Red blood cells

In studying Diamond-Blackfan anemia (DBA), researchers have found evidence to suggest that ribosome levels play a key role in hematopoiesis.

The researchers found that a reduction in ribosomes is responsible for the disruption in red blood cell production observed in patients with DBA.

This reduction in ribosomes impairs the translation of certain messenger RNAs (mRNAs), which inhibits erythroid lineage commitment in hematopoietic stem and progenitor cells (HSCPs).

The researchers said this work has provided insight into how lineage commitment functions normally and in the setting of DBA.

Vijay Sankaran, MD, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues described these findings in Cell.

The team noted that most cases of DBA are caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, which result in RP haploinsufficiency.

Past research revealed DBA-causing mutations in the transcription factor GATA1. Subsequent work showed that RP haploinsufficiency results in reduced translation of GATA1 mRNA, and increasing GATA1 protein levels can reduce the erythroid defects in DBA cells.

However, the mechanisms underlying these phenomena were unclear.

In the current study, the researchers found that DBA-associated perturbations reduced ribosome levels but did not affect the composition of ribosomes.

“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes,” Dr Sankaran said. “We know now that it is the latter.”

The researchers said the reduction of ribosome levels was largely promoted through reduced translation of RP mRNAs.

The team identified 525 transcripts with translation efficiencies that were downregulated by RP haploinsufficiency. They said a subset of these transcripts, including GATA1, have proven essential for hematopoietic cell growth and are upregulated during early erythropoiesis.

The researchers confirmed their prior findings that translation of GATA1 mRNA is decreased by about 2-fold in differentiating HSPCs with RP haploinsufficiency.

The team also found that GATA1 has “unique” 5’ untranslated region features that confer sensitivity to ribosome levels.

Taken together, these findings suggest the presence of GATA1 proteins in HSPCs helps prime them for erythroid lineage commitment. Without enough ribosomes to produce enough GATA1 proteins, the HSPCs never receive the signal to become red blood cells.

“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency,” Dr Sankaran said. “We now have a tremendous interest in this approach and believe it can be done.”

Red blood cells

In studying Diamond-Blackfan anemia (DBA), researchers have found evidence to suggest that ribosome levels play a key role in hematopoiesis.

The researchers found that a reduction in ribosomes is responsible for the disruption in red blood cell production observed in patients with DBA.

This reduction in ribosomes impairs the translation of certain messenger RNAs (mRNAs), which inhibits erythroid lineage commitment in hematopoietic stem and progenitor cells (HSCPs).

The researchers said this work has provided insight into how lineage commitment functions normally and in the setting of DBA.

Vijay Sankaran, MD, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues described these findings in Cell.

The team noted that most cases of DBA are caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, which result in RP haploinsufficiency.

Past research revealed DBA-causing mutations in the transcription factor GATA1. Subsequent work showed that RP haploinsufficiency results in reduced translation of GATA1 mRNA, and increasing GATA1 protein levels can reduce the erythroid defects in DBA cells.

However, the mechanisms underlying these phenomena were unclear.

In the current study, the researchers found that DBA-associated perturbations reduced ribosome levels but did not affect the composition of ribosomes.

“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes,” Dr Sankaran said. “We know now that it is the latter.”

The researchers said the reduction of ribosome levels was largely promoted through reduced translation of RP mRNAs.

The team identified 525 transcripts with translation efficiencies that were downregulated by RP haploinsufficiency. They said a subset of these transcripts, including GATA1, have proven essential for hematopoietic cell growth and are upregulated during early erythropoiesis.

The researchers confirmed their prior findings that translation of GATA1 mRNA is decreased by about 2-fold in differentiating HSPCs with RP haploinsufficiency.

The team also found that GATA1 has “unique” 5’ untranslated region features that confer sensitivity to ribosome levels.

Taken together, these findings suggest the presence of GATA1 proteins in HSPCs helps prime them for erythroid lineage commitment. Without enough ribosomes to produce enough GATA1 proteins, the HSPCs never receive the signal to become red blood cells.

“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency,” Dr Sankaran said. “We now have a tremendous interest in this approach and believe it can be done.”

Red blood cells

In studying Diamond-Blackfan anemia (DBA), researchers have found evidence to suggest that ribosome levels play a key role in hematopoiesis.

The researchers found that a reduction in ribosomes is responsible for the disruption in red blood cell production observed in patients with DBA.

This reduction in ribosomes impairs the translation of certain messenger RNAs (mRNAs), which inhibits erythroid lineage commitment in hematopoietic stem and progenitor cells (HSCPs).

The researchers said this work has provided insight into how lineage commitment functions normally and in the setting of DBA.

Vijay Sankaran, MD, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues described these findings in Cell.

The team noted that most cases of DBA are caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, which result in RP haploinsufficiency.

Past research revealed DBA-causing mutations in the transcription factor GATA1. Subsequent work showed that RP haploinsufficiency results in reduced translation of GATA1 mRNA, and increasing GATA1 protein levels can reduce the erythroid defects in DBA cells.

However, the mechanisms underlying these phenomena were unclear.

In the current study, the researchers found that DBA-associated perturbations reduced ribosome levels but did not affect the composition of ribosomes.

“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes,” Dr Sankaran said. “We know now that it is the latter.”

The researchers said the reduction of ribosome levels was largely promoted through reduced translation of RP mRNAs.

The team identified 525 transcripts with translation efficiencies that were downregulated by RP haploinsufficiency. They said a subset of these transcripts, including GATA1, have proven essential for hematopoietic cell growth and are upregulated during early erythropoiesis.

The researchers confirmed their prior findings that translation of GATA1 mRNA is decreased by about 2-fold in differentiating HSPCs with RP haploinsufficiency.

The team also found that GATA1 has “unique” 5’ untranslated region features that confer sensitivity to ribosome levels.

Taken together, these findings suggest the presence of GATA1 proteins in HSPCs helps prime them for erythroid lineage commitment. Without enough ribosomes to produce enough GATA1 proteins, the HSPCs never receive the signal to become red blood cells.

“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency,” Dr Sankaran said. “We now have a tremendous interest in this approach and believe it can be done.”

Foy, A.J., et al, JAMA Intern Med 177(11):1623, November 1, 2017

BACKGROUND: Coronary computed tomography angiography (CCTA) is more accurate than functional stress testing for the diagnosis of coronary artery disease, but it is unclear whether this superiority leads to better clinical outcomes.

METHODS: The authors performed a systematic review and meta-analysis of 13 randomized, controlled trials that included 20,092 patients (mean age 58) and compared CCTA (n=10,315) with functional stress testing (n=9,777) in patients being evaluated for coronary artery disease. The primary endpoints included clinical outcomes and changes in therapy.

RESULTS: There was no difference between the groups in the overall mortality rate or the rate of cardiac hospitalization (2.7% in both groups). The CCTA group had a lower incidence of myocardial infarction (0.7% vs. 1.1% in the stress test group), and a higher incidence of revascularization (7.2 vs. 4.5), invasive coronary angiography (11.7% vs. 9.1%), and a new CAD diagnosis (18.3% vs. 8.3%). The CCTA group also had a higher rate of use of aspirin (21.6% vs. 8.2%) and statins (20.0% vs. 7.3%).

CONCLUSIONS: When compared with functional stress testing, CCTA appears to be associated with a decreased incidence of myocardial infarction in patients with chest pain, but an increased probability of revascularization, invasive angiography and medication change. However, rates of cardiac hospitalization and overall mortality were similar in patients evaluated with CCTA vs. functional stress testing. 23 references ([email protected] – no reprints)

Foy, A.J., et al, JAMA Intern Med 177(11):1623, November 1, 2017

BACKGROUND: Coronary computed tomography angiography (CCTA) is more accurate than functional stress testing for the diagnosis of coronary artery disease, but it is unclear whether this superiority leads to better clinical outcomes.

METHODS: The authors performed a systematic review and meta-analysis of 13 randomized, controlled trials that included 20,092 patients (mean age 58) and compared CCTA (n=10,315) with functional stress testing (n=9,777) in patients being evaluated for coronary artery disease. The primary endpoints included clinical outcomes and changes in therapy.

RESULTS: There was no difference between the groups in the overall mortality rate or the rate of cardiac hospitalization (2.7% in both groups). The CCTA group had a lower incidence of myocardial infarction (0.7% vs. 1.1% in the stress test group), and a higher incidence of revascularization (7.2 vs. 4.5), invasive coronary angiography (11.7% vs. 9.1%), and a new CAD diagnosis (18.3% vs. 8.3%). The CCTA group also had a higher rate of use of aspirin (21.6% vs. 8.2%) and statins (20.0% vs. 7.3%).

