from the flu.
As far as the influenza virus is concerned, the new year started in the same way as the old one ended: with almost half of the states at the highest level of flu activity, according to the Centers for Disease Control and Prevention.
For the week ending Jan. 6, 2018, there were 23 states – including California, Illinois, and Texas – at level 10 on the CDC’s 1-10 scale for influenza-like illness (ILI) activity, which was up from 22 for the last full week of 2017. Joining the 23 states in the “high” range were New Jersey and Ohio at level 9 and Colorado at level 8, the CDC’s influenza division reported Jan. 12.
Seven flu-related pediatric deaths were reported during the week ending Jan. 6, although one occurred during the week ending Dec. 16 and two were during the week ending Dec. 23. There have been a total of 20 pediatric deaths related to influenza so far for the 2017-2018 season, the CDC said. In 2016-2017, there were 110 pediatric deaths from the flu.
FDA panel doesn’t back inhaled ciprofloxacin for chronic lung infections
HYATTSVILLE, MD – A Food and Drug Administration advisory panel voted against recommending Linhaliq, ciprofloxacin dispersion for inhalation, to treat adult non-cystic fibrosis bronchiectasis (NCFBE) patients who have chronic lung infections with Pseudomonas aeruginosa.
“Two trials that have two very different outcomes – and no matter how we try and explain what the difference was, there was something really missing there,” said advisory committee member Peter Weina, MD, chief of the department of research programs at Walter Reed National Military Medical Center, Bethesda, Md.
NCFBE is often treated with antibacterial drugs, which temporarily reduce inflammation and bacterial load. One of the most common colonizing bacteria in NCFBE infections is P. aeruginosa, which is often associated with increased risk of death and hospital admission.
Prior studies involving inhaled bacterial drugs such as gentamicin and colistin to treat NCFBE have yielded mixed results, and none has been approved for that indication by the FDA.
The FDA granted cipro DI orphan drug status in June 2011 and fast-track approval in August 2014. Cipro DI’s developer, Aradigm, conducted two phase 3 clinical trials to support inhaled ciprofloxacin for the NCFBE indication.
The two phase 3 clinical trials, ORBIT-3 and ORBIT-4, were nearly identical in design. Patients in both were randomized 2:1 to receive cipro DI or placebo once daily for six cycles of 56 days each.
The efficacy results of the ORBIT-3 and ORBIT-4 trials were mixed. In ORBIT-3, there was very little difference between the treatment and placebo arms, with a median difference of 78 days for the primary endpoint of time to first pulmonary exacerbation (PE) (hazard ratio, 0.99; P = .974). ORBIT-3 also showed no difference between treatment and placebo in the frequency of PEs by week 48 of the study (incidence ratio, 0.852).
In contrast, a marginal treatment effect was observed in ORBIT-4, with a median time difference to first PE of 72 days between the placebo and treatment arms (HR, 0.71; P = .032). ORBIT-4 also demonstrated an ability to reduce the number of PEs (incidence ratio, 0.631) by approximately 36.9% by week 48.
Adverse events were the most common reason leading to patient discontinuation in both studies, accounting for 13.1% and 5.3% in the treatment arms of ORBIT-3 and ORBIT-4, respectively.
Despite some of the positive findings in ORBIT-4, FDA presenter LaRee Tracy, PhD, of the FDA’s office of biostatistics, voiced concerns about the trial data – specifically, the failure to reach the primary endpoint in ORBIT-3.
“If I were to be a [statistically speaking] ‘strict’ person, I wouldn’t be looking at the frequency of the [secondary] endpoints, because the primary [endpoint] failed,” Dr. Tracy noted. She also voiced concerns about a re-analysis Aradigm conducted after the trial data were unblinded, stating that the changes made to the original analysis plan “lend a lot of concerns for me.”
Both ORBIT-3 and ORBIT-4 presented uncertainties related to the long-term use of cipro DI. The durability of efficacy and safety findings did not extend beyond a year, leaving some committee members wondering about the development of antibiotic resistance in cipro DI-treated patients. In addition, members were concerned that long-term use of cipro DI could limit the utility of systemic fluoroquinolones to treat severe bacterial and pneumonia infections in NCFBE patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding.
This article was updated 1/11/18.
HYATTSVILLE, MD – A Food and Drug Administration advisory panel voted against recommending Linhaliq, ciprofloxacin dispersion for inhalation, to treat adult non-cystic fibrosis bronchiectasis (NCFBE) patients who have chronic lung infections with Pseudomonas aeruginosa.
“Two trials that have two very different outcomes – and no matter how we try and explain what the difference was, there was something really missing there,” said advisory committee member Peter Weina, MD, chief of the department of research programs at Walter Reed National Military Medical Center, Bethesda, Md.
NCFBE is often treated with antibacterial drugs, which temporarily reduce inflammation and bacterial load. One of the most common colonizing bacteria in NCFBE infections is P. aeruginosa, which is often associated with increased risk of death and hospital admission.
Prior studies involving inhaled bacterial drugs such as gentamicin and colistin to treat NCFBE have yielded mixed results, and none has been approved for that indication by the FDA.
The FDA granted cipro DI orphan drug status in June 2011 and fast-track approval in August 2014. Cipro DI’s developer, Aradigm, conducted two phase 3 clinical trials to support inhaled ciprofloxacin for the NCFBE indication.
The two phase 3 clinical trials, ORBIT-3 and ORBIT-4, were nearly identical in design. Patients in both were randomized 2:1 to receive cipro DI or placebo once daily for six cycles of 56 days each.
The efficacy results of the ORBIT-3 and ORBIT-4 trials were mixed. In ORBIT-3, there was very little difference between the treatment and placebo arms, with a median difference of 78 days for the primary endpoint of time to first pulmonary exacerbation (PE) (hazard ratio, 0.99; P = .974). ORBIT-3 also showed no difference between treatment and placebo in the frequency of PEs by week 48 of the study (incidence ratio, 0.852).
In contrast, a marginal treatment effect was observed in ORBIT-4, with a median time difference to first PE of 72 days between the placebo and treatment arms (HR, 0.71; P = .032). ORBIT-4 also demonstrated an ability to reduce the number of PEs (incidence ratio, 0.631) by approximately 36.9% by week 48.
Adverse events were the most common reason leading to patient discontinuation in both studies, accounting for 13.1% and 5.3% in the treatment arms of ORBIT-3 and ORBIT-4, respectively.
Despite some of the positive findings in ORBIT-4, FDA presenter LaRee Tracy, PhD, of the FDA’s office of biostatistics, voiced concerns about the trial data – specifically, the failure to reach the primary endpoint in ORBIT-3.
“If I were to be a [statistically speaking] ‘strict’ person, I wouldn’t be looking at the frequency of the [secondary] endpoints, because the primary [endpoint] failed,” Dr. Tracy noted. She also voiced concerns about a re-analysis Aradigm conducted after the trial data were unblinded, stating that the changes made to the original analysis plan “lend a lot of concerns for me.”
Both ORBIT-3 and ORBIT-4 presented uncertainties related to the long-term use of cipro DI. The durability of efficacy and safety findings did not extend beyond a year, leaving some committee members wondering about the development of antibiotic resistance in cipro DI-treated patients. In addition, members were concerned that long-term use of cipro DI could limit the utility of systemic fluoroquinolones to treat severe bacterial and pneumonia infections in NCFBE patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding.
This article was updated 1/11/18.
HYATTSVILLE, MD – A Food and Drug Administration advisory panel voted against recommending Linhaliq, ciprofloxacin dispersion for inhalation, to treat adult non-cystic fibrosis bronchiectasis (NCFBE) patients who have chronic lung infections with Pseudomonas aeruginosa.
“Two trials that have two very different outcomes – and no matter how we try and explain what the difference was, there was something really missing there,” said advisory committee member Peter Weina, MD, chief of the department of research programs at Walter Reed National Military Medical Center, Bethesda, Md.
NCFBE is often treated with antibacterial drugs, which temporarily reduce inflammation and bacterial load. One of the most common colonizing bacteria in NCFBE infections is P. aeruginosa, which is often associated with increased risk of death and hospital admission.
Prior studies involving inhaled bacterial drugs such as gentamicin and colistin to treat NCFBE have yielded mixed results, and none has been approved for that indication by the FDA.
The FDA granted cipro DI orphan drug status in June 2011 and fast-track approval in August 2014. Cipro DI’s developer, Aradigm, conducted two phase 3 clinical trials to support inhaled ciprofloxacin for the NCFBE indication.
The two phase 3 clinical trials, ORBIT-3 and ORBIT-4, were nearly identical in design. Patients in both were randomized 2:1 to receive cipro DI or placebo once daily for six cycles of 56 days each.
The efficacy results of the ORBIT-3 and ORBIT-4 trials were mixed. In ORBIT-3, there was very little difference between the treatment and placebo arms, with a median difference of 78 days for the primary endpoint of time to first pulmonary exacerbation (PE) (hazard ratio, 0.99; P = .974). ORBIT-3 also showed no difference between treatment and placebo in the frequency of PEs by week 48 of the study (incidence ratio, 0.852).
In contrast, a marginal treatment effect was observed in ORBIT-4, with a median time difference to first PE of 72 days between the placebo and treatment arms (HR, 0.71; P = .032). ORBIT-4 also demonstrated an ability to reduce the number of PEs (incidence ratio, 0.631) by approximately 36.9% by week 48.
Adverse events were the most common reason leading to patient discontinuation in both studies, accounting for 13.1% and 5.3% in the treatment arms of ORBIT-3 and ORBIT-4, respectively.
Despite some of the positive findings in ORBIT-4, FDA presenter LaRee Tracy, PhD, of the FDA’s office of biostatistics, voiced concerns about the trial data – specifically, the failure to reach the primary endpoint in ORBIT-3.
“If I were to be a [statistically speaking] ‘strict’ person, I wouldn’t be looking at the frequency of the [secondary] endpoints, because the primary [endpoint] failed,” Dr. Tracy noted. She also voiced concerns about a re-analysis Aradigm conducted after the trial data were unblinded, stating that the changes made to the original analysis plan “lend a lot of concerns for me.”
Both ORBIT-3 and ORBIT-4 presented uncertainties related to the long-term use of cipro DI. The durability of efficacy and safety findings did not extend beyond a year, leaving some committee members wondering about the development of antibiotic resistance in cipro DI-treated patients. In addition, members were concerned that long-term use of cipro DI could limit the utility of systemic fluoroquinolones to treat severe bacterial and pneumonia infections in NCFBE patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding.
This article was updated 1/11/18.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
Budesonide fails to cut deaths in preemies
The administration of inhaled budesonide to extremely preterm infants did not increase the risk of neurodevelopmental disability, but did increase mortality, in a study by Dirk Bassler, MD, of the University of Zürich and his associates.
An older study led by Dr. Bassler and published in the New England Journal of Medicine showed that inhaled budesonide significantly reduced the incidence of bronchopulmonary dysplasia, which has been linked to higher mortality and chronic respiratory and cardiovascular impairment (N Engl J Med. 2015;373:1497-506).
Systemic glucocorticoids have been linked to greater risk of neurodevelopmental disability, but only a few studies have examined the effect of inhaled glucocorticoids, such as budesonide, in preterm infants. These studies, including the earlier one by Dr. Bassler and his colleagues, were either small, covered a short period of time or involved late administering of the drug.
In the two studies by Dr. Bassler and his colleagues, 863 preterm infants between 23 weeks’ and just under 28 weeks’ gestation who required any form of positive-pressure respiratory support were randomized to receive inhaled budesonide (two puffs, 200 mcg per puff) or placebo every 12 hours. They began within 24 hours of birth and continued for the first 14 days of life. Following that, patients received 1 puff every 12 hours until they no longer required supplemental oxygen and positive-pressure support, or reached a postmenstrual age of 32 weeks.