CONCLUSIONS: When compared with functional stress testing, CCTA appears to be associated with a decreased incidence of myocardial infarction in patients with chest pain, but an increased probability of revascularization, invasive angiography and medication change. However, rates of cardiac hospitalization and overall mortality were similar in patients evaluated with CCTA vs. functional stress testing. 23 references ([email protected] – no reprints)

Foy, A.J., et al, JAMA Intern Med 177(11):1623, November 1, 2017

BACKGROUND: Coronary computed tomography angiography (CCTA) is more accurate than functional stress testing for the diagnosis of coronary artery disease, but it is unclear whether this superiority leads to better clinical outcomes.

METHODS: The authors performed a systematic review and meta-analysis of 13 randomized, controlled trials that included 20,092 patients (mean age 58) and compared CCTA (n=10,315) with functional stress testing (n=9,777) in patients being evaluated for coronary artery disease. The primary endpoints included clinical outcomes and changes in therapy.

RESULTS: There was no difference between the groups in the overall mortality rate or the rate of cardiac hospitalization (2.7% in both groups). The CCTA group had a lower incidence of myocardial infarction (0.7% vs. 1.1% in the stress test group), and a higher incidence of revascularization (7.2 vs. 4.5), invasive coronary angiography (11.7% vs. 9.1%), and a new CAD diagnosis (18.3% vs. 8.3%). The CCTA group also had a higher rate of use of aspirin (21.6% vs. 8.2%) and statins (20.0% vs. 7.3%).

CONCLUSIONS: When compared with functional stress testing, CCTA appears to be associated with a decreased incidence of myocardial infarction in patients with chest pain, but an increased probability of revascularization, invasive angiography and medication change. However, rates of cardiac hospitalization and overall mortality were similar in patients evaluated with CCTA vs. functional stress testing. 23 references ([email protected] – no reprints)

IN THIS ARTICLE

• Confirming the diagnosis
• Pirfenidone treatment
• Nintedanib treatment

A 64-year-old man has a one-year history of dyspnea on exertion and a nonproductive cough. His symptoms are gradually worsening and increasingly bothersome to him.

His medical history includes mild seasonal allergies and GERD, which is well-controlled by oral antihistamines and proton pump inhibitors. He has spent the past 30 years working a desk job as an accountant. He denies a history of smoking, exposure to secondhand smoke, and initiation of new medication.

He admits to increased fatigue, but denies fever, chills, lymphadenopathy, weight change, chest pain, wheezing, abdominal pain, diarrhea, vomiting, claudication, and swelling in the extremities. The rest of the review of systems is negative.

Lab results—complete blood count, comprehensive metabolic panel, TSH, antinuclear antibodies, erythrocyte sedimentation rate, and C-reactive protein—are within normal limits. Spirometry shows very mild restriction. A chest x-ray is abnormal but nonspecific, showing peripheral opacities. An ECG shows normal sinus rhythm.

The patient is given a trial of an inhaled steroid, which yields no improvement. Six months later, the patient is seen by a pulmonologist. Idiopathic pulmonary fibrosis (IPF) is diagnosed based on high-resolution CT (HRCT) and lung biopsy results.

IPF is a chronic, progressive, fibrosing interstitial disease that is limited to lung tissue. It most commonly manifests in older adults with vague symptoms of dyspnea on exertion and nonproductive cough, but symptoms can also include fatigue, muscle and joint aches, clubbing of the fingernails, and weight loss.¹ The average life expectancy following diagnosis of IPF is two to five years, and the mortality rate is estimated at 64.3 per million men and 58.4 per million women per year.^2,3

Continue to: DIAGNOSIS

IPF belongs in the general class of idiopathic interstitial pneumonias (IIPs), which are characterized by varying degrees of inflammation and fibrosis of lung interstitium.⁴ All subtypes of IIPs cause dyspnea and diffuse abnormalities on HRCT, and all vary from each other histologically. Table 1 outlines the key features of each.^5-8

Because of its vague symptomology and the extensive workup needed to rule out other diseases, patients with IPF often have symptoms for one to two years before a diagnosis is made.¹ Physical exam may reveal fine inspiratory rales in both lung bases and digital clubbing; eventual signs of pulmonary hypertension and right-sided heart failure may be appreciated.^1,9

There are no specific diagnostic laboratory tests to confirm IPF; however, baseline labwork (as outlined in the case presentation) is typically ordered to rule out infection, thyroid disease, or connective tissue disease.¹⁰ Many patients are referred to a cardiologist before being seen by a pulmonologist; cardiac stress testing may be done, and an echocardiogram may be performed to rule out heart failure.

Diagnostic testing may include pulmonary function testing, HRCT of the chest, and lung biopsy.¹⁰ Tissue samples from patients with IPF reveal different stages of disease, including dense fibrosis with honeycombing, subpleural or paraseptal distribution, fibroblast foci, and normal tissue.¹¹ Pulmonary function test results will show a restrictive pattern. Both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) will be reduced, and the FEV₁/FVC ratio preserved. Due to decreased functional lung volume, diffusing capacity of the lung for carbon monoxide (DL_CO) will also be reduced.^4,12

The differential is broad and includes allergic asthma, bronchitis, COPD, lung cancer, hypersensitivity pneumonitis, asbestosis, or pulmonary embolism.

Continue to: TREATMENT HISTORY

IPF has a long history of tried and failed treatment options. The American Thoracic Society (ATS), in concert with other professional organizations, has published comprehensive guidelines and recommendations pertaining to the use of pharmacologic medications to control disease progression. Warfarin and other anticoagulants have been studied, based on the observation that a procoagulant state promotes fibrotic changes in the lung tissue.¹³ However, anticoagulant use is not recommended in patients with IPF due to lack of efficacy and high potential for harm.¹³

Immunosuppressants have also been in the spotlight as possible treatment for IPF, but a clinical study investigating the efficacy of a three-drug regimen including prednisone, azathioprine, and N-acetylcysteine was stopped early due to increased risk for harm. Endothelin antagonists and potent tyrosine kinase inhibitors are also not recommended in the most recent edition of IPF guidelines, as they lack benefit.¹³

In fact, prior to the 2015 edition of the guidelines, no single medication was routinely recommended for patients with IPF. But this is now changing, following the 2014 FDA approval of two new drugs, nintedanib and pirfenidone, designed specifically to treat IPF.¹⁴ These drugs have shown promise in clinical trials (results of which are summarized in Table 2).

Continue to: NEW PHARMACOLOGIC OPTIONS

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

In 2008, a study was conducted in Japan to determine the mechanism of action of pirfenidone.¹⁵ Through in vitro studies of healthy adult lung fibroblasts with added pro-fibrotic factor and transforming growth factor (TGF-ß 1), the researchers found that pirfenidone was effective at decreasing the production of a collagen-binding protein called HSP47. This protein is ubiquitous in fibrotic tissue. The study also showed that pirfenidone decreased the production of collagen type 1, which, when uninhibited, increases fibrosis.¹⁵

CAPACITY trials. In the CAPACITY trials, two phase 3 multinational studies conducted from 2006 to 2008, patients were given either pirfenidone or placebo.¹⁶ In the first study arm, patients were assigned to pirfenidone 2,403 mg/d (n = 174), pirfenidone 1,197 mg/d (n = 87), or placebo (n = 174). In the second study arm, 171 patients received pirfenidone 2,403 mg/d and 173 patients received placebo. Endpoints were measured at baseline and up to week 72.

The first study arm found that the mean rate of decline of FVC—the primary endpoint—was 4.4% less in the treatment group than in the placebo group (p = 0.001), and there was a 36% decrease in risk for death or disease progression in the treatment group (HR, 0.64; p, 0.023). (Endpoints were defined as: time to confirmed > 10% decline in percentage predicted FVC, > 15% decline in percentage predicted DL_CO, or death.) The researchers found no clinically significant change in the six-minute walk test—a secondary endpoint of the study.¹⁶

The second study arm, however, found no statistically significant change in FVC between the treatment and placebo groups (with a 0.6% smaller decrease in FVC in the pirfenidone group), nor did they see a difference in progression-free survival. However, there was a significant change in the six-minute walk test between the treatment and placebo groups (p = 0.0009). Throughout the study, the most common adverse effects included nausea (36%), rash (32%), and dyspepsia (19%).¹⁶

ASCEND trial. The 2014 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial was a phase 3, multinational, randomized, double-blind, placebo-controlled study of the use of pirfenidone 2,403 mg/d.¹⁷ The study was conducted from 2012 to 2013. Of the total number of patients (N = 522), half received pirfenidone and half received placebo. After 52 weeks of treatment (the end of the study), the researchers found a smaller decline in FVC—the primary endpoint—in the treatment group compared to placebo (mean decline, 235 mL vs 428 mL, respectively [p < 0.001]). Regarding the six-minute walk test, the investigators found that 25.9% of the treatment group exhibited a decrease of ≥ 50 meters, compared to 35.7% of the placebo group (p = 0.04). (Progression-free survival was defined as a confirmed ≥ 10% decrease in predicted FVC, a confirmed decrease of 50 meters in the six-minute walk test, or death.)

The pirfenidone group in the ASCEND trial showed a 43% reduced risk for death or disease progression (HR, 0.57; p, < 0.001).^16,17 All-cause mortality was lower in the pirfenidone group (4%) than in the placebo group (7.2%), but this was not statistically significant. Deaths from IPF in the pirfenidone group totaled three patients (1.1%) versus seven patients (2.5%) in the placebo group; this was also not statistically significant. The most common adverse effects seen during the study were nausea (36%), rash (28.1%), and headache (25.9%).¹⁷

Recommendations for use. Liver function testing should be performed at baseline, monthly for six months, and every three months afterward, as elevations in liver enzymes have been observed.¹⁸ Pirfenidone is a CYP1A2 substrate; moderate-to-strong CYP1A2 inhibitors should therefore be discontinued prior to initiation, as they are likely to decrease exposure and efficacy of pirfenidone. There are currently no black box warnings.¹⁸

Continue to: Nintedanib

Hostettler et al studied lung samples from patients with IPF to determine the mechanism of action of nintedanib.¹⁹ Evaluation of fibroblasts derived from IPF samples revealed that they contained higher levels of platelet-derived growth factor (PDGF) than did nonfibrotic control cells. They also found that nintedanib, a tyrosine kinase inhibitor, significantly inhibited the phosphorylation of fibrotic-inducing growth factors—PDGF as well as vascular endothelial growth factor (VEGF).

INPULSIS trials. A phase 3 replicate of randomized, double-blind, multinational studies, the INPULSIS trials were performed between 2011 and 2012.²⁰ Two study arms were used to evaluate a total of 638 patients who received nintedanib 150 mg bid for 52 weeks. The primary endpoint was annual rate of decline of FVC.

The researchers also evaluated efficacy through two other endpoints: patient-reported quality of life and symptoms via the St. George’s Respiratory Questionnaire (SGRQ) and evaluation of time to acute exacerbation. The latter was defined as worsening or new dyspnea, new diffuse pulmonary infiltrates visualized on chest radiography and/or HRCT, or the development of parenchymal abnormalities with no pneumothorax or pleural effusion since the preceding visit; and exclusion of any known causes of acute worsening, including infection, heart failure, pulmonary embolism, and any identifiable cause of acute lung injury.²⁰

INPULSIS 1 (first arm) included 309 patients in the treatment group. Results showed an adjusted annual rate of decline in FVC of 114.7 mL/year, versus 239.9 mL/year in the placebo group (p < 0.001). In the treatment group, 52.8% exhibited ≤ 5% decline in FVC, compared to 38.2% in the placebo group (p = 0.001). No significant between-group differences were found in SGRQ score or time to acute exacerbation.²⁰

INPULSIS 2 had 329 patients receiving nintedanib. An annual rate of decline in FVC of 113.6 mL/year from baseline was observed in the treatment group, compared to 207.3 mL/year in the placebo group (p < 0.001). In the treatment group, 53.2% showed ≤ 5% decline in FVC, versus 39.3% in the placebo group (p = 0.001). There was also a significantly smaller increase in total SGRQ score (meaning, less deterioration in quality of life) in the nintedanib group versus the placebo group (p = 0.02). A statistically significant increase in time to first acute exacerbation was observed in the nintedanib group (p = 0.005).²⁰

There was no significant difference between groups in death from any cause, death from respiratory causation, or death that occurred between randomization and 28 days post treatment. The most common adverse effects seen throughout the two trials included diarrhea (trial 1, 61.5%; trial 2, 63.2%), nausea (trial 1, 22.7%; trial 2, 26.1%), and nasopharyngitis (trial 1, 12.6%; trial 2, 14.6%).²⁰

Recommendations for use. Liver function testing should be performed at baseline, at regular intervals during the first three months, then periodically thereafter; patients in the treatment group of both INPULSIS trials had elevated liver enzymes, and cases of drug-induced liver injury have been observed with use of nintedanib.²¹ This medication may increase risk for bleeding due to its mechanism of action (VEGFR inhibition). Coadministration with CYP3A4 inhibitors may increase concentration of nintedanib; therefore, close monitoring is recommended. Avoid coadministration with CYP3A4 inducers, as this may decrease concentration of nintedanib by 50%. There are currently no black box warnings.²¹

Continue to: Patient monitoring

Patient monitoring

The ATS recommends measuring FVC and DL_CO every three to six months, or sooner if clinically indicated.¹³ Pulse oximetry should be measured at rest and on exertion in all patients, regardless of symptoms, to assure proper saturation and identify the need for supplemental oxygen; this should also be done every three to six months.

The ATS recommends prompt detection and treatment of comorbidities such as pulmonary hypertension, emphysema, airflow obstruction, GERD, sleep apnea, and coronary artery disease.¹³ These recommendations are based on the organization’s 2015 guidelines.

OUTCOME FOR THE CASE PATIENT

The patient was started on pirfenidone (2,403 mg/d). He is continuing treatment and showing improvements in quality of life and slowed deterioration of lung function.

CONCLUSION

IPF causes progressive fibrosis of lung interstitium. The etiology is unknown, the symptoms and signs are vague, and mean life expectancy following diagnosis is two to five years. The most recent IPF guidelines recommend avoiding use of anticoagulants and immunosuppressants (eg, steroids, azathioprine, and N-acetylcysteine), due to their proven ineffectiveness and harm to patients with IPF.

Since the FDA’s approval of pirfenidone and nintedanib, the ATS has made recommendations for their use in patients with IPF. Despite mixed results in clinical trials, both drugs have demonstrated the ability to slow the decline in FVC over time, with relatively benign adverse effects. It is difficult to compare pirfenidone and nintedanib, or to recommend use of one drug over the other. However, it is promising that patients with this routinely fatal disease now have treatment options that can potentially modulate their disease progression.

IN THIS ARTICLE

• Confirming the diagnosis
• Pirfenidone treatment
• Nintedanib treatment

A 64-year-old man has a one-year history of dyspnea on exertion and a nonproductive cough. His symptoms are gradually worsening and increasingly bothersome to him.

His medical history includes mild seasonal allergies and GERD, which is well-controlled by oral antihistamines and proton pump inhibitors. He has spent the past 30 years working a desk job as an accountant. He denies a history of smoking, exposure to secondhand smoke, and initiation of new medication.

He admits to increased fatigue, but denies fever, chills, lymphadenopathy, weight change, chest pain, wheezing, abdominal pain, diarrhea, vomiting, claudication, and swelling in the extremities. The rest of the review of systems is negative.

Lab results—complete blood count, comprehensive metabolic panel, TSH, antinuclear antibodies, erythrocyte sedimentation rate, and C-reactive protein—are within normal limits. Spirometry shows very mild restriction. A chest x-ray is abnormal but nonspecific, showing peripheral opacities. An ECG shows normal sinus rhythm.

The patient is given a trial of an inhaled steroid, which yields no improvement. Six months later, the patient is seen by a pulmonologist. Idiopathic pulmonary fibrosis (IPF) is diagnosed based on high-resolution CT (HRCT) and lung biopsy results.

IPF is a chronic, progressive, fibrosing interstitial disease that is limited to lung tissue. It most commonly manifests in older adults with vague symptoms of dyspnea on exertion and nonproductive cough, but symptoms can also include fatigue, muscle and joint aches, clubbing of the fingernails, and weight loss.¹ The average life expectancy following diagnosis of IPF is two to five years, and the mortality rate is estimated at 64.3 per million men and 58.4 per million women per year.^2,3

Continue to: DIAGNOSIS

IPF belongs in the general class of idiopathic interstitial pneumonias (IIPs), which are characterized by varying degrees of inflammation and fibrosis of lung interstitium.⁴ All subtypes of IIPs cause dyspnea and diffuse abnormalities on HRCT, and all vary from each other histologically. Table 1 outlines the key features of each.^5-8

Because of its vague symptomology and the extensive workup needed to rule out other diseases, patients with IPF often have symptoms for one to two years before a diagnosis is made.¹ Physical exam may reveal fine inspiratory rales in both lung bases and digital clubbing; eventual signs of pulmonary hypertension and right-sided heart failure may be appreciated.^1,9

There are no specific diagnostic laboratory tests to confirm IPF; however, baseline labwork (as outlined in the case presentation) is typically ordered to rule out infection, thyroid disease, or connective tissue disease.¹⁰ Many patients are referred to a cardiologist before being seen by a pulmonologist; cardiac stress testing may be done, and an echocardiogram may be performed to rule out heart failure.