The treatment resulted in a significant reduction in bronchopulmonary dysplasia at a postmenstrual age of 36 weeks (28.2% in the budesonide group vs. 37.4%; P = .01), in the older study.
In the new study, which was also published in the New England Journal of Medicine, Dr. Bassler and his associates found higher mortality (19.9% vs. 14.5%; relative risk, 1.37; 95% confidence interval, 1.01-1.86; P = .04) in the group of patients who had received inhaled budesonide. Additionally, at a corrected age of 18-22 months, surviving infants who received inhaled budesonide had a similar risk of neurodevelopmental disability as those patients who took the placebo.
Broadly speaking, 48.1% of infants who received budesonide had a neurodevelopmental disability, compared with 51.4% of infants who received placebo (RR adjusted for gestational age, 0.93; 95% CI, 0.80-1.09; P = .40). The two groups also had no statistically significant differences in their frequencies of cerebral palsy, blindness, hearing loss, or cognitive delay.
“There was no significant difference between the groups in adverse long-term outcomes in our study. However, the fact that fewer infants died in the placebo group than in the budesonide group complicates the interpretation of the treatment of budesonide,” the researchers wrote.
Supported by a grant from the European Union and by Chiesi Farmaceutici. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
SOURCE: N Engl J Med. 2018;378:148-57.
This is an important study regarding bronchopulmonary dysplasia prevention. The study suggests starting budesonide within 24 hours of life resulted in a lower rate of bronchopulmonary dysplasia than placebo but fewer infants died in the placebo group. A bigger question for me is “what is the evidence for starting inhaled steroids prior to neonatal intensive care unit discharge?” Pediatric pulmonologists would like to know if it decreases subsequent respiratory-related ER visits and readmissions.
This is an important study regarding bronchopulmonary dysplasia prevention. The study suggests starting budesonide within 24 hours of life resulted in a lower rate of bronchopulmonary dysplasia than placebo but fewer infants died in the placebo group. A bigger question for me is “what is the evidence for starting inhaled steroids prior to neonatal intensive care unit discharge?” Pediatric pulmonologists would like to know if it decreases subsequent respiratory-related ER visits and readmissions.
This is an important study regarding bronchopulmonary dysplasia prevention. The study suggests starting budesonide within 24 hours of life resulted in a lower rate of bronchopulmonary dysplasia than placebo but fewer infants died in the placebo group. A bigger question for me is “what is the evidence for starting inhaled steroids prior to neonatal intensive care unit discharge?” Pediatric pulmonologists would like to know if it decreases subsequent respiratory-related ER visits and readmissions.
The administration of inhaled budesonide to extremely preterm infants did not increase the risk of neurodevelopmental disability, but did increase mortality, in a study by Dirk Bassler, MD, of the University of Zürich and his associates.
An older study led by Dr. Bassler and published in the New England Journal of Medicine showed that inhaled budesonide significantly reduced the incidence of bronchopulmonary dysplasia, which has been linked to higher mortality and chronic respiratory and cardiovascular impairment (N Engl J Med. 2015;373:1497-506).
Systemic glucocorticoids have been linked to greater risk of neurodevelopmental disability, but only a few studies have examined the effect of inhaled glucocorticoids, such as budesonide, in preterm infants. These studies, including the earlier one by Dr. Bassler and his colleagues, were either small, covered a short period of time or involved late administering of the drug.
In the two studies by Dr. Bassler and his colleagues, 863 preterm infants between 23 weeks’ and just under 28 weeks’ gestation who required any form of positive-pressure respiratory support were randomized to receive inhaled budesonide (two puffs, 200 mcg per puff) or placebo every 12 hours. They began within 24 hours of birth and continued for the first 14 days of life. Following that, patients received 1 puff every 12 hours until they no longer required supplemental oxygen and positive-pressure support, or reached a postmenstrual age of 32 weeks.
The treatment resulted in a significant reduction in bronchopulmonary dysplasia at a postmenstrual age of 36 weeks (28.2% in the budesonide group vs. 37.4%; P = .01), in the older study.
In the new study, which was also published in the New England Journal of Medicine, Dr. Bassler and his associates found higher mortality (19.9% vs. 14.5%; relative risk, 1.37; 95% confidence interval, 1.01-1.86; P = .04) in the group of patients who had received inhaled budesonide. Additionally, at a corrected age of 18-22 months, surviving infants who received inhaled budesonide had a similar risk of neurodevelopmental disability as those patients who took the placebo.
Broadly speaking, 48.1% of infants who received budesonide had a neurodevelopmental disability, compared with 51.4% of infants who received placebo (RR adjusted for gestational age, 0.93; 95% CI, 0.80-1.09; P = .40). The two groups also had no statistically significant differences in their frequencies of cerebral palsy, blindness, hearing loss, or cognitive delay.
“There was no significant difference between the groups in adverse long-term outcomes in our study. However, the fact that fewer infants died in the placebo group than in the budesonide group complicates the interpretation of the treatment of budesonide,” the researchers wrote.
Supported by a grant from the European Union and by Chiesi Farmaceutici. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
SOURCE: N Engl J Med. 2018;378:148-57.
The administration of inhaled budesonide to extremely preterm infants did not increase the risk of neurodevelopmental disability, but did increase mortality, in a study by Dirk Bassler, MD, of the University of Zürich and his associates.
An older study led by Dr. Bassler and published in the New England Journal of Medicine showed that inhaled budesonide significantly reduced the incidence of bronchopulmonary dysplasia, which has been linked to higher mortality and chronic respiratory and cardiovascular impairment (N Engl J Med. 2015;373:1497-506).
Systemic glucocorticoids have been linked to greater risk of neurodevelopmental disability, but only a few studies have examined the effect of inhaled glucocorticoids, such as budesonide, in preterm infants. These studies, including the earlier one by Dr. Bassler and his colleagues, were either small, covered a short period of time or involved late administering of the drug.
In the two studies by Dr. Bassler and his colleagues, 863 preterm infants between 23 weeks’ and just under 28 weeks’ gestation who required any form of positive-pressure respiratory support were randomized to receive inhaled budesonide (two puffs, 200 mcg per puff) or placebo every 12 hours. They began within 24 hours of birth and continued for the first 14 days of life. Following that, patients received 1 puff every 12 hours until they no longer required supplemental oxygen and positive-pressure support, or reached a postmenstrual age of 32 weeks.
The treatment resulted in a significant reduction in bronchopulmonary dysplasia at a postmenstrual age of 36 weeks (28.2% in the budesonide group vs. 37.4%; P = .01), in the older study.
In the new study, which was also published in the New England Journal of Medicine, Dr. Bassler and his associates found higher mortality (19.9% vs. 14.5%; relative risk, 1.37; 95% confidence interval, 1.01-1.86; P = .04) in the group of patients who had received inhaled budesonide. Additionally, at a corrected age of 18-22 months, surviving infants who received inhaled budesonide had a similar risk of neurodevelopmental disability as those patients who took the placebo.
Broadly speaking, 48.1% of infants who received budesonide had a neurodevelopmental disability, compared with 51.4% of infants who received placebo (RR adjusted for gestational age, 0.93; 95% CI, 0.80-1.09; P = .40). The two groups also had no statistically significant differences in their frequencies of cerebral palsy, blindness, hearing loss, or cognitive delay.
“There was no significant difference between the groups in adverse long-term outcomes in our study. However, the fact that fewer infants died in the placebo group than in the budesonide group complicates the interpretation of the treatment of budesonide,” the researchers wrote.
Supported by a grant from the European Union and by Chiesi Farmaceutici. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
SOURCE: N Engl J Med. 2018;378:148-57.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Nearly 20% of infants in the budesonide group died, compared with 14.5% of the placebo group.
Data source: Randomized, controlled trial of 863 extremely preterm infants.
Disclosures: Supported by a grant from the European Union and by Chiesi Farmaceutici. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Source: N Engl J Med. 2018;378:148-57.
California tops state tobacco prevention spending
California will spend almost as much money on tobacco prevention and smoking cessation as the other states combined in 2018, putting it closest to the spending level recommended for each state by the Centers for Disease Control and Prevention, according to a report on the effects of the 1998 tobacco settlement.
The Golden State has budgeted almost $328 million for tobacco prevention and cessation this year, which amounts to just over 45% of all states’ total spending of $722 million and 94% of the CDC’s recommendation of $348 million. Alaska is the only state close to that in terms of the CDC-recommended level, reaching 93% of its spending target of $10.2 million. In third place for recommended spending is North Dakota, which has budgeted $5.3 million for 2018, or 54% of its CDC target, the report said. 
“Broken Promises to Our Children: A State-by-State Look at the 1998 Tobacco Settlement 19 Years Later” was released by the Campaign for Tobacco-Free Kids, American Cancer Society Cancer Action Network, American Heart Association, American Lung Association, Robert Wood Johnson Foundation, Americans for Nonsmokers’ Rights, and Truth Initiative.
As for actual spending, Florida is second behind California with almost $69 million – 35% of its CDC-recommended level – budgeted for tobacco prevention and smoking cessation in 2018, and New York is third at just over $39 million, which is 19.4% of the CDC recommendation. Two states – Connecticut and West Virginia – will spend no money on such programs this year, the report noted.
The CDC has said that all states combined should be spending $3.3 billion for the year on prevention and cessation efforts, which is about 4.5 times higher than actual budgeted spending. The report also pointed out that the $722 million the states will spend this year amounts to just 2.6% of the $27.5 billion they will collect from the 1998 tobacco settlement and tobacco taxes. By comparison, the report cited data from the Federal Trade Commission showing that the tobacco companies spent $8.9 billion on marketing in 2015.
California will spend almost as much money on tobacco prevention and smoking cessation as the other states combined in 2018, putting it closest to the spending level recommended for each state by the Centers for Disease Control and Prevention, according to a report on the effects of the 1998 tobacco settlement.
The Golden State has budgeted almost $328 million for tobacco prevention and cessation this year, which amounts to just over 45% of all states’ total spending of $722 million and 94% of the CDC’s recommendation of $348 million. Alaska is the only state close to that in terms of the CDC-recommended level, reaching 93% of its spending target of $10.2 million. In third place for recommended spending is North Dakota, which has budgeted $5.3 million for 2018, or 54% of its CDC target, the report said.
“Broken Promises to Our Children: A State-by-State Look at the 1998 Tobacco Settlement 19 Years Later” was released by the Campaign for Tobacco-Free Kids, American Cancer Society Cancer Action Network, American Heart Association, American Lung Association, Robert Wood Johnson Foundation, Americans for Nonsmokers’ Rights, and Truth Initiative.
As for actual spending, Florida is second behind California with almost $69 million – 35% of its CDC-recommended level – budgeted for tobacco prevention and smoking cessation in 2018, and New York is third at just over $39 million, which is 19.4% of the CDC recommendation. Two states – Connecticut and West Virginia – will spend no money on such programs this year, the report noted.
The CDC has said that all states combined should be spending $3.3 billion for the year on prevention and cessation efforts, which is about 4.5 times higher than actual budgeted spending. The report also pointed out that the $722 million the states will spend this year amounts to just 2.6% of the $27.5 billion they will collect from the 1998 tobacco settlement and tobacco taxes. By comparison, the report cited data from the Federal Trade Commission showing that the tobacco companies spent $8.9 billion on marketing in 2015.
California will spend almost as much money on tobacco prevention and smoking cessation as the other states combined in 2018, putting it closest to the spending level recommended for each state by the Centers for Disease Control and Prevention, according to a report on the effects of the 1998 tobacco settlement.