Diagnostic testing may include pulmonary function testing, HRCT of the chest, and lung biopsy.¹⁰ Tissue samples from patients with IPF reveal different stages of disease, including dense fibrosis with honeycombing, subpleural or paraseptal distribution, fibroblast foci, and normal tissue.¹¹ Pulmonary function test results will show a restrictive pattern. Both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) will be reduced, and the FEV₁/FVC ratio preserved. Due to decreased functional lung volume, diffusing capacity of the lung for carbon monoxide (DL_CO) will also be reduced.^4,12

The differential is broad and includes allergic asthma, bronchitis, COPD, lung cancer, hypersensitivity pneumonitis, asbestosis, or pulmonary embolism.

Continue to: TREATMENT HISTORY

IPF has a long history of tried and failed treatment options. The American Thoracic Society (ATS), in concert with other professional organizations, has published comprehensive guidelines and recommendations pertaining to the use of pharmacologic medications to control disease progression. Warfarin and other anticoagulants have been studied, based on the observation that a procoagulant state promotes fibrotic changes in the lung tissue.¹³ However, anticoagulant use is not recommended in patients with IPF due to lack of efficacy and high potential for harm.¹³

Immunosuppressants have also been in the spotlight as possible treatment for IPF, but a clinical study investigating the efficacy of a three-drug regimen including prednisone, azathioprine, and N-acetylcysteine was stopped early due to increased risk for harm. Endothelin antagonists and potent tyrosine kinase inhibitors are also not recommended in the most recent edition of IPF guidelines, as they lack benefit.¹³

In fact, prior to the 2015 edition of the guidelines, no single medication was routinely recommended for patients with IPF. But this is now changing, following the 2014 FDA approval of two new drugs, nintedanib and pirfenidone, designed specifically to treat IPF.¹⁴ These drugs have shown promise in clinical trials (results of which are summarized in Table 2).

Continue to: NEW PHARMACOLOGIC OPTIONS

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

In 2008, a study was conducted in Japan to determine the mechanism of action of pirfenidone.¹⁵ Through in vitro studies of healthy adult lung fibroblasts with added pro-fibrotic factor and transforming growth factor (TGF-ß 1), the researchers found that pirfenidone was effective at decreasing the production of a collagen-binding protein called HSP47. This protein is ubiquitous in fibrotic tissue. The study also showed that pirfenidone decreased the production of collagen type 1, which, when uninhibited, increases fibrosis.¹⁵

CAPACITY trials. In the CAPACITY trials, two phase 3 multinational studies conducted from 2006 to 2008, patients were given either pirfenidone or placebo.¹⁶ In the first study arm, patients were assigned to pirfenidone 2,403 mg/d (n = 174), pirfenidone 1,197 mg/d (n = 87), or placebo (n = 174). In the second study arm, 171 patients received pirfenidone 2,403 mg/d and 173 patients received placebo. Endpoints were measured at baseline and up to week 72.

The first study arm found that the mean rate of decline of FVC—the primary endpoint—was 4.4% less in the treatment group than in the placebo group (p = 0.001), and there was a 36% decrease in risk for death or disease progression in the treatment group (HR, 0.64; p, 0.023). (Endpoints were defined as: time to confirmed > 10% decline in percentage predicted FVC, > 15% decline in percentage predicted DL_CO, or death.) The researchers found no clinically significant change in the six-minute walk test—a secondary endpoint of the study.¹⁶

The second study arm, however, found no statistically significant change in FVC between the treatment and placebo groups (with a 0.6% smaller decrease in FVC in the pirfenidone group), nor did they see a difference in progression-free survival. However, there was a significant change in the six-minute walk test between the treatment and placebo groups (p = 0.0009). Throughout the study, the most common adverse effects included nausea (36%), rash (32%), and dyspepsia (19%).¹⁶

ASCEND trial. The 2014 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial was a phase 3, multinational, randomized, double-blind, placebo-controlled study of the use of pirfenidone 2,403 mg/d.¹⁷ The study was conducted from 2012 to 2013. Of the total number of patients (N = 522), half received pirfenidone and half received placebo. After 52 weeks of treatment (the end of the study), the researchers found a smaller decline in FVC—the primary endpoint—in the treatment group compared to placebo (mean decline, 235 mL vs 428 mL, respectively [p < 0.001]). Regarding the six-minute walk test, the investigators found that 25.9% of the treatment group exhibited a decrease of ≥ 50 meters, compared to 35.7% of the placebo group (p = 0.04). (Progression-free survival was defined as a confirmed ≥ 10% decrease in predicted FVC, a confirmed decrease of 50 meters in the six-minute walk test, or death.)

The pirfenidone group in the ASCEND trial showed a 43% reduced risk for death or disease progression (HR, 0.57; p, < 0.001).^16,17 All-cause mortality was lower in the pirfenidone group (4%) than in the placebo group (7.2%), but this was not statistically significant. Deaths from IPF in the pirfenidone group totaled three patients (1.1%) versus seven patients (2.5%) in the placebo group; this was also not statistically significant. The most common adverse effects seen during the study were nausea (36%), rash (28.1%), and headache (25.9%).¹⁷

Recommendations for use. Liver function testing should be performed at baseline, monthly for six months, and every three months afterward, as elevations in liver enzymes have been observed.¹⁸ Pirfenidone is a CYP1A2 substrate; moderate-to-strong CYP1A2 inhibitors should therefore be discontinued prior to initiation, as they are likely to decrease exposure and efficacy of pirfenidone. There are currently no black box warnings.¹⁸

Continue to: Nintedanib

Hostettler et al studied lung samples from patients with IPF to determine the mechanism of action of nintedanib.¹⁹ Evaluation of fibroblasts derived from IPF samples revealed that they contained higher levels of platelet-derived growth factor (PDGF) than did nonfibrotic control cells. They also found that nintedanib, a tyrosine kinase inhibitor, significantly inhibited the phosphorylation of fibrotic-inducing growth factors—PDGF as well as vascular endothelial growth factor (VEGF).

INPULSIS trials. A phase 3 replicate of randomized, double-blind, multinational studies, the INPULSIS trials were performed between 2011 and 2012.²⁰ Two study arms were used to evaluate a total of 638 patients who received nintedanib 150 mg bid for 52 weeks. The primary endpoint was annual rate of decline of FVC.

The researchers also evaluated efficacy through two other endpoints: patient-reported quality of life and symptoms via the St. George’s Respiratory Questionnaire (SGRQ) and evaluation of time to acute exacerbation. The latter was defined as worsening or new dyspnea, new diffuse pulmonary infiltrates visualized on chest radiography and/or HRCT, or the development of parenchymal abnormalities with no pneumothorax or pleural effusion since the preceding visit; and exclusion of any known causes of acute worsening, including infection, heart failure, pulmonary embolism, and any identifiable cause of acute lung injury.²⁰

INPULSIS 1 (first arm) included 309 patients in the treatment group. Results showed an adjusted annual rate of decline in FVC of 114.7 mL/year, versus 239.9 mL/year in the placebo group (p < 0.001). In the treatment group, 52.8% exhibited ≤ 5% decline in FVC, compared to 38.2% in the placebo group (p = 0.001). No significant between-group differences were found in SGRQ score or time to acute exacerbation.²⁰

INPULSIS 2 had 329 patients receiving nintedanib. An annual rate of decline in FVC of 113.6 mL/year from baseline was observed in the treatment group, compared to 207.3 mL/year in the placebo group (p < 0.001). In the treatment group, 53.2% showed ≤ 5% decline in FVC, versus 39.3% in the placebo group (p = 0.001). There was also a significantly smaller increase in total SGRQ score (meaning, less deterioration in quality of life) in the nintedanib group versus the placebo group (p = 0.02). A statistically significant increase in time to first acute exacerbation was observed in the nintedanib group (p = 0.005).²⁰

There was no significant difference between groups in death from any cause, death from respiratory causation, or death that occurred between randomization and 28 days post treatment. The most common adverse effects seen throughout the two trials included diarrhea (trial 1, 61.5%; trial 2, 63.2%), nausea (trial 1, 22.7%; trial 2, 26.1%), and nasopharyngitis (trial 1, 12.6%; trial 2, 14.6%).²⁰

Recommendations for use. Liver function testing should be performed at baseline, at regular intervals during the first three months, then periodically thereafter; patients in the treatment group of both INPULSIS trials had elevated liver enzymes, and cases of drug-induced liver injury have been observed with use of nintedanib.²¹ This medication may increase risk for bleeding due to its mechanism of action (VEGFR inhibition). Coadministration with CYP3A4 inhibitors may increase concentration of nintedanib; therefore, close monitoring is recommended. Avoid coadministration with CYP3A4 inducers, as this may decrease concentration of nintedanib by 50%. There are currently no black box warnings.²¹

Continue to: Patient monitoring

Patient monitoring

The ATS recommends measuring FVC and DL_CO every three to six months, or sooner if clinically indicated.¹³ Pulse oximetry should be measured at rest and on exertion in all patients, regardless of symptoms, to assure proper saturation and identify the need for supplemental oxygen; this should also be done every three to six months.