The Golden State has budgeted almost $328 million for tobacco prevention and cessation this year, which amounts to just over 45% of all states’ total spending of $722 million and 94% of the CDC’s recommendation of $348 million. Alaska is the only state close to that in terms of the CDC-recommended level, reaching 93% of its spending target of $10.2 million. In third place for recommended spending is North Dakota, which has budgeted $5.3 million for 2018, or 54% of its CDC target, the report said.
“Broken Promises to Our Children: A State-by-State Look at the 1998 Tobacco Settlement 19 Years Later” was released by the Campaign for Tobacco-Free Kids, American Cancer Society Cancer Action Network, American Heart Association, American Lung Association, Robert Wood Johnson Foundation, Americans for Nonsmokers’ Rights, and Truth Initiative.
As for actual spending, Florida is second behind California with almost $69 million – 35% of its CDC-recommended level – budgeted for tobacco prevention and smoking cessation in 2018, and New York is third at just over $39 million, which is 19.4% of the CDC recommendation. Two states – Connecticut and West Virginia – will spend no money on such programs this year, the report noted.
The CDC has said that all states combined should be spending $3.3 billion for the year on prevention and cessation efforts, which is about 4.5 times higher than actual budgeted spending. The report also pointed out that the $722 million the states will spend this year amounts to just 2.6% of the $27.5 billion they will collect from the 1998 tobacco settlement and tobacco taxes. By comparison, the report cited data from the Federal Trade Commission showing that the tobacco companies spent $8.9 billion on marketing in 2015.
Don’t give up on influenza vaccine
I suspect most health care providers have heard the complaint, “The vaccine doesn’t work. One year I got the vaccine, and I still came down with the flu.”
Over the years, I’ve polished my responses to vaccine naysayers.
Influenza vaccine doesn’t protect you against every virus that can cause cold and flu symptoms. It only prevents influenza. It’s possible you had a different virus, such as adenovirus, coronavirus, parainfluenza virus, or respiratory syncytial virus.
Some years, the vaccine works better than others because there is a mismatch between the viruses chosen for the vaccine, and the viruses that end up circulating. Even when it doesn’t prevent flu, the vaccine can potentially reduce the severity of illness.
The discussion became a little more complicated in 2016 when the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices withdrew its support for the live attenuated influenza virus vaccine (LAIV4) because of concerns about effectiveness. During the 2015-2016 influenza season, LAIV4 demonstrated no statistically significant effectiveness in children 2-17 years of age against H1N1pdm09, the predominant influenza strain. Fortunately, inactivated injectable vaccine did offer protection. An estimated 41.8 million children aged 6 months to 17 years ultimately received this vaccine during the 2016-2017 influenza season.
Now with the 2017-2018 influenza season in full swing, some media reports are proclaiming the influenza vaccine is only 10% effective this year. This claim is based on an interim analysis of data from the most recent flu season in Australia and the effectiveness of the vaccine against the circulating H3N2 virus strain. News from the U.S. CDC is more encouraging. The H3N2 virus contained in this year’s vaccine is the same as that used last year, and so far, circulating H3N2 viruses in the United States are similar to the vaccine virus. Public health officials suggest that we can hope that the vaccine works as well as it did last year, when overall vaccine effectiveness against all circulating flu viruses was 39%, and effectiveness against the H3N2 virus specifically was 32%.
I’m upping my game when talking to parents about flu vaccine. I mention one study conducted between 2010 and 2012 in which influenza immunization reduced a child’s risk of being admitted to an intensive care unit with flu by 74% (J Infect Dis. 2014 Sep 1;210[5]:674-83). I emphasize that flu vaccine reduces the chance that a child will die from flu. According to a study published in 2017, influenza vaccine reduced the risk of death from flu by 65% in healthy children and 51% in children with high-risk medical conditions (Pediatrics. 2017 May. doi: 10.1542/peds.2016-4244).
When I’m talking to trainees, I no longer just focus on the match between circulating strains of flu and vaccine strains. I mention that viruses used to produce most seasonal flu vaccines are grown in eggs, a process that can result in minor antigenic changes in the hemagglutinin protein, especially in H3N2 viruses. These “egg-adapted changes” may result in a vaccine that stimulates a less effective immune response, even with a good match between circulating strains and vaccine strains. For example, Zost et al. found that the H3N2 virus that emerged during the 2014-2015 season possessed a new hemagglutinin-associated glycosylation site (Proc Natl Acad Sci U S A. 2017 Nov 21;114[47]:12578-83). Although this virus was represented in the 2016-2017 influenza vaccine, the egg-adapted version lost the glycosylation site, resulting in decreased vaccine immunogenicity and less protection against H3N2 viruses circulating in the community.
The real take-home message here is that we need better flu vaccines. In the short term, cell-based flu vaccines that use virus grown in animal cells are a potential alternative to egg-based vaccines. In the long term, we need a universal flu vaccine. The National Institute of Allergy and Infectious Diseases is prioritizing work on a vaccine that could provide long-lasting protection against multiple subtypes of the virus. According to a report on the National Institutes of Health website, such a vaccine could “eliminate the need to update and administer the seasonal flu vaccine each year and could provide protection against newly emerging flu strains,” including those with the potential to cause a pandemic. The NIH researchers acknowledge, however, that achieving this goal will require “a broad range of expertise and substantial resources.”
Until new vaccines are available, we need to do a better job of using available, albeit imperfect, flu vaccines. During the 2016-2017 season, only 59% of children 6 months to 17 years were immunized, and there were 110 influenza-associated deaths in children, according to the CDC. It’s likely that some of these were preventable.
The total magnitude of suffering associated with flu is more difficult to quantify, but anecdotes can be illuminating. A friend recently diagnosed with influenza shared her experience via Facebook. “Rough night. I’m seconds away from a meltdown. My body aches so bad that I can’t get comfortable on the couch or my bed. Can’t breathe, and I cough until I vomit. My head is about to burst along with my ears. Just took a hot bath hoping that would help. I don’t know what else to do. The flu really sucks.”
Indeed. Even a 1 in 10 chance of preventing the flu is better than no chance at all.
Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital in Louisville. She said she had no relevant financial disclosures. Email her at [email protected].
I suspect most health care providers have heard the complaint, “The vaccine doesn’t work. One year I got the vaccine, and I still came down with the flu.”
Over the years, I’ve polished my responses to vaccine naysayers.
Influenza vaccine doesn’t protect you against every virus that can cause cold and flu symptoms. It only prevents influenza. It’s possible you had a different virus, such as adenovirus, coronavirus, parainfluenza virus, or respiratory syncytial virus.
Some years, the vaccine works better than others because there is a mismatch between the viruses chosen for the vaccine, and the viruses that end up circulating. Even when it doesn’t prevent flu, the vaccine can potentially reduce the severity of illness.
The discussion became a little more complicated in 2016 when the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices withdrew its support for the live attenuated influenza virus vaccine (LAIV4) because of concerns about effectiveness. During the 2015-2016 influenza season, LAIV4 demonstrated no statistically significant effectiveness in children 2-17 years of age against H1N1pdm09, the predominant influenza strain. Fortunately, inactivated injectable vaccine did offer protection. An estimated 41.8 million children aged 6 months to 17 years ultimately received this vaccine during the 2016-2017 influenza season.
Now with the 2017-2018 influenza season in full swing, some media reports are proclaiming the influenza vaccine is only 10% effective this year. This claim is based on an interim analysis of data from the most recent flu season in Australia and the effectiveness of the vaccine against the circulating H3N2 virus strain. News from the U.S. CDC is more encouraging. The H3N2 virus contained in this year’s vaccine is the same as that used last year, and so far, circulating H3N2 viruses in the United States are similar to the vaccine virus. Public health officials suggest that we can hope that the vaccine works as well as it did last year, when overall vaccine effectiveness against all circulating flu viruses was 39%, and effectiveness against the H3N2 virus specifically was 32%.
I’m upping my game when talking to parents about flu vaccine. I mention one study conducted between 2010 and 2012 in which influenza immunization reduced a child’s risk of being admitted to an intensive care unit with flu by 74% (J Infect Dis. 2014 Sep 1;210[5]:674-83). I emphasize that flu vaccine reduces the chance that a child will die from flu. According to a study published in 2017, influenza vaccine reduced the risk of death from flu by 65% in healthy children and 51% in children with high-risk medical conditions (Pediatrics. 2017 May. doi: 10.1542/peds.2016-4244).
When I’m talking to trainees, I no longer just focus on the match between circulating strains of flu and vaccine strains. I mention that viruses used to produce most seasonal flu vaccines are grown in eggs, a process that can result in minor antigenic changes in the hemagglutinin protein, especially in H3N2 viruses. These “egg-adapted changes” may result in a vaccine that stimulates a less effective immune response, even with a good match between circulating strains and vaccine strains. For example, Zost et al. found that the H3N2 virus that emerged during the 2014-2015 season possessed a new hemagglutinin-associated glycosylation site (Proc Natl Acad Sci U S A. 2017 Nov 21;114[47]:12578-83). Although this virus was represented in the 2016-2017 influenza vaccine, the egg-adapted version lost the glycosylation site, resulting in decreased vaccine immunogenicity and less protection against H3N2 viruses circulating in the community.
The real take-home message here is that we need better flu vaccines. In the short term, cell-based flu vaccines that use virus grown in animal cells are a potential alternative to egg-based vaccines. In the long term, we need a universal flu vaccine. The National Institute of Allergy and Infectious Diseases is prioritizing work on a vaccine that could provide long-lasting protection against multiple subtypes of the virus. According to a report on the National Institutes of Health website, such a vaccine could “eliminate the need to update and administer the seasonal flu vaccine each year and could provide protection against newly emerging flu strains,” including those with the potential to cause a pandemic. The NIH researchers acknowledge, however, that achieving this goal will require “a broad range of expertise and substantial resources.”
Until new vaccines are available, we need to do a better job of using available, albeit imperfect, flu vaccines. During the 2016-2017 season, only 59% of children 6 months to 17 years were immunized, and there were 110 influenza-associated deaths in children, according to the CDC. It’s likely that some of these were preventable.
The total magnitude of suffering associated with flu is more difficult to quantify, but anecdotes can be illuminating. A friend recently diagnosed with influenza shared her experience via Facebook. “Rough night. I’m seconds away from a meltdown. My body aches so bad that I can’t get comfortable on the couch or my bed. Can’t breathe, and I cough until I vomit. My head is about to burst along with my ears. Just took a hot bath hoping that would help. I don’t know what else to do. The flu really sucks.”
Indeed. Even a 1 in 10 chance of preventing the flu is better than no chance at all.
Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital in Louisville. She said she had no relevant financial disclosures. Email her at [email protected].
I suspect most health care providers have heard the complaint, “The vaccine doesn’t work. One year I got the vaccine, and I still came down with the flu.”
Over the years, I’ve polished my responses to vaccine naysayers.
Influenza vaccine doesn’t protect you against every virus that can cause cold and flu symptoms. It only prevents influenza. It’s possible you had a different virus, such as adenovirus, coronavirus, parainfluenza virus, or respiratory syncytial virus.
Some years, the vaccine works better than others because there is a mismatch between the viruses chosen for the vaccine, and the viruses that end up circulating. Even when it doesn’t prevent flu, the vaccine can potentially reduce the severity of illness.
The discussion became a little more complicated in 2016 when the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices withdrew its support for the live attenuated influenza virus vaccine (LAIV4) because of concerns about effectiveness. During the 2015-2016 influenza season, LAIV4 demonstrated no statistically significant effectiveness in children 2-17 years of age against H1N1pdm09, the predominant influenza strain. Fortunately, inactivated injectable vaccine did offer protection. An estimated 41.8 million children aged 6 months to 17 years ultimately received this vaccine during the 2016-2017 influenza season.
Now with the 2017-2018 influenza season in full swing, some media reports are proclaiming the influenza vaccine is only 10% effective this year. This claim is based on an interim analysis of data from the most recent flu season in Australia and the effectiveness of the vaccine against the circulating H3N2 virus strain. News from the U.S. CDC is more encouraging. The H3N2 virus contained in this year’s vaccine is the same as that used last year, and so far, circulating H3N2 viruses in the United States are similar to the vaccine virus. Public health officials suggest that we can hope that the vaccine works as well as it did last year, when overall vaccine effectiveness against all circulating flu viruses was 39%, and effectiveness against the H3N2 virus specifically was 32%.
I’m upping my game when talking to parents about flu vaccine. I mention one study conducted between 2010 and 2012 in which influenza immunization reduced a child’s risk of being admitted to an intensive care unit with flu by 74% (J Infect Dis. 2014 Sep 1;210[5]:674-83). I emphasize that flu vaccine reduces the chance that a child will die from flu. According to a study published in 2017, influenza vaccine reduced the risk of death from flu by 65% in healthy children and 51% in children with high-risk medical conditions (Pediatrics. 2017 May. doi: 10.1542/peds.2016-4244).
When I’m talking to trainees, I no longer just focus on the match between circulating strains of flu and vaccine strains. I mention that viruses used to produce most seasonal flu vaccines are grown in eggs, a process that can result in minor antigenic changes in the hemagglutinin protein, especially in H3N2 viruses. These “egg-adapted changes” may result in a vaccine that stimulates a less effective immune response, even with a good match between circulating strains and vaccine strains. For example, Zost et al. found that the H3N2 virus that emerged during the 2014-2015 season possessed a new hemagglutinin-associated glycosylation site (Proc Natl Acad Sci U S A. 2017 Nov 21;114[47]:12578-83). Although this virus was represented in the 2016-2017 influenza vaccine, the egg-adapted version lost the glycosylation site, resulting in decreased vaccine immunogenicity and less protection against H3N2 viruses circulating in the community.
The real take-home message here is that we need better flu vaccines. In the short term, cell-based flu vaccines that use virus grown in animal cells are a potential alternative to egg-based vaccines. In the long term, we need a universal flu vaccine. The National Institute of Allergy and Infectious Diseases is prioritizing work on a vaccine that could provide long-lasting protection against multiple subtypes of the virus. According to a report on the National Institutes of Health website, such a vaccine could “eliminate the need to update and administer the seasonal flu vaccine each year and could provide protection against newly emerging flu strains,” including those with the potential to cause a pandemic. The NIH researchers acknowledge, however, that achieving this goal will require “a broad range of expertise and substantial resources.”
Until new vaccines are available, we need to do a better job of using available, albeit imperfect, flu vaccines. During the 2016-2017 season, only 59% of children 6 months to 17 years were immunized, and there were 110 influenza-associated deaths in children, according to the CDC. It’s likely that some of these were preventable.
The total magnitude of suffering associated with flu is more difficult to quantify, but anecdotes can be illuminating. A friend recently diagnosed with influenza shared her experience via Facebook. “Rough night. I’m seconds away from a meltdown. My body aches so bad that I can’t get comfortable on the couch or my bed. Can’t breathe, and I cough until I vomit. My head is about to burst along with my ears. Just took a hot bath hoping that would help. I don’t know what else to do. The flu really sucks.”
Indeed. Even a 1 in 10 chance of preventing the flu is better than no chance at all.
Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital in Louisville. She said she had no relevant financial disclosures. Email her at [email protected].
Majority of influenza-related deaths among hospitalized patients occur after discharge
SAN DIEGO – Over half of hospitalized, influenza-related deaths occurred within 30 days of discharge, according to a study presented at an annual scientific meeting on infectious diseases.
As physicians and pharmaceutical companies attempt to measure the burden of seasonal influenza, discharged patients are currently not considered as much as they should be, according to investigators.
Among 968 deceased patients studied, 444 (46%) died in hospital, while 524 (54%) died within 30 days of discharge.
Investigators conducted a retrospective study of 15,562 patients hospitalized for influenza-related cases between 2014 and 2015, as recorded in Influenza-Associated Hospitalizations Surveillance (FluSurv-NET), a database of the Centers for Disease Control and Prevention.
The majority of the studied patients were women (55%) and the majority were white.
Those who died were more likely to have been admitted to the hospital immediately after influenza onset, with 26% of those who died after discharge and 22% of those who died in hospital having been admitted the same day. In contrast, 13% of those who lived past 30 days were admitted immediately after onset.
A total of 46% of those who died after hospitalization had a length of stay longer than 1 week, compared to 15% of those who lived.
Among patients who died after discharge, 356 (68%) died within 2 weeks of discharge, with the highest number of deaths occurring within the first few days, according to presenter Craig McGowan of the Influenza Division of the CDC in Atlanta.
Age also seemed to be a possible mortality predictor, according to Mr. McGowan and his fellow investigators. “Those who died were more likely to be elderly, and those who died after discharge were even more likely to be 85 [years or older] than those who died during their influenza-related hospitalizations,” said Mr. McGowan, who added that patients aged 85 years and older made up more than half of those who died after discharge.
Patients who died in hospital were significantly more likely to have influenza listed as a cause of death. Overall, influenza-related and non–influenza-related respiratory issues were the two most common causes of death listed on death certificates of patients who died during hospitalization or within 14 days of discharge, while cardiovascular or other symptoms were listed for those who died between 15 and 30 days after discharge.
Admission and discharge locations among patients who did not die were almost 80% from a private residence to a private residence, while observations of those who died revealed a different pattern. “Those individuals who died after discharge were almost evenly split between admission from a nursing home or a private residence,” Mr. McGowan said. “Those who were admitted from the nursing home were almost exclusively discharged to either hospice care or back to a nursing home.”
Mr. McGowan noted rehospitalization to be a significant factor among those who died, with 34% of deaths occurring back in the hospital after initial discharge.
Influenza testing of studied patients was given at clinicians’ discretion, which may make the sample not generalizable to the overall influenza population, and the investigators included only bivariate associations, which means there were likely confounding effects that could not be accounted for.
Mr. McGowan and his fellow investigators plan to expand their research by determining underlying causes of death in these patients, to create more accurate estimates of influenza-associated mortality.
Mr. McGowan reported no relevant financial disclosures.
SOURCE: McGowan, C., et al., ID Week 2017, Abstract 951.
SAN DIEGO – Over half of hospitalized, influenza-related deaths occurred within 30 days of discharge, according to a study presented at an annual scientific meeting on infectious diseases.
As physicians and pharmaceutical companies attempt to measure the burden of seasonal influenza, discharged patients are currently not considered as much as they should be, according to investigators.
Among 968 deceased patients studied, 444 (46%) died in hospital, while 524 (54%) died within 30 days of discharge.
Investigators conducted a retrospective study of 15,562 patients hospitalized for influenza-related cases between 2014 and 2015, as recorded in Influenza-Associated Hospitalizations Surveillance (FluSurv-NET), a database of the Centers for Disease Control and Prevention.
The majority of the studied patients were women (55%) and the majority were white.
Those who died were more likely to have been admitted to the hospital immediately after influenza onset, with 26% of those who died after discharge and 22% of those who died in hospital having been admitted the same day. In contrast, 13% of those who lived past 30 days were admitted immediately after onset.
A total of 46% of those who died after hospitalization had a length of stay longer than 1 week, compared to 15% of those who lived.
Among patients who died after discharge, 356 (68%) died within 2 weeks of discharge, with the highest number of deaths occurring within the first few days, according to presenter Craig McGowan of the Influenza Division of the CDC in Atlanta.
Age also seemed to be a possible mortality predictor, according to Mr. McGowan and his fellow investigators. “Those who died were more likely to be elderly, and those who died after discharge were even more likely to be 85 [years or older] than those who died during their influenza-related hospitalizations,” said Mr. McGowan, who added that patients aged 85 years and older made up more than half of those who died after discharge.
Patients who died in hospital were significantly more likely to have influenza listed as a cause of death. Overall, influenza-related and non–influenza-related respiratory issues were the two most common causes of death listed on death certificates of patients who died during hospitalization or within 14 days of discharge, while cardiovascular or other symptoms were listed for those who died between 15 and 30 days after discharge.
Admission and discharge locations among patients who did not die were almost 80% from a private residence to a private residence, while observations of those who died revealed a different pattern. “Those individuals who died after discharge were almost evenly split between admission from a nursing home or a private residence,” Mr. McGowan said. “Those who were admitted from the nursing home were almost exclusively discharged to either hospice care or back to a nursing home.”
Mr. McGowan noted rehospitalization to be a significant factor among those who died, with 34% of deaths occurring back in the hospital after initial discharge.
Influenza testing of studied patients was given at clinicians’ discretion, which may make the sample not generalizable to the overall influenza population, and the investigators included only bivariate associations, which means there were likely confounding effects that could not be accounted for.
Mr. McGowan and his fellow investigators plan to expand their research by determining underlying causes of death in these patients, to create more accurate estimates of influenza-associated mortality.
Mr. McGowan reported no relevant financial disclosures.
SOURCE: McGowan, C., et al., ID Week 2017, Abstract 951.
SAN DIEGO – Over half of hospitalized, influenza-related deaths occurred within 30 days of discharge, according to a study presented at an annual scientific meeting on infectious diseases.
As physicians and pharmaceutical companies attempt to measure the burden of seasonal influenza, discharged patients are currently not considered as much as they should be, according to investigators.
Among 968 deceased patients studied, 444 (46%) died in hospital, while 524 (54%) died within 30 days of discharge.
Investigators conducted a retrospective study of 15,562 patients hospitalized for influenza-related cases between 2014 and 2015, as recorded in Influenza-Associated Hospitalizations Surveillance (FluSurv-NET), a database of the Centers for Disease Control and Prevention.
The majority of the studied patients were women (55%) and the majority were white.
Those who died were more likely to have been admitted to the hospital immediately after influenza onset, with 26% of those who died after discharge and 22% of those who died in hospital having been admitted the same day. In contrast, 13% of those who lived past 30 days were admitted immediately after onset.
A total of 46% of those who died after hospitalization had a length of stay longer than 1 week, compared to 15% of those who lived.
Among patients who died after discharge, 356 (68%) died within 2 weeks of discharge, with the highest number of deaths occurring within the first few days, according to presenter Craig McGowan of the Influenza Division of the CDC in Atlanta.
Age also seemed to be a possible mortality predictor, according to Mr. McGowan and his fellow investigators. “Those who died were more likely to be elderly, and those who died after discharge were even more likely to be 85 [years or older] than those who died during their influenza-related hospitalizations,” said Mr. McGowan, who added that patients aged 85 years and older made up more than half of those who died after discharge.
Patients who died in hospital were significantly more likely to have influenza listed as a cause of death. Overall, influenza-related and non–influenza-related respiratory issues were the two most common causes of death listed on death certificates of patients who died during hospitalization or within 14 days of discharge, while cardiovascular or other symptoms were listed for those who died between 15 and 30 days after discharge.
Admission and discharge locations among patients who did not die were almost 80% from a private residence to a private residence, while observations of those who died revealed a different pattern. “Those individuals who died after discharge were almost evenly split between admission from a nursing home or a private residence,” Mr. McGowan said. “Those who were admitted from the nursing home were almost exclusively discharged to either hospice care or back to a nursing home.”