The ATS recommends prompt detection and treatment of comorbidities such as pulmonary hypertension, emphysema, airflow obstruction, GERD, sleep apnea, and coronary artery disease.¹³ These recommendations are based on the organization’s 2015 guidelines.

OUTCOME FOR THE CASE PATIENT

The patient was started on pirfenidone (2,403 mg/d). He is continuing treatment and showing improvements in quality of life and slowed deterioration of lung function.

CONCLUSION

IPF causes progressive fibrosis of lung interstitium. The etiology is unknown, the symptoms and signs are vague, and mean life expectancy following diagnosis is two to five years. The most recent IPF guidelines recommend avoiding use of anticoagulants and immunosuppressants (eg, steroids, azathioprine, and N-acetylcysteine), due to their proven ineffectiveness and harm to patients with IPF.

Since the FDA’s approval of pirfenidone and nintedanib, the ATS has made recommendations for their use in patients with IPF. Despite mixed results in clinical trials, both drugs have demonstrated the ability to slow the decline in FVC over time, with relatively benign adverse effects. It is difficult to compare pirfenidone and nintedanib, or to recommend use of one drug over the other. However, it is promising that patients with this routinely fatal disease now have treatment options that can potentially modulate their disease progression.

IN THIS ARTICLE

• Confirming the diagnosis
• Pirfenidone treatment
• Nintedanib treatment

A 64-year-old man has a one-year history of dyspnea on exertion and a nonproductive cough. His symptoms are gradually worsening and increasingly bothersome to him.

His medical history includes mild seasonal allergies and GERD, which is well-controlled by oral antihistamines and proton pump inhibitors. He has spent the past 30 years working a desk job as an accountant. He denies a history of smoking, exposure to secondhand smoke, and initiation of new medication.

He admits to increased fatigue, but denies fever, chills, lymphadenopathy, weight change, chest pain, wheezing, abdominal pain, diarrhea, vomiting, claudication, and swelling in the extremities. The rest of the review of systems is negative.

Lab results—complete blood count, comprehensive metabolic panel, TSH, antinuclear antibodies, erythrocyte sedimentation rate, and C-reactive protein—are within normal limits. Spirometry shows very mild restriction. A chest x-ray is abnormal but nonspecific, showing peripheral opacities. An ECG shows normal sinus rhythm.

The patient is given a trial of an inhaled steroid, which yields no improvement. Six months later, the patient is seen by a pulmonologist. Idiopathic pulmonary fibrosis (IPF) is diagnosed based on high-resolution CT (HRCT) and lung biopsy results.

IPF is a chronic, progressive, fibrosing interstitial disease that is limited to lung tissue. It most commonly manifests in older adults with vague symptoms of dyspnea on exertion and nonproductive cough, but symptoms can also include fatigue, muscle and joint aches, clubbing of the fingernails, and weight loss.¹ The average life expectancy following diagnosis of IPF is two to five years, and the mortality rate is estimated at 64.3 per million men and 58.4 per million women per year.^2,3

Continue to: DIAGNOSIS

IPF belongs in the general class of idiopathic interstitial pneumonias (IIPs), which are characterized by varying degrees of inflammation and fibrosis of lung interstitium.⁴ All subtypes of IIPs cause dyspnea and diffuse abnormalities on HRCT, and all vary from each other histologically. Table 1 outlines the key features of each.^5-8

Because of its vague symptomology and the extensive workup needed to rule out other diseases, patients with IPF often have symptoms for one to two years before a diagnosis is made.¹ Physical exam may reveal fine inspiratory rales in both lung bases and digital clubbing; eventual signs of pulmonary hypertension and right-sided heart failure may be appreciated.^1,9

There are no specific diagnostic laboratory tests to confirm IPF; however, baseline labwork (as outlined in the case presentation) is typically ordered to rule out infection, thyroid disease, or connective tissue disease.¹⁰ Many patients are referred to a cardiologist before being seen by a pulmonologist; cardiac stress testing may be done, and an echocardiogram may be performed to rule out heart failure.

Diagnostic testing may include pulmonary function testing, HRCT of the chest, and lung biopsy.¹⁰ Tissue samples from patients with IPF reveal different stages of disease, including dense fibrosis with honeycombing, subpleural or paraseptal distribution, fibroblast foci, and normal tissue.¹¹ Pulmonary function test results will show a restrictive pattern. Both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) will be reduced, and the FEV₁/FVC ratio preserved. Due to decreased functional lung volume, diffusing capacity of the lung for carbon monoxide (DL_CO) will also be reduced.^4,12

The differential is broad and includes allergic asthma, bronchitis, COPD, lung cancer, hypersensitivity pneumonitis, asbestosis, or pulmonary embolism.

Continue to: TREATMENT HISTORY

IPF has a long history of tried and failed treatment options. The American Thoracic Society (ATS), in concert with other professional organizations, has published comprehensive guidelines and recommendations pertaining to the use of pharmacologic medications to control disease progression. Warfarin and other anticoagulants have been studied, based on the observation that a procoagulant state promotes fibrotic changes in the lung tissue.¹³ However, anticoagulant use is not recommended in patients with IPF due to lack of efficacy and high potential for harm.¹³

Immunosuppressants have also been in the spotlight as possible treatment for IPF, but a clinical study investigating the efficacy of a three-drug regimen including prednisone, azathioprine, and N-acetylcysteine was stopped early due to increased risk for harm. Endothelin antagonists and potent tyrosine kinase inhibitors are also not recommended in the most recent edition of IPF guidelines, as they lack benefit.¹³

In fact, prior to the 2015 edition of the guidelines, no single medication was routinely recommended for patients with IPF. But this is now changing, following the 2014 FDA approval of two new drugs, nintedanib and pirfenidone, designed specifically to treat IPF.¹⁴ These drugs have shown promise in clinical trials (results of which are summarized in Table 2).

Continue to: NEW PHARMACOLOGIC OPTIONS

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

In 2008, a study was conducted in Japan to determine the mechanism of action of pirfenidone.¹⁵ Through in vitro studies of healthy adult lung fibroblasts with added pro-fibrotic factor and transforming growth factor (TGF-ß 1), the researchers found that pirfenidone was effective at decreasing the production of a collagen-binding protein called HSP47. This protein is ubiquitous in fibrotic tissue. The study also showed that pirfenidone decreased the production of collagen type 1, which, when uninhibited, increases fibrosis.¹⁵

CAPACITY trials. In the CAPACITY trials, two phase 3 multinational studies conducted from 2006 to 2008, patients were given either pirfenidone or placebo.¹⁶ In the first study arm, patients were assigned to pirfenidone 2,403 mg/d (n = 174), pirfenidone 1,197 mg/d (n = 87), or placebo (n = 174). In the second study arm, 171 patients received pirfenidone 2,403 mg/d and 173 patients received placebo. Endpoints were measured at baseline and up to week 72.