Mr. McGowan noted rehospitalization to be a significant factor among those who died, with 34% of deaths occurring back in the hospital after initial discharge.
Influenza testing of studied patients was given at clinicians’ discretion, which may make the sample not generalizable to the overall influenza population, and the investigators included only bivariate associations, which means there were likely confounding effects that could not be accounted for.
Mr. McGowan and his fellow investigators plan to expand their research by determining underlying causes of death in these patients, to create more accurate estimates of influenza-associated mortality.
Mr. McGowan reported no relevant financial disclosures.
SOURCE: McGowan, C., et al., ID Week 2017, Abstract 951.
AT IDWEEK 2017
Key clinical point:
Major finding: Among patients who died with confirmed influenza, 46% died in hospital, while 54% died within 30 days of discharge.
Data source: Retrospective study of 15,562 influenza patients hospitalized or within 30 days of discharge between 2014 and 2015, recorded in Influenza-Associated Hospitalizations Surveillance (FluSurv-NET).
Disclosures: Mr. McGowen reported no relevant financial disclosures.
Heart failure treatment: Keeping up with best practices
Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.1 The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,2 is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.3,4
Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.5 In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.
The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.6 Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.
This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.
Causes are many and diverse
HF has a variety of cardiac and non-cardiac etiologies.2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).2,7,8
Diagnosing an elusive culprit
HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.
Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),9 which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),10 which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.
Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.5 Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.
The initial evaluation: Necessary lab work and imaging studies
The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.5,7 TABLE 15,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.
Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.8
Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.5
Classification of HF is determined by ejection fraction
Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.
More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.8 Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.5 Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.5
Treatment of HFrEF: The evidence is clear
The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.12
Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.13
MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.14
And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).15
Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.2,7,8
Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.5,7,8
Cautionary notes
Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:
- Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).16,17
- ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.18
- Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
- Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.5,19
When more Tx is needed
For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.
Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.5 Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.
Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).5 They significantly reduce all-cause mortality (NNT=26).20
Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.5 Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.5
Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.5,8
H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.21 Headache and dizziness are commonly reported adverse effects.
Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.22
Also, hypokalemia can intensify digoxin toxicity.23 Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.5
New classes, new agents
Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.24,25 Early trials with sacubitril alone showed limited clinical efficacy;25 however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.6,25
The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.26 The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.
After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).26 There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.26
Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.6 Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.26
Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.6
Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.27 Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.28 Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.28
Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.6 The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.27
Nonpharmacologic options
Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.5
Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).5 CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.30 It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.5,31
Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.5 LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.5
Treatment of HFpEF: Evidence is lacking
While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.32 Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”37 Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).
Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.40 Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.7 A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.33
Common contributing causes of HFpEF
HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.40 Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.
CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.
AF is poorly tolerated by patients with HFpEF.37 Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.33
Obesity is more prevalent in patients with HFpEF than in those with HFrEF.41 Although there is indirect evidence that weight loss improves cardiac function,34,42,43 and studies have shown bariatric surgery to improve diastolic function,44,45 there are no studies reporting clinical outcomes.
Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.46,47
Keeping HF patients out of the hospital
Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.7,52
A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.5,7
At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.5,52
Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.2
Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.2,5
CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; [email protected].
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47. Shah RV, Abbasi SA, Heydari B, et al. Obesity and sleep apnea are independently associated with adverse left ventricular remodeling and clinical outcome in patients with atrial fibrillation and preserved ventricular function. Am Heart J. 2014;167:620-626.
48. Riegel B, Moser DK, Anker SD, et al. State of the science: promoting self-care in persons with heart failure: a scientific statement from the American Heart Association. Circulation. 2009;120:1141-1163.
49. Moser DK, Doering LV, Chung ML. Vulnerabilities of patients recovering from an exacerbation of chronic heart failure. Am Heart J. 2005;150:984.
50. Bernheim SM, Grady JN, Lin Z, et al. National patterns of risk-standardized mortality and readmission for acute myocardial infarction and heart failure: update on publicly reported outcomes measures based on the 2010 release. Circ Cardiovasc Qual Outcomes. 2010;3:459-467.
51. Krumholz HM, Merrill AR, Schone EM, et al. Patterns of hospital performance in acute myocardial infarction and heart failure 30-day mortality and readmission. Circ Cardiovasc Qual Outcomes. 2009;2:407-413.
52. Cowie MR, Anker SD, Cleland JG, et al. Improving care for patients with acute heart failure: before, during and after hospitalization. Available at: http://www.oxfordhealthpolicyforum.org/files/reports/ahf-report.pdf. Accessed November 27, 2017.
Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.1 The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,2 is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.3,4
Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.5 In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.
The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.6 Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.
This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.
Causes are many and diverse
HF has a variety of cardiac and non-cardiac etiologies.2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).2,7,8
Diagnosing an elusive culprit
HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.
Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),9 which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),10 which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.
Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.5 Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.
The initial evaluation: Necessary lab work and imaging studies
The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.5,7 TABLE 15,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.
Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.8
Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.5
Classification of HF is determined by ejection fraction
Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.
More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.8 Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.5 Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.5
Treatment of HFrEF: The evidence is clear
The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.12
Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.13
MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.14
And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).15
Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.2,7,8
Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.5,7,8
Cautionary notes
Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:
- Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).16,17
- ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.18
- Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
- Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.5,19
When more Tx is needed
For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.
Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.5 Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.
Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).5 They significantly reduce all-cause mortality (NNT=26).20
Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.5 Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.5
Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.5,8
H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.21 Headache and dizziness are commonly reported adverse effects.
Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.22
Also, hypokalemia can intensify digoxin toxicity.23 Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.5
New classes, new agents
Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.24,25 Early trials with sacubitril alone showed limited clinical efficacy;25 however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.6,25
The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.26 The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.
After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).26 There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.26
Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.6 Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.26
Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.6
Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.27 Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.28 Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.28
Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.6 The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.27
Nonpharmacologic options
Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.5
Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).5 CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.30 It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.5,31
Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.5 LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.5
Treatment of HFpEF: Evidence is lacking
While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.32 Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”37 Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).
Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.40 Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.7 A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.33
Common contributing causes of HFpEF
HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.40 Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.
CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.
AF is poorly tolerated by patients with HFpEF.37 Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.33
Obesity is more prevalent in patients with HFpEF than in those with HFrEF.41 Although there is indirect evidence that weight loss improves cardiac function,34,42,43 and studies have shown bariatric surgery to improve diastolic function,44,45 there are no studies reporting clinical outcomes.
Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.46,47
Keeping HF patients out of the hospital
Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.7,52
A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.5,7
At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.5,52
Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.2
Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.2,5
CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; [email protected].
Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.1 The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,2 is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.3,4
Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.5 In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.
The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.6 Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.
This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.
Causes are many and diverse
HF has a variety of cardiac and non-cardiac etiologies.2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).2,7,8
Diagnosing an elusive culprit
HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.
Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),9 which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),10 which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.
Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.5 Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.
The initial evaluation: Necessary lab work and imaging studies
The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.5,7 TABLE 15,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.
Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.8
Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.5
Classification of HF is determined by ejection fraction
Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.
More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.8 Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.5 Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.5
Treatment of HFrEF: The evidence is clear
The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.12
Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.13
MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.14
And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).15
Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.2,7,8
Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.5,7,8
Cautionary notes
Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:
- Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).16,17
- ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.18
- Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
- Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.5,19
When more Tx is needed
For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.
Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.5 Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.
Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).5 They significantly reduce all-cause mortality (NNT=26).20
Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.5 Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.5
Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.5,8
H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.21 Headache and dizziness are commonly reported adverse effects.
Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.22
Also, hypokalemia can intensify digoxin toxicity.23 Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.5
New classes, new agents
Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.24,25 Early trials with sacubitril alone showed limited clinical efficacy;25 however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.6,25
The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.26 The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.
After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).26 There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.26
Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.6 Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.26
Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.6
Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.27 Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.28 Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.28
Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.6 The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.27
Nonpharmacologic options
Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.5
Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).5 CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.30 It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.5,31
Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.5 LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.5
Treatment of HFpEF: Evidence is lacking
While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.32 Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”37 Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).
Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.40 Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.7 A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.33
Common contributing causes of HFpEF
HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.40 Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.
CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.
AF is poorly tolerated by patients with HFpEF.37 Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.33
Obesity is more prevalent in patients with HFpEF than in those with HFrEF.41 Although there is indirect evidence that weight loss improves cardiac function,34,42,43 and studies have shown bariatric surgery to improve diastolic function,44,45 there are no studies reporting clinical outcomes.
Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.46,47
Keeping HF patients out of the hospital
Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.7,52
A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.5,7
At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.5,52
Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.2
Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.2,5
CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; [email protected].
1. Hall MJ, Levant S, DeFrances CJ. Hospitalization for congestive heart failure: United States, 2000-2010. NCHS Data Brief. 2012;(108):1-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23102190. Accessed April 26, 2017.
2. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
3. Passantino A, Guida P, Lagioia R, et al. Predictors of long-term mortality in older patients hospitalized for acutely decompensated heart failure: clinical relevance of natriuretic peptides. J Am Geriatr Soc. 2017;65:822-826.
4. Lassus JP, Siirilä-Waris K, Nieminen MS, et al. Long-term survival after hospitalization for acute heart failure—differences in prognosis of acutely decompensated chronic and new-onset acute heart failure. Int J Cardiol. 2013;168:458-462.
5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240-e327.
6. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2016;68:1476-1488.
7. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129-2200.
8. Pinkerman CP, Sander JE, Breeding D, et al. Institute for Clinical Systems Improvement. Heart failure in adults. Available at: https://www.scribd.com/document/310893227/HeartFailure-pdf. Accessed December 6, 2017.
9. McKee PA, Castelli WP, McNamara PM, et al. The natural history of congestive heart failure: the Framingham Study. N Engl J Med. 1971;285:1441-1446.
10. Kelder JC, Cramer MJ, van Wijngaarden J, et al. The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure. Circulation. 2011;124:2865-2873.
11. Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16:e1-194.
12. Pouleur H, The SOLVD Investigators. Results of the treatment trial of the studies of left ventricular dysfunction (SOLVD). Am J Cardiol. 1992;70:135-136.
13. Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002;40:1414-1421.
14. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007.
15. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362:7-13.
16. Gehr TW, Sica DA. Pharmacotherapy in congestive heart failure: Hyperkalemia in congestive heart failure. Congest Heart Fail. 2001;7:97-100.
17. National Institute for Health and Clinical Excellence (NICE). Chronic heart failure in adults: management. 2010. Available at: https://www.nice.org.uk/guidance/cg108. Accessed November 27, 2017.
18. Barreras A, Gurk-Turner C. Angiotensin II receptor blockers. Proc (Bayl Univ Med Cent). 2003;16:123-126.
19. Epstein SE, Braunwald E. The effect of beta adrenergic blockade on patterns of urinary sodium excretion: studies in normal subjects and in patients with heart disease. Ann Intern Med. 1966;65:20-27.
20. Berbenetz NM, Mrkobrada M. Mineralocorticoid receptor antagonists for heart failure: systematic review and meta-analysis. BMC Cardiovasc Disord. 2016;16:246.
21. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057.
22. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol. 1992;69:108G-118G.
23. Sundar S, Burma DP, Vaish SK. Digoxin toxicity and electrolytes: a correlative study. Acta Cardiol. 1983;38:115-123.
24. McDowell G, Nicholls DP. The endopeptidase inhibitor, candoxatril, and its therapeutic potential in the treatment of chronic cardiac failure in man. Expert Opin Investig Drugs. 1999;8:79-84.
25. Prenner SB, Shah SJ, Yancy CW. Role of angiotensin receptor-neprilysin inhibition in heart failure. Curr Atheroscler Rep. 2016;18:48.
26. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
27. Corlanor package insert. Amgen Inc., Thousand Oaks, CA. Available at: http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/corlanor/corlanor_pi.pdf. Accessed November 28, 2017.
28. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.
29. Kusumoto FM, Calkins H, Boehmer J, et al. HRS/ACC/AHA expert consensus statement on the use of implantable cardioverter-defibrillator therapy in patients who are not included or not well represented in clinical trials. Circulation. 2014;130:94-125.
30. Leyva F, Nisam S, Auricchio A. 20 years of cardiac resynchronization therapy. J Am Coll Cardiol. 2014;64:1047-1058.
31. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS Focused Update Incorporated Into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2013;127:e283-e352.
32. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670-679.
33. Redfield MM. Heart failure with preserved ejection fraction. N Engl J Med. 2016;375:1868-1877.
34. Nanayakkara S, Kaye DM. Management of heart failure with preserved ejection fraction: a review. Clin Ther. 2015;37:2186-2198.
35. Cleland JG, Pellicori P, Dierckx R. Clinical trials in patients with heart failure and preserved left ventricular ejection fraction. Heart Fail Clin. 2014;10:511-523.
36. Ferrari R, Böhm M, Cleland JGF, et al. Heart failure with preserved ejection fraction: uncertainties and dilemmas. Eur J Heart Fail. 2015;17:665-671.
37. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2014;11:507-515.
38. Sharp A, Tapp R, Francis DP, et al. Ethnicity and left ventricular diastolic function in hypertension an ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) substudy. J Am Coll Cardiol. 2008;52:1015-1021.
39. Zile MR. Heart failure with a preserved ejection fraction. In: Mann DL, Zipes D, Libby P BR, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Phila
40. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70:776-803.
41. Mentz RJ, Kelly JP, von Lueder TG, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64:2281-2293.
42. de las Fuentes L, Waggoner AD, Mohammed BS, et al. Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function. J Am Coll Cardiol. 2009;54:2376-2381.
43. Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction. JAMA. 2016;315:36-46.
44. Rider OJ, Francis JM, Ali MK, et al. Beneficial cardiovascular effects of bariatric surgical and dietary weight loss in obesity. J Am Coll Cardiol. 2009;54:718-726.
45. Ristow B, Rabkin J, Haeusslein E. Improvement in dilated cardiomyopathy after bariatric surgery. J Card Fail. 2008;14:198-202.
46. Yoshihisa A, Suzuki S, Yamauchi H, et al. Beneficial effects of positive airway pressure therapy for sleep-disordered breathing in heart failure patients with preserved left ventricular ejection fraction. Clin Cardiol. 2015;38:413-421.
47. Shah RV, Abbasi SA, Heydari B, et al. Obesity and sleep apnea are independently associated with adverse left ventricular remodeling and clinical outcome in patients with atrial fibrillation and preserved ventricular function. Am Heart J. 2014;167:620-626.
48. Riegel B, Moser DK, Anker SD, et al. State of the science: promoting self-care in persons with heart failure: a scientific statement from the American Heart Association. Circulation. 2009;120:1141-1163.
49. Moser DK, Doering LV, Chung ML. Vulnerabilities of patients recovering from an exacerbation of chronic heart failure. Am Heart J. 2005;150:984.
50. Bernheim SM, Grady JN, Lin Z, et al. National patterns of risk-standardized mortality and readmission for acute myocardial infarction and heart failure: update on publicly reported outcomes measures based on the 2010 release. Circ Cardiovasc Qual Outcomes. 2010;3:459-467.
51. Krumholz HM, Merrill AR, Schone EM, et al. Patterns of hospital performance in acute myocardial infarction and heart failure 30-day mortality and readmission. Circ Cardiovasc Qual Outcomes. 2009;2:407-413.
52. Cowie MR, Anker SD, Cleland JG, et al. Improving care for patients with acute heart failure: before, during and after hospitalization. Available at: http://www.oxfordhealthpolicyforum.org/files/reports/ahf-report.pdf. Accessed November 27, 2017.
1. Hall MJ, Levant S, DeFrances CJ. Hospitalization for congestive heart failure: United States, 2000-2010. NCHS Data Brief. 2012;(108):1-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23102190. Accessed April 26, 2017.
2. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
3. Passantino A, Guida P, Lagioia R, et al. Predictors of long-term mortality in older patients hospitalized for acutely decompensated heart failure: clinical relevance of natriuretic peptides. J Am Geriatr Soc. 2017;65:822-826.
4. Lassus JP, Siirilä-Waris K, Nieminen MS, et al. Long-term survival after hospitalization for acute heart failure—differences in prognosis of acutely decompensated chronic and new-onset acute heart failure. Int J Cardiol. 2013;168:458-462.
5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240-e327.
6. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2016;68:1476-1488.
7. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129-2200.
8. Pinkerman CP, Sander JE, Breeding D, et al. Institute for Clinical Systems Improvement. Heart failure in adults. Available at: https://www.scribd.com/document/310893227/HeartFailure-pdf. Accessed December 6, 2017.
9. McKee PA, Castelli WP, McNamara PM, et al. The natural history of congestive heart failure: the Framingham Study. N Engl J Med. 1971;285:1441-1446.
10. Kelder JC, Cramer MJ, van Wijngaarden J, et al. The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure. Circulation. 2011;124:2865-2873.
11. Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16:e1-194.
12. Pouleur H, The SOLVD Investigators. Results of the treatment trial of the studies of left ventricular dysfunction (SOLVD). Am J Cardiol. 1992;70:135-136.
13. Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002;40:1414-1421.
14. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007.
15. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362:7-13.
16. Gehr TW, Sica DA. Pharmacotherapy in congestive heart failure: Hyperkalemia in congestive heart failure. Congest Heart Fail. 2001;7:97-100.
17. National Institute for Health and Clinical Excellence (NICE). Chronic heart failure in adults: management. 2010. Available at: https://www.nice.org.uk/guidance/cg108. Accessed November 27, 2017.
18. Barreras A, Gurk-Turner C. Angiotensin II receptor blockers. Proc (Bayl Univ Med Cent). 2003;16:123-126.
19. Epstein SE, Braunwald E. The effect of beta adrenergic blockade on patterns of urinary sodium excretion: studies in normal subjects and in patients with heart disease. Ann Intern Med. 1966;65:20-27.
20. Berbenetz NM, Mrkobrada M. Mineralocorticoid receptor antagonists for heart failure: systematic review and meta-analysis. BMC Cardiovasc Disord. 2016;16:246.
21. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057.
22. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol. 1992;69:108G-118G.
23. Sundar S, Burma DP, Vaish SK. Digoxin toxicity and electrolytes: a correlative study. Acta Cardiol. 1983;38:115-123.
24. McDowell G, Nicholls DP. The endopeptidase inhibitor, candoxatril, and its therapeutic potential in the treatment of chronic cardiac failure in man. Expert Opin Investig Drugs. 1999;8:79-84.
25. Prenner SB, Shah SJ, Yancy CW. Role of angiotensin receptor-neprilysin inhibition in heart failure. Curr Atheroscler Rep. 2016;18:48.
26. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
27. Corlanor package insert. Amgen Inc., Thousand Oaks, CA. Available at: http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/corlanor/corlanor_pi.pdf. Accessed November 28, 2017.
28. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.
29. Kusumoto FM, Calkins H, Boehmer J, et al. HRS/ACC/AHA expert consensus statement on the use of implantable cardioverter-defibrillator therapy in patients who are not included or not well represented in clinical trials. Circulation. 2014;130:94-125.
30. Leyva F, Nisam S, Auricchio A. 20 years of cardiac resynchronization therapy. J Am Coll Cardiol. 2014;64:1047-1058.
31. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS Focused Update Incorporated Into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2013;127:e283-e352.
32. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670-679.
33. Redfield MM. Heart failure with preserved ejection fraction. N Engl J Med. 2016;375:1868-1877.
34. Nanayakkara S, Kaye DM. Management of heart failure with preserved ejection fraction: a review. Clin Ther. 2015;37:2186-2198.
35. Cleland JG, Pellicori P, Dierckx R. Clinical trials in patients with heart failure and preserved left ventricular ejection fraction. Heart Fail Clin. 2014;10:511-523.
36. Ferrari R, Böhm M, Cleland JGF, et al. Heart failure with preserved ejection fraction: uncertainties and dilemmas. Eur J Heart Fail. 2015;17:665-671.
37. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2014;11:507-515.
38. Sharp A, Tapp R, Francis DP, et al. Ethnicity and left ventricular diastolic function in hypertension an ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) substudy. J Am Coll Cardiol. 2008;52:1015-1021.
39. Zile MR. Heart failure with a preserved ejection fraction. In: Mann DL, Zipes D, Libby P BR, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Phila
40. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70:776-803.
41. Mentz RJ, Kelly JP, von Lueder TG, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64:2281-2293.
42. de las Fuentes L, Waggoner AD, Mohammed BS, et al. Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function. J Am Coll Cardiol. 2009;54:2376-2381.
43. Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction. JAMA. 2016;315:36-46.
44. Rider OJ, Francis JM, Ali MK, et al. Beneficial cardiovascular effects of bariatric surgical and dietary weight loss in obesity. J Am Coll Cardiol. 2009;54:718-726.
45. Ristow B, Rabkin J, Haeusslein E. Improvement in dilated cardiomyopathy after bariatric surgery. J Card Fail. 2008;14:198-202.
46. Yoshihisa A, Suzuki S, Yamauchi H, et al. Beneficial effects of positive airway pressure therapy for sleep-disordered breathing in heart failure patients with preserved left ventricular ejection fraction. Clin Cardiol. 2015;38:413-421.
47. Shah RV, Abbasi SA, Heydari B, et al. Obesity and sleep apnea are independently associated with adverse left ventricular remodeling and clinical outcome in patients with atrial fibrillation and preserved ventricular function. Am Heart J. 2014;167:620-626.
48. Riegel B, Moser DK, Anker SD, et al. State of the science: promoting self-care in persons with heart failure: a scientific statement from the American Heart Association. Circulation. 2009;120:1141-1163.
49. Moser DK, Doering LV, Chung ML. Vulnerabilities of patients recovering from an exacerbation of chronic heart failure. Am Heart J. 2005;150:984.
50. Bernheim SM, Grady JN, Lin Z, et al. National patterns of risk-standardized mortality and readmission for acute myocardial infarction and heart failure: update on publicly reported outcomes measures based on the 2010 release. Circ Cardiovasc Qual Outcomes. 2010;3:459-467.
51. Krumholz HM, Merrill AR, Schone EM, et al. Patterns of hospital performance in acute myocardial infarction and heart failure 30-day mortality and readmission. Circ Cardiovasc Qual Outcomes. 2009;2:407-413.
52. Cowie MR, Anker SD, Cleland JG, et al. Improving care for patients with acute heart failure: before, during and after hospitalization. Available at: http://www.oxfordhealthpolicyforum.org/files/reports/ahf-report.pdf. Accessed November 27, 2017.
From The Journal of Family Practice | 2018;67(1):18-26.
PRACTICE RECOMMENDATIONS
› Order a measurement of B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide in patients with dyspnea to help diagnose and manage heart failure (HF). A
› Refer patients with symptomatic HF and a left ventricular ejection fraction (LVEF) ≤35% that persists despite ≥3 months of optimal medical therapy for an implantable cardioverter defibrillator to reduce the risk of sudden death and all-cause mortality. A
› Consider cardiac resynchronization therapy for patients with an LVEF ≤35%, sinus rhythm, left bundle branch block, and a QRS duration ≥150 ms who remain symptomatic despite optimal medical therapy. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Worsening dyspnea
A 62-year-old woman presented with a 2- to 3-week history of fatigue, nonproductive cough, dyspnea on exertion, and intermittent fever/chills. Her past medical history was significant for rheumatoid arthritis (RA) that had been treated with methotrexate and prednisone for the past 6 years. The patient was currently smoking half a pack a day with a 40-pack year history. The patient was a lifelong resident of Arizona and had previously worked in a stone mine.
On physical examination she appeared comfortable without any increased work of breathing. Her vital signs included a temperature of 36.6° C, a blood pressure of 110/54 mm Hg, a pulse of 90 beats/min, respirations of 16/min, and room-air oxygen saturation of 87%. Pulmonary examination revealed scattered wheezes with fine bibasilar crackles. The remainder of her physical exam was normal. Because she was hypoxic, she was admitted to the hospital.
At the hospital, a chest x-ray showed diffuse, bilateral interstitial changes (FIGURE 1). Laboratory tests revealed a white blood cell count of 13,800/mcL (normal: 4500-10,500/mcL) with 73% neutrophils (normal: 40%-60%), 3% bands (normal: 0-3%), 14% monocytes (normal: 2%-8%), 6% eosinophils (normal: 1%-4%), and 3% lymphocytes (normal: 20%-30%). Community-acquired pneumonia was suspected, and the patient was started on levofloxacin. Over the next 2 days, her dyspnea worsened. She became tachycardic, and her oxygen requirement increased to 15 L/min via a non-rebreather mask. She was transferred to the intensive care unit.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Interstitial lung disease
Given the patient’s worsening respiratory status, a computed tomography (CT) scan was ordered (FIGURE 2). Review of the CT scan showed ground-glass opacification, mild subpleural honeycombing, reticularity, and traction bronchiectasis bilaterally at the lung bases. Bronchoscopy with lavage was performed to rule out infectious etiologies and was negative. These findings, along with the patient’s medical history of RA and use of methotrexate, led us to diagnose interstitial lung disease (ILD) in this patient.
ILD refers to a group of disorders that primarily affects the pulmonary interstitium, rather than the alveolar spaces or pleura.1 The most common causes of ILD seen in primary care are idiopathic pulmonary fibrosis, connective tissue disease, and hypersensitivity pneumonitis secondary to drugs (such as methotrexate, citalopram, fluoxetine, nitrofurantoin, and cephalosporins), radiation, or occupational exposures. (Textile, metal, and plastic workers are at a heightened risk, as are painters and individuals who work with animals.)1 In 2010, idiopathic pulmonary fibrosis had a prevalence of 18.2 cases per 100,000 people.2 Determining the underlying cause of ILD is important, as it may influence prognosis and treatment decisions.
The most common presenting symptoms of ILD are exertional dyspnea, cough with insidious onset, fatigue, and weakness.1,3 Bear in mind, however, that patients with ILD associated with a connective tissue disease may have more subtle manifestations of exertional dyspnea, such as a change in activity level or low resting oxygen saturations. The pulmonary exam can be normal or can reveal fine end-inspiratory crackles, and may include high-pitched, inspiratory rhonchi, or “squeaks.”1
When a diagnosis of ILD is suspected, investigation should begin with high-resolution CT (HRCT).1.3-5 In patients for whom a potential cause of ILD is not identified or who have more than one potential cause, specific patterns seen on the HRCT can help determine the most likely etiology.5 Chest x-ray has low sensitivity and specificity for ILD and can frequently be misinterpreted, as occurred with our patient.1
Rule out other causes of dyspnea
The differential diagnosis for dyspnea includes:
Heart failure. Congestive heart failure can present with acutely worsening dyspnea and cough, but is also commonly associated with orthopnea and/or paroxysmal nocturnal dyspnea. On physical examination, findings of volume overload such as pulmonary crackles, lower extremity edema, and elevated jugular venous pressure are additional signs that heart failure is present.
Pulmonary embolism (PE). Patients with PE commonly present with acute dyspnea, chest pain, and may also have a cough. Additional risk factors for PE (prolonged immobility, fracture, recent hospitalization) may also be present. A Wells score and a D-dimer test can be used to determine the probability of a patient having PE.
Asthma/chronic obstructive pulmonary disease. COPD exacerbations commonly present with a productive cough and worsening dyspnea. Pulmonary exam findings include wheezing, tachypnea, increased respiratory effort, and poor air movement.
Infection (including coccidioidomycosis in the desert southwest, where this patient lived). Our patient was initially treated for pneumonia because she had reported fevers associated with dyspnea and cough along with an elevated white blood cell count. Chest x-ray findings in patients with pneumonia can reveal either lobar consolidation or interstitial infiltrates.
Failure to respond to treatment of the more common causes of dyspnea, as occurred with our patient, should prompt consideration of ILD, particularly in those who have a history of connective tissue disease. Once a diagnosis of ILD is made, referral to a pulmonary specialist is advised.1,3
A poor prognosis and a focus on quality of life
Immunosuppressive therapy is currently the standard treatment for ILD, although there is little evidence to support this practice.1,3,4 Therapy usually includes corticosteroids with or without the addition of a second immunosuppressive agent such as azathioprine, mycophenolate mofetil, or cyclophosphamide.1,4
In addition to drug therapy, the American College of Chest Physicians recommends routine assessment of quality-of-life (QOL) concerns in patients with ILD (TABLE).6,7 Additional QOL tools available to physicians include the Medical Outcomes Study Short-Form 36-Item Instrument8 and the St. George’s Respiratory Questionnaire.9
The prognosis is poor, even with treatment. Patients with ILD have a life expectancy that averages 2 to 4 years from diagnosis.6 Patients with ILD are frequently distressed about worsening control of dyspnea and becoming a burden to family members; they also have anxiety about dying.6 It’s important to allocate sufficient time for end-of-life discussions, as studies have shown that patients would like their physicians to address the issue more thoroughly.10
Our patient was started on high-flow oxygen and high-dose steroids. Azathioprine was later added. The patient’s methotrexate was stopped, in light of its association with ILD. Unfortunately, the treatments were not successful and the patient’s respiratory status continued to deteriorate. A family meeting was held with the patient to discuss end-of-life wishes, and the patient expressed a preference for hospice care. She died a few days after hospice enrollment.
CORRESPONDENCE
Karyn B. Kolman, MD, University of Arizona College of Medicine at South Campus Family Medicine Residency, 2800 E Ajo Way, Room 3006, Tucson, AZ 85713; [email protected].
1. Wallis A, Spinks K. The diagnosis and management of interstial lung disease. BMJ. 2015;350:h2072.
2. Raghu G, Chen SY, Hou Q, et al. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 2016;48:179-186.
3. Yunt ZX, Solomon JJ. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am. 2015;41:225-236.
4. Vij R, Strek ME. Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest. 2013;143:814-824.
5. Nair A, Walsh SL, Desai SR. Imaging of pulmonary involvement in rheumatic disease. Rheum Dis Clin North Am. 2015;41:167-196.
6. Gilbert CR, Smith CM. Advanced parenchymal lung disease: quality of life and palliative care. Mt Sinai J Med. 2009;76:63-70.
7. Swigris JJ, Stewart AL, Gould MK, et al. Patients’ perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives. Health Qual Life Outcomes. 2005;3:61.
8. RAND. Medical Outcomes Study 36-Item Short Form Survey (SF-36). Available at: http://www.rand.org/health/surveys_tools/mos/mos_core_36item.html. Accessed May 27, 2016.
9. St George’s Respiratory Questionnaire. Available at: http://www.healthstatus.sgul.ac.uk/. Accessed May 27, 2016.
10. Bajwah S, Koffman J, Higginson IJ, et. al. ‘I wish I knew more…’ the end-of-life planning and information needs for end-stage fibrotic interstitial lung disease: views of patients, carers, and health professionals. BMJ Support Palliat Care. 2013;3;84-90.
A 62-year-old woman presented with a 2- to 3-week history of fatigue, nonproductive cough, dyspnea on exertion, and intermittent fever/chills. Her past medical history was significant for rheumatoid arthritis (RA) that had been treated with methotrexate and prednisone for the past 6 years. The patient was currently smoking half a pack a day with a 40-pack year history. The patient was a lifelong resident of Arizona and had previously worked in a stone mine.
On physical examination she appeared comfortable without any increased work of breathing. Her vital signs included a temperature of 36.6° C, a blood pressure of 110/54 mm Hg, a pulse of 90 beats/min, respirations of 16/min, and room-air oxygen saturation of 87%. Pulmonary examination revealed scattered wheezes with fine bibasilar crackles. The remainder of her physical exam was normal. Because she was hypoxic, she was admitted to the hospital.
At the hospital, a chest x-ray showed diffuse, bilateral interstitial changes (FIGURE 1). Laboratory tests revealed a white blood cell count of 13,800/mcL (normal: 4500-10,500/mcL) with 73% neutrophils (normal: 40%-60%), 3% bands (normal: 0-3%), 14% monocytes (normal: 2%-8%), 6% eosinophils (normal: 1%-4%), and 3% lymphocytes (normal: 20%-30%). Community-acquired pneumonia was suspected, and the patient was started on levofloxacin. Over the next 2 days, her dyspnea worsened. She became tachycardic, and her oxygen requirement increased to 15 L/min via a non-rebreather mask. She was transferred to the intensive care unit.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Interstitial lung disease
Given the patient’s worsening respiratory status, a computed tomography (CT) scan was ordered (FIGURE 2). Review of the CT scan showed ground-glass opacification, mild subpleural honeycombing, reticularity, and traction bronchiectasis bilaterally at the lung bases. Bronchoscopy with lavage was performed to rule out infectious etiologies and was negative. These findings, along with the patient’s medical history of RA and use of methotrexate, led us to diagnose interstitial lung disease (ILD) in this patient.
ILD refers to a group of disorders that primarily affects the pulmonary interstitium, rather than the alveolar spaces or pleura.1 The most common causes of ILD seen in primary care are idiopathic pulmonary fibrosis, connective tissue disease, and hypersensitivity pneumonitis secondary to drugs (such as methotrexate, citalopram, fluoxetine, nitrofurantoin, and cephalosporins), radiation, or occupational exposures. (Textile, metal, and plastic workers are at a heightened risk, as are painters and individuals who work with animals.)1 In 2010, idiopathic pulmonary fibrosis had a prevalence of 18.2 cases per 100,000 people.2 Determining the underlying cause of ILD is important, as it may influence prognosis and treatment decisions.
The most common presenting symptoms of ILD are exertional dyspnea, cough with insidious onset, fatigue, and weakness.1,3 Bear in mind, however, that patients with ILD associated with a connective tissue disease may have more subtle manifestations of exertional dyspnea, such as a change in activity level or low resting oxygen saturations. The pulmonary exam can be normal or can reveal fine end-inspiratory crackles, and may include high-pitched, inspiratory rhonchi, or “squeaks.”1
When a diagnosis of ILD is suspected, investigation should begin with high-resolution CT (HRCT).1.3-5 In patients for whom a potential cause of ILD is not identified or who have more than one potential cause, specific patterns seen on the HRCT can help determine the most likely etiology.5 Chest x-ray has low sensitivity and specificity for ILD and can frequently be misinterpreted, as occurred with our patient.1
Rule out other causes of dyspnea
The differential diagnosis for dyspnea includes:
Heart failure. Congestive heart failure can present with acutely worsening dyspnea and cough, but is also commonly associated with orthopnea and/or paroxysmal nocturnal dyspnea. On physical examination, findings of volume overload such as pulmonary crackles, lower extremity edema, and elevated jugular venous pressure are additional signs that heart failure is present.
Pulmonary embolism (PE). Patients with PE commonly present with acute dyspnea, chest pain, and may also have a cough. Additional risk factors for PE (prolonged immobility, fracture, recent hospitalization) may also be present. A Wells score and a D-dimer test can be used to determine the probability of a patient having PE.