The first study arm found that the mean rate of decline of FVC—the primary endpoint—was 4.4% less in the treatment group than in the placebo group (p = 0.001), and there was a 36% decrease in risk for death or disease progression in the treatment group (HR, 0.64; p, 0.023). (Endpoints were defined as: time to confirmed > 10% decline in percentage predicted FVC, > 15% decline in percentage predicted DL_CO, or death.) The researchers found no clinically significant change in the six-minute walk test—a secondary endpoint of the study.¹⁶

The second study arm, however, found no statistically significant change in FVC between the treatment and placebo groups (with a 0.6% smaller decrease in FVC in the pirfenidone group), nor did they see a difference in progression-free survival. However, there was a significant change in the six-minute walk test between the treatment and placebo groups (p = 0.0009). Throughout the study, the most common adverse effects included nausea (36%), rash (32%), and dyspepsia (19%).¹⁶

ASCEND trial. The 2014 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial was a phase 3, multinational, randomized, double-blind, placebo-controlled study of the use of pirfenidone 2,403 mg/d.¹⁷ The study was conducted from 2012 to 2013. Of the total number of patients (N = 522), half received pirfenidone and half received placebo. After 52 weeks of treatment (the end of the study), the researchers found a smaller decline in FVC—the primary endpoint—in the treatment group compared to placebo (mean decline, 235 mL vs 428 mL, respectively [p < 0.001]). Regarding the six-minute walk test, the investigators found that 25.9% of the treatment group exhibited a decrease of ≥ 50 meters, compared to 35.7% of the placebo group (p = 0.04). (Progression-free survival was defined as a confirmed ≥ 10% decrease in predicted FVC, a confirmed decrease of 50 meters in the six-minute walk test, or death.)

The pirfenidone group in the ASCEND trial showed a 43% reduced risk for death or disease progression (HR, 0.57; p, < 0.001).^16,17 All-cause mortality was lower in the pirfenidone group (4%) than in the placebo group (7.2%), but this was not statistically significant. Deaths from IPF in the pirfenidone group totaled three patients (1.1%) versus seven patients (2.5%) in the placebo group; this was also not statistically significant. The most common adverse effects seen during the study were nausea (36%), rash (28.1%), and headache (25.9%).¹⁷

Recommendations for use. Liver function testing should be performed at baseline, monthly for six months, and every three months afterward, as elevations in liver enzymes have been observed.¹⁸ Pirfenidone is a CYP1A2 substrate; moderate-to-strong CYP1A2 inhibitors should therefore be discontinued prior to initiation, as they are likely to decrease exposure and efficacy of pirfenidone. There are currently no black box warnings.¹⁸

Continue to: Nintedanib

Hostettler et al studied lung samples from patients with IPF to determine the mechanism of action of nintedanib.¹⁹ Evaluation of fibroblasts derived from IPF samples revealed that they contained higher levels of platelet-derived growth factor (PDGF) than did nonfibrotic control cells. They also found that nintedanib, a tyrosine kinase inhibitor, significantly inhibited the phosphorylation of fibrotic-inducing growth factors—PDGF as well as vascular endothelial growth factor (VEGF).

INPULSIS trials. A phase 3 replicate of randomized, double-blind, multinational studies, the INPULSIS trials were performed between 2011 and 2012.²⁰ Two study arms were used to evaluate a total of 638 patients who received nintedanib 150 mg bid for 52 weeks. The primary endpoint was annual rate of decline of FVC.

The researchers also evaluated efficacy through two other endpoints: patient-reported quality of life and symptoms via the St. George’s Respiratory Questionnaire (SGRQ) and evaluation of time to acute exacerbation. The latter was defined as worsening or new dyspnea, new diffuse pulmonary infiltrates visualized on chest radiography and/or HRCT, or the development of parenchymal abnormalities with no pneumothorax or pleural effusion since the preceding visit; and exclusion of any known causes of acute worsening, including infection, heart failure, pulmonary embolism, and any identifiable cause of acute lung injury.²⁰

INPULSIS 1 (first arm) included 309 patients in the treatment group. Results showed an adjusted annual rate of decline in FVC of 114.7 mL/year, versus 239.9 mL/year in the placebo group (p < 0.001). In the treatment group, 52.8% exhibited ≤ 5% decline in FVC, compared to 38.2% in the placebo group (p = 0.001). No significant between-group differences were found in SGRQ score or time to acute exacerbation.²⁰

INPULSIS 2 had 329 patients receiving nintedanib. An annual rate of decline in FVC of 113.6 mL/year from baseline was observed in the treatment group, compared to 207.3 mL/year in the placebo group (p < 0.001). In the treatment group, 53.2% showed ≤ 5% decline in FVC, versus 39.3% in the placebo group (p = 0.001). There was also a significantly smaller increase in total SGRQ score (meaning, less deterioration in quality of life) in the nintedanib group versus the placebo group (p = 0.02). A statistically significant increase in time to first acute exacerbation was observed in the nintedanib group (p = 0.005).²⁰

There was no significant difference between groups in death from any cause, death from respiratory causation, or death that occurred between randomization and 28 days post treatment. The most common adverse effects seen throughout the two trials included diarrhea (trial 1, 61.5%; trial 2, 63.2%), nausea (trial 1, 22.7%; trial 2, 26.1%), and nasopharyngitis (trial 1, 12.6%; trial 2, 14.6%).²⁰

Recommendations for use. Liver function testing should be performed at baseline, at regular intervals during the first three months, then periodically thereafter; patients in the treatment group of both INPULSIS trials had elevated liver enzymes, and cases of drug-induced liver injury have been observed with use of nintedanib.²¹ This medication may increase risk for bleeding due to its mechanism of action (VEGFR inhibition). Coadministration with CYP3A4 inhibitors may increase concentration of nintedanib; therefore, close monitoring is recommended. Avoid coadministration with CYP3A4 inducers, as this may decrease concentration of nintedanib by 50%. There are currently no black box warnings.²¹

Continue to: Patient monitoring

Patient monitoring

The ATS recommends measuring FVC and DL_CO every three to six months, or sooner if clinically indicated.¹³ Pulse oximetry should be measured at rest and on exertion in all patients, regardless of symptoms, to assure proper saturation and identify the need for supplemental oxygen; this should also be done every three to six months.

The ATS recommends prompt detection and treatment of comorbidities such as pulmonary hypertension, emphysema, airflow obstruction, GERD, sleep apnea, and coronary artery disease.¹³ These recommendations are based on the organization’s 2015 guidelines.

OUTCOME FOR THE CASE PATIENT

The patient was started on pirfenidone (2,403 mg/d). He is continuing treatment and showing improvements in quality of life and slowed deterioration of lung function.

CONCLUSION

IPF causes progressive fibrosis of lung interstitium. The etiology is unknown, the symptoms and signs are vague, and mean life expectancy following diagnosis is two to five years. The most recent IPF guidelines recommend avoiding use of anticoagulants and immunosuppressants (eg, steroids, azathioprine, and N-acetylcysteine), due to their proven ineffectiveness and harm to patients with IPF.

Since the FDA’s approval of pirfenidone and nintedanib, the ATS has made recommendations for their use in patients with IPF. Despite mixed results in clinical trials, both drugs have demonstrated the ability to slow the decline in FVC over time, with relatively benign adverse effects. It is difficult to compare pirfenidone and nintedanib, or to recommend use of one drug over the other. However, it is promising that patients with this routinely fatal disease now have treatment options that can potentially modulate their disease progression.

Unless you’ve been hibernating for the past decade, you know how important websites have become to the continued success of private practices. Nowadays, almost half of all Americans (and nearly all millennials) seek out doctors online. But your practice website should be doing a lot more than simply describing your practice. How many visitors to your site actually schedule an appointment? With a few relatively simple but important modifications, you can convert casual website viewers to patients.

Start with a good title, one that not only describes your practice but also anticipates how prospective patients will search for you – usually by specialty plus geographic location. My site’s title, for example, is “Belleville Dermatology Center,” so when someone searches for a dermatologist near Belleville, N.J., my site will invariably rank near the top of their search results.
 

Follow with an understandable URL. Search engines use URLs to determine how well your site, or a portion of it, matches search criteria. URLs also need to make sense to searchers, especially when they link specific areas of expertise (more on that in a minute). For example, a URL like “bellevilledermatology[dot]com/?p=89021” is meaningless to anyone except programmers; but “bellevilledermatology[dot]com/psoriasistreatments” obviously leads to a page about psoriasis treatments. Search engines look for not only the most relevant, but also the most helpful and user-friendly, answers to a user’s query.
Incidentally, if the URL for your site is not your own name, you should register your name as a separate domain name – even if you never use it – to be sure that a trickster or troll, or someone with the same name but a bad reputation, doesn’t get it.

Georgijevic/E+/Getty Images

Describe your principal services in detail. You never know which specific service a prospective patient is searching for, so describe everything you offer. Don’t try to summarize everything on a single page; relevance is determined by how deeply a topic is covered, so each principal service should have a detailed description on its own page. Not only will your skills become more visible to search engines, but you can also use the space to enumerate your qualifications and expertise in each area. Whenever possible, write your descriptions in question-and-answer form. Searchers tend to ask questions (“what is the best…?”), particularly in voice searches. Search engines increasingly value sites that ask and answer common questions.

How does your site look on small screens? More than half of all searches are now made on smartphones, so the more “mobile friendly” your site is, the higher it will be ranked. Besides, prospective patients who are forced to scroll forever, or zoom in to tap a link, are likely to become frustrated and move on. Mobile searchers prefer sites that provide the best experience for the least amount of effort, and rankings tend to reflect that preference.

Include photos. Especially yours; new patients are more comfortable when they know what you look like. Although some disagree, I feel family photos are also important; they help to present you as a person, as well as a doctor. Photos of your office – professional ones, not casual snapshots – will reassure prospective patients that they will be visiting a clean, modern, professional facility.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Unless you’ve been hibernating for the past decade, you know how important websites have become to the continued success of private practices. Nowadays, almost half of all Americans (and nearly all millennials) seek out doctors online. But your practice website should be doing a lot more than simply describing your practice. How many visitors to your site actually schedule an appointment? With a few relatively simple but important modifications, you can convert casual website viewers to patients.

Start with a good title, one that not only describes your practice but also anticipates how prospective patients will search for you – usually by specialty plus geographic location. My site’s title, for example, is “Belleville Dermatology Center,” so when someone searches for a dermatologist near Belleville, N.J., my site will invariably rank near the top of their search results.
 

Follow with an understandable URL. Search engines use URLs to determine how well your site, or a portion of it, matches search criteria. URLs also need to make sense to searchers, especially when they link specific areas of expertise (more on that in a minute). For example, a URL like “bellevilledermatology[dot]com/?p=89021” is meaningless to anyone except programmers; but “bellevilledermatology[dot]com/psoriasistreatments” obviously leads to a page about psoriasis treatments. Search engines look for not only the most relevant, but also the most helpful and user-friendly, answers to a user’s query.
Incidentally, if the URL for your site is not your own name, you should register your name as a separate domain name – even if you never use it – to be sure that a trickster or troll, or someone with the same name but a bad reputation, doesn’t get it.

Georgijevic/E+/Getty Images

Describe your principal services in detail. You never know which specific service a prospective patient is searching for, so describe everything you offer. Don’t try to summarize everything on a single page; relevance is determined by how deeply a topic is covered, so each principal service should have a detailed description on its own page. Not only will your skills become more visible to search engines, but you can also use the space to enumerate your qualifications and expertise in each area. Whenever possible, write your descriptions in question-and-answer form. Searchers tend to ask questions (“what is the best…?”), particularly in voice searches. Search engines increasingly value sites that ask and answer common questions.

How does your site look on small screens? More than half of all searches are now made on smartphones, so the more “mobile friendly” your site is, the higher it will be ranked. Besides, prospective patients who are forced to scroll forever, or zoom in to tap a link, are likely to become frustrated and move on. Mobile searchers prefer sites that provide the best experience for the least amount of effort, and rankings tend to reflect that preference.

Include photos. Especially yours; new patients are more comfortable when they know what you look like. Although some disagree, I feel family photos are also important; they help to present you as a person, as well as a doctor. Photos of your office – professional ones, not casual snapshots – will reassure prospective patients that they will be visiting a clean, modern, professional facility.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Unless you’ve been hibernating for the past decade, you know how important websites have become to the continued success of private practices. Nowadays, almost half of all Americans (and nearly all millennials) seek out doctors online. But your practice website should be doing a lot more than simply describing your practice. How many visitors to your site actually schedule an appointment? With a few relatively simple but important modifications, you can convert casual website viewers to patients.

Start with a good title, one that not only describes your practice but also anticipates how prospective patients will search for you – usually by specialty plus geographic location. My site’s title, for example, is “Belleville Dermatology Center,” so when someone searches for a dermatologist near Belleville, N.J., my site will invariably rank near the top of their search results.
 

Follow with an understandable URL. Search engines use URLs to determine how well your site, or a portion of it, matches search criteria. URLs also need to make sense to searchers, especially when they link specific areas of expertise (more on that in a minute). For example, a URL like “bellevilledermatology[dot]com/?p=89021” is meaningless to anyone except programmers; but “bellevilledermatology[dot]com/psoriasistreatments” obviously leads to a page about psoriasis treatments. Search engines look for not only the most relevant, but also the most helpful and user-friendly, answers to a user’s query.
Incidentally, if the URL for your site is not your own name, you should register your name as a separate domain name – even if you never use it – to be sure that a trickster or troll, or someone with the same name but a bad reputation, doesn’t get it.

Georgijevic/E+/Getty Images

Describe your principal services in detail. You never know which specific service a prospective patient is searching for, so describe everything you offer. Don’t try to summarize everything on a single page; relevance is determined by how deeply a topic is covered, so each principal service should have a detailed description on its own page. Not only will your skills become more visible to search engines, but you can also use the space to enumerate your qualifications and expertise in each area. Whenever possible, write your descriptions in question-and-answer form. Searchers tend to ask questions (“what is the best…?”), particularly in voice searches. Search engines increasingly value sites that ask and answer common questions.

How does your site look on small screens? More than half of all searches are now made on smartphones, so the more “mobile friendly” your site is, the higher it will be ranked. Besides, prospective patients who are forced to scroll forever, or zoom in to tap a link, are likely to become frustrated and move on. Mobile searchers prefer sites that provide the best experience for the least amount of effort, and rankings tend to reflect that preference.

Include photos. Especially yours; new patients are more comfortable when they know what you look like. Although some disagree, I feel family photos are also important; they help to present you as a person, as well as a doctor. Photos of your office – professional ones, not casual snapshots – will reassure prospective patients that they will be visiting a clean, modern, professional facility.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

ORLANDO – The risk of stroke and TIA – but not of acute MI – is significantly increased during the period surrounding diagnosis of herpes zoster, compared with the rate in matched zoster-free controls, according to a retrospective study of nearly 70,000 U.S. adults. A particularly striking study finding was the marked age disparity in the magnitude of vascular event risk associated with herpes zoster (HZ), with younger adults being at higher risk.

Asvmdrn/Wikimedia Commons /CCA-SA 3.0

[email protected]

SOURCE: Rausch DA. ACC 18

ORLANDO – The risk of stroke and TIA – but not of acute MI – is significantly increased during the period surrounding diagnosis of herpes zoster, compared with the rate in matched zoster-free controls, according to a retrospective study of nearly 70,000 U.S. adults. A particularly striking study finding was the marked age disparity in the magnitude of vascular event risk associated with herpes zoster (HZ), with younger adults being at higher risk.

Asvmdrn/Wikimedia Commons /CCA-SA 3.0

[email protected]

SOURCE: Rausch DA. ACC 18

ORLANDO – The risk of stroke and TIA – but not of acute MI – is significantly increased during the period surrounding diagnosis of herpes zoster, compared with the rate in matched zoster-free controls, according to a retrospective study of nearly 70,000 U.S. adults. A particularly striking study finding was the marked age disparity in the magnitude of vascular event risk associated with herpes zoster (HZ), with younger adults being at higher risk.

Asvmdrn/Wikimedia Commons /CCA-SA 3.0

[email protected]

SOURCE: Rausch DA. ACC 18

NEW ORLEANS – Indocyanine green (ICG) worked better than isosulfan blue for mapping sentinel lymph nodes (SLNs) in a pivotal phase 3 trial with 176 patients who had stage I endometrial or cervical cancer.

Four injections of ICG resulted in detection of 96% of the identified SLNs in these patients, including bilateral SLNs in 78% of the patients. In contrast, four injections with isosulfan blue dye led to detection of 74% of all SLNs and identified bilateral SLNs in 31% of the patients, Michael M. Frumovitz, MD, said at the annual meeting of the Society for Gynecologic Oncology.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Frumovitz MM. SGO 2018, Abstract 12. Backes FJ. SGO 2018, Abstract 13.

NEW ORLEANS – Indocyanine green (ICG) worked better than isosulfan blue for mapping sentinel lymph nodes (SLNs) in a pivotal phase 3 trial with 176 patients who had stage I endometrial or cervical cancer.

Four injections of ICG resulted in detection of 96% of the identified SLNs in these patients, including bilateral SLNs in 78% of the patients. In contrast, four injections with isosulfan blue dye led to detection of 74% of all SLNs and identified bilateral SLNs in 31% of the patients, Michael M. Frumovitz, MD, said at the annual meeting of the Society for Gynecologic Oncology.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Frumovitz MM. SGO 2018, Abstract 12. Backes FJ. SGO 2018, Abstract 13.

NEW ORLEANS – Indocyanine green (ICG) worked better than isosulfan blue for mapping sentinel lymph nodes (SLNs) in a pivotal phase 3 trial with 176 patients who had stage I endometrial or cervical cancer.

Four injections of ICG resulted in detection of 96% of the identified SLNs in these patients, including bilateral SLNs in 78% of the patients. In contrast, four injections with isosulfan blue dye led to detection of 74% of all SLNs and identified bilateral SLNs in 31% of the patients, Michael M. Frumovitz, MD, said at the annual meeting of the Society for Gynecologic Oncology.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Frumovitz MM. SGO 2018, Abstract 12. Backes FJ. SGO 2018, Abstract 13.

The levels of delta-9-tetrahydrocannabinol in breast milk peak around 1 hour after smoking, according to a pilot pharmacokinetic study.

Eight mothers who were either occasional or chronic cannabis smokers, and who exclusively breastfed their infants, were directed to smoke a preweighed, standardized amount of “Prezidential Kush” from a preselected Denver dispensary after initially discontinuing for 24 hours. Researchers collected breast milk samples from just before smoking, and at 20 minutes, 1 hour, 2 hours, and 4 hours after smoking, according to a paper published in the May issue of Obstetrics & Gynecology.

Smithore

Two of the participants had a low but measurable concentration of delta-9-tetrahydrocannabinol at zero time (the samples collected just before smoking), suggesting some residual accumulation of it from prior heavy use or use close to the start of breast milk collection.

“Although the transfer of delta-9-tetrahydrocannabinol into the plasma compartment is almost instantaneous, the transfer of delta-9-tetrahydrocannabinol into breast milk in our study appears to be slightly slower than the transfer into the plasma compartment,” the authors wrote.

The women in the study were all 2-5 months postpartum. The authors noted that in these women who were exclusively breastfeeding, the breast milk compartment, along with drug entry and exit, “remains fairly consistent.”

The researchers also noted that the lack of corresponding plasma samples was a major limitation of the study, but because of the nature of the study, anonymity was important.

No conflicts of interest were declared.

SOURCE: Baker T et al. Obstet Gynecol. 2018;131:783-8.

The levels of delta-9-tetrahydrocannabinol in breast milk peak around 1 hour after smoking, according to a pilot pharmacokinetic study.

Eight mothers who were either occasional or chronic cannabis smokers, and who exclusively breastfed their infants, were directed to smoke a preweighed, standardized amount of “Prezidential Kush” from a preselected Denver dispensary after initially discontinuing for 24 hours. Researchers collected breast milk samples from just before smoking, and at 20 minutes, 1 hour, 2 hours, and 4 hours after smoking, according to a paper published in the May issue of Obstetrics & Gynecology.

Smithore

Two of the participants had a low but measurable concentration of delta-9-tetrahydrocannabinol at zero time (the samples collected just before smoking), suggesting some residual accumulation of it from prior heavy use or use close to the start of breast milk collection.

“Although the transfer of delta-9-tetrahydrocannabinol into the plasma compartment is almost instantaneous, the transfer of delta-9-tetrahydrocannabinol into breast milk in our study appears to be slightly slower than the transfer into the plasma compartment,” the authors wrote.

The women in the study were all 2-5 months postpartum. The authors noted that in these women who were exclusively breastfeeding, the breast milk compartment, along with drug entry and exit, “remains fairly consistent.”

The researchers also noted that the lack of corresponding plasma samples was a major limitation of the study, but because of the nature of the study, anonymity was important.

No conflicts of interest were declared.

SOURCE: Baker T et al. Obstet Gynecol. 2018;131:783-8.

The levels of delta-9-tetrahydrocannabinol in breast milk peak around 1 hour after smoking, according to a pilot pharmacokinetic study.

Eight mothers who were either occasional or chronic cannabis smokers, and who exclusively breastfed their infants, were directed to smoke a preweighed, standardized amount of “Prezidential Kush” from a preselected Denver dispensary after initially discontinuing for 24 hours. Researchers collected breast milk samples from just before smoking, and at 20 minutes, 1 hour, 2 hours, and 4 hours after smoking, according to a paper published in the May issue of Obstetrics & Gynecology.

Smithore

Two of the participants had a low but measurable concentration of delta-9-tetrahydrocannabinol at zero time (the samples collected just before smoking), suggesting some residual accumulation of it from prior heavy use or use close to the start of breast milk collection.

“Although the transfer of delta-9-tetrahydrocannabinol into the plasma compartment is almost instantaneous, the transfer of delta-9-tetrahydrocannabinol into breast milk in our study appears to be slightly slower than the transfer into the plasma compartment,” the authors wrote.

The women in the study were all 2-5 months postpartum. The authors noted that in these women who were exclusively breastfeeding, the breast milk compartment, along with drug entry and exit, “remains fairly consistent.”

The researchers also noted that the lack of corresponding plasma samples was a major limitation of the study, but because of the nature of the study, anonymity was important.

No conflicts of interest were declared.

SOURCE: Baker T et al. Obstet Gynecol. 2018;131:783-8.

Heightened alexithymia may explain poor sleep quality, a pair of studies shows.

Alexithymia is a condition characterized by difficulty identifying and expressing one’s emotions. “The mechanism by which alexithymia confers risk of disrupted sleep remains unclear, [but] suggestions include increased nocturnal arousal as a result of poor verbalization of emotions and increased light sleep,” wrote Jennifer Murphy, citing previous research.

©KatarzynaBialasiewicz/Thinkstock

Jennifer Murphy

[email protected]

SOURCE: Murphy J et al. Pers Individ Dif. 2018 Mar 27;129:175-8.

Heightened alexithymia may explain poor sleep quality, a pair of studies shows.

Alexithymia is a condition characterized by difficulty identifying and expressing one’s emotions. “The mechanism by which alexithymia confers risk of disrupted sleep remains unclear, [but] suggestions include increased nocturnal arousal as a result of poor verbalization of emotions and increased light sleep,” wrote Jennifer Murphy, citing previous research.

©KatarzynaBialasiewicz/Thinkstock

Jennifer Murphy

[email protected]

SOURCE: Murphy J et al. Pers Individ Dif. 2018 Mar 27;129:175-8.

Heightened alexithymia may explain poor sleep quality, a pair of studies shows.

Alexithymia is a condition characterized by difficulty identifying and expressing one’s emotions. “The mechanism by which alexithymia confers risk of disrupted sleep remains unclear, [but] suggestions include increased nocturnal arousal as a result of poor verbalization of emotions and increased light sleep,” wrote Jennifer Murphy, citing previous research.

©KatarzynaBialasiewicz/Thinkstock

Jennifer Murphy

[email protected]

SOURCE: Murphy J et al. Pers Individ Dif. 2018 Mar 27;129:175-8.

WASHINGTON – Transcatheter heart valves (THV) developed for the treatment of symptomatic aortic stenosis have been used off label for the treatment of native aortic valve regurgitation (NAVR), but registry data suggest that outcomes have been disappointing, according to a presentation at CRT 2018 sponsored by the Cardiovascular Research Institute at Washington Hospital Center.

“Although significant improvement was seen with newer-generation THV devices, TAVR [transcatheter aortic valve replacement] for NAVR is a challenging approach associated with limited procedural efficacy,” reported Danny Dvir, MD, a prosthetic heart valve specialist and assistant professor of cardiology at the University of Washington, Seattle.

Ted Bosworth/Frontline Medical News

These improvements were reflected in clinical outcomes at 30 days. When second-generation devices were compared with first-generation devices, there was a reduction in all cause mortality (8% vs. 17%) and cardiac mortality (7% vs. 12%). There were also reductions from first- to second-generation devices in noncardiac mortality (1% vs. 5%), valve-related dysfunction (10% vs. 29%), and proportion of patients in New York Heart Association class III or IV (13% vs. 18%).

The improvement in outcomes from first- to second-generation devices is encouraging, but Dr. Dvir indicated that the main message is that TAVR for NAVR is producing success rates that “are suboptimal” and “not comparable to those being achieved when the indication is aortic stenosis.” The reasons cannot be derived from these data, but he suggested that optimal sizing of the device for NAVR might be different than it is for aortic stenosis.

“I wonder if we should have better devices designed specifically for aortic regurgitation,” Dr. Dvir said.

Despite the improved results with second-generation THV, receipt of a first-generation device was not a significant predictor of mortality at 1 year. Rather, in an analysis of predictors, mortality was significantly increased in those with moderate or worse aortic regurgitation, Society of