Asthma/chronic obstructive pulmonary disease. COPD exacerbations commonly present with a productive cough and worsening dyspnea. Pulmonary exam findings include wheezing, tachypnea, increased respiratory effort, and poor air movement.
Infection (including coccidioidomycosis in the desert southwest, where this patient lived). Our patient was initially treated for pneumonia because she had reported fevers associated with dyspnea and cough along with an elevated white blood cell count. Chest x-ray findings in patients with pneumonia can reveal either lobar consolidation or interstitial infiltrates.
Failure to respond to treatment of the more common causes of dyspnea, as occurred with our patient, should prompt consideration of ILD, particularly in those who have a history of connective tissue disease. Once a diagnosis of ILD is made, referral to a pulmonary specialist is advised.1,3
A poor prognosis and a focus on quality of life
Immunosuppressive therapy is currently the standard treatment for ILD, although there is little evidence to support this practice.1,3,4 Therapy usually includes corticosteroids with or without the addition of a second immunosuppressive agent such as azathioprine, mycophenolate mofetil, or cyclophosphamide.1,4
In addition to drug therapy, the American College of Chest Physicians recommends routine assessment of quality-of-life (QOL) concerns in patients with ILD (TABLE).6,7 Additional QOL tools available to physicians include the Medical Outcomes Study Short-Form 36-Item Instrument8 and the St. George’s Respiratory Questionnaire.9
The prognosis is poor, even with treatment. Patients with ILD have a life expectancy that averages 2 to 4 years from diagnosis.6 Patients with ILD are frequently distressed about worsening control of dyspnea and becoming a burden to family members; they also have anxiety about dying.6 It’s important to allocate sufficient time for end-of-life discussions, as studies have shown that patients would like their physicians to address the issue more thoroughly.10
Our patient was started on high-flow oxygen and high-dose steroids. Azathioprine was later added. The patient’s methotrexate was stopped, in light of its association with ILD. Unfortunately, the treatments were not successful and the patient’s respiratory status continued to deteriorate. A family meeting was held with the patient to discuss end-of-life wishes, and the patient expressed a preference for hospice care. She died a few days after hospice enrollment.
CORRESPONDENCE
Karyn B. Kolman, MD, University of Arizona College of Medicine at South Campus Family Medicine Residency, 2800 E Ajo Way, Room 3006, Tucson, AZ 85713; [email protected].
A 62-year-old woman presented with a 2- to 3-week history of fatigue, nonproductive cough, dyspnea on exertion, and intermittent fever/chills. Her past medical history was significant for rheumatoid arthritis (RA) that had been treated with methotrexate and prednisone for the past 6 years. The patient was currently smoking half a pack a day with a 40-pack year history. The patient was a lifelong resident of Arizona and had previously worked in a stone mine.
On physical examination she appeared comfortable without any increased work of breathing. Her vital signs included a temperature of 36.6° C, a blood pressure of 110/54 mm Hg, a pulse of 90 beats/min, respirations of 16/min, and room-air oxygen saturation of 87%. Pulmonary examination revealed scattered wheezes with fine bibasilar crackles. The remainder of her physical exam was normal. Because she was hypoxic, she was admitted to the hospital.
At the hospital, a chest x-ray showed diffuse, bilateral interstitial changes (FIGURE 1). Laboratory tests revealed a white blood cell count of 13,800/mcL (normal: 4500-10,500/mcL) with 73% neutrophils (normal: 40%-60%), 3% bands (normal: 0-3%), 14% monocytes (normal: 2%-8%), 6% eosinophils (normal: 1%-4%), and 3% lymphocytes (normal: 20%-30%). Community-acquired pneumonia was suspected, and the patient was started on levofloxacin. Over the next 2 days, her dyspnea worsened. She became tachycardic, and her oxygen requirement increased to 15 L/min via a non-rebreather mask. She was transferred to the intensive care unit.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Interstitial lung disease
Given the patient’s worsening respiratory status, a computed tomography (CT) scan was ordered (FIGURE 2). Review of the CT scan showed ground-glass opacification, mild subpleural honeycombing, reticularity, and traction bronchiectasis bilaterally at the lung bases. Bronchoscopy with lavage was performed to rule out infectious etiologies and was negative. These findings, along with the patient’s medical history of RA and use of methotrexate, led us to diagnose interstitial lung disease (ILD) in this patient.
ILD refers to a group of disorders that primarily affects the pulmonary interstitium, rather than the alveolar spaces or pleura.1 The most common causes of ILD seen in primary care are idiopathic pulmonary fibrosis, connective tissue disease, and hypersensitivity pneumonitis secondary to drugs (such as methotrexate, citalopram, fluoxetine, nitrofurantoin, and cephalosporins), radiation, or occupational exposures. (Textile, metal, and plastic workers are at a heightened risk, as are painters and individuals who work with animals.)1 In 2010, idiopathic pulmonary fibrosis had a prevalence of 18.2 cases per 100,000 people.2 Determining the underlying cause of ILD is important, as it may influence prognosis and treatment decisions.
The most common presenting symptoms of ILD are exertional dyspnea, cough with insidious onset, fatigue, and weakness.1,3 Bear in mind, however, that patients with ILD associated with a connective tissue disease may have more subtle manifestations of exertional dyspnea, such as a change in activity level or low resting oxygen saturations. The pulmonary exam can be normal or can reveal fine end-inspiratory crackles, and may include high-pitched, inspiratory rhonchi, or “squeaks.”1
When a diagnosis of ILD is suspected, investigation should begin with high-resolution CT (HRCT).1.3-5 In patients for whom a potential cause of ILD is not identified or who have more than one potential cause, specific patterns seen on the HRCT can help determine the most likely etiology.5 Chest x-ray has low sensitivity and specificity for ILD and can frequently be misinterpreted, as occurred with our patient.1
Rule out other causes of dyspnea
The differential diagnosis for dyspnea includes:
Heart failure. Congestive heart failure can present with acutely worsening dyspnea and cough, but is also commonly associated with orthopnea and/or paroxysmal nocturnal dyspnea. On physical examination, findings of volume overload such as pulmonary crackles, lower extremity edema, and elevated jugular venous pressure are additional signs that heart failure is present.
Pulmonary embolism (PE). Patients with PE commonly present with acute dyspnea, chest pain, and may also have a cough. Additional risk factors for PE (prolonged immobility, fracture, recent hospitalization) may also be present. A Wells score and a D-dimer test can be used to determine the probability of a patient having PE.
Asthma/chronic obstructive pulmonary disease. COPD exacerbations commonly present with a productive cough and worsening dyspnea. Pulmonary exam findings include wheezing, tachypnea, increased respiratory effort, and poor air movement.
Infection (including coccidioidomycosis in the desert southwest, where this patient lived). Our patient was initially treated for pneumonia because she had reported fevers associated with dyspnea and cough along with an elevated white blood cell count. Chest x-ray findings in patients with pneumonia can reveal either lobar consolidation or interstitial infiltrates.
Failure to respond to treatment of the more common causes of dyspnea, as occurred with our patient, should prompt consideration of ILD, particularly in those who have a history of connective tissue disease. Once a diagnosis of ILD is made, referral to a pulmonary specialist is advised.1,3
A poor prognosis and a focus on quality of life
Immunosuppressive therapy is currently the standard treatment for ILD, although there is little evidence to support this practice.1,3,4 Therapy usually includes corticosteroids with or without the addition of a second immunosuppressive agent such as azathioprine, mycophenolate mofetil, or cyclophosphamide.1,4
In addition to drug therapy, the American College of Chest Physicians recommends routine assessment of quality-of-life (QOL) concerns in patients with ILD (TABLE).6,7 Additional QOL tools available to physicians include the Medical Outcomes Study Short-Form 36-Item Instrument8 and the St. George’s Respiratory Questionnaire.9
The prognosis is poor, even with treatment. Patients with ILD have a life expectancy that averages 2 to 4 years from diagnosis.6 Patients with ILD are frequently distressed about worsening control of dyspnea and becoming a burden to family members; they also have anxiety about dying.6 It’s important to allocate sufficient time for end-of-life discussions, as studies have shown that patients would like their physicians to address the issue more thoroughly.10
Our patient was started on high-flow oxygen and high-dose steroids. Azathioprine was later added. The patient’s methotrexate was stopped, in light of its association with ILD. Unfortunately, the treatments were not successful and the patient’s respiratory status continued to deteriorate. A family meeting was held with the patient to discuss end-of-life wishes, and the patient expressed a preference for hospice care. She died a few days after hospice enrollment.
CORRESPONDENCE
Karyn B. Kolman, MD, University of Arizona College of Medicine at South Campus Family Medicine Residency, 2800 E Ajo Way, Room 3006, Tucson, AZ 85713; [email protected].
1. Wallis A, Spinks K. The diagnosis and management of interstial lung disease. BMJ. 2015;350:h2072.
2. Raghu G, Chen SY, Hou Q, et al. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 2016;48:179-186.
3. Yunt ZX, Solomon JJ. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am. 2015;41:225-236.
4. Vij R, Strek ME. Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest. 2013;143:814-824.
5. Nair A, Walsh SL, Desai SR. Imaging of pulmonary involvement in rheumatic disease. Rheum Dis Clin North Am. 2015;41:167-196.
6. Gilbert CR, Smith CM. Advanced parenchymal lung disease: quality of life and palliative care. Mt Sinai J Med. 2009;76:63-70.
7. Swigris JJ, Stewart AL, Gould MK, et al. Patients’ perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives. Health Qual Life Outcomes. 2005;3:61.
8. RAND. Medical Outcomes Study 36-Item Short Form Survey (SF-36). Available at: http://www.rand.org/health/surveys_tools/mos/mos_core_36item.html. Accessed May 27, 2016.
9. St George’s Respiratory Questionnaire. Available at: http://www.healthstatus.sgul.ac.uk/. Accessed May 27, 2016.
10. Bajwah S, Koffman J, Higginson IJ, et. al. ‘I wish I knew more…’ the end-of-life planning and information needs for end-stage fibrotic interstitial lung disease: views of patients, carers, and health professionals. BMJ Support Palliat Care. 2013;3;84-90.
1. Wallis A, Spinks K. The diagnosis and management of interstial lung disease. BMJ. 2015;350:h2072.
2. Raghu G, Chen SY, Hou Q, et al. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 2016;48:179-186.
3. Yunt ZX, Solomon JJ. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am. 2015;41:225-236.
4. Vij R, Strek ME. Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest. 2013;143:814-824.
5. Nair A, Walsh SL, Desai SR. Imaging of pulmonary involvement in rheumatic disease. Rheum Dis Clin North Am. 2015;41:167-196.
6. Gilbert CR, Smith CM. Advanced parenchymal lung disease: quality of life and palliative care. Mt Sinai J Med. 2009;76:63-70.
7. Swigris JJ, Stewart AL, Gould MK, et al. Patients’ perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives. Health Qual Life Outcomes. 2005;3:61.
8. RAND. Medical Outcomes Study 36-Item Short Form Survey (SF-36). Available at: http://www.rand.org/health/surveys_tools/mos/mos_core_36item.html. Accessed May 27, 2016.
9. St George’s Respiratory Questionnaire. Available at: http://www.healthstatus.sgul.ac.uk/. Accessed May 27, 2016.
10. Bajwah S, Koffman J, Higginson IJ, et. al. ‘I wish I knew more…’ the end-of-life planning and information needs for end-stage fibrotic interstitial lung disease: views of patients, carers, and health professionals. BMJ Support Palliat Care. 2013;3;84-90.
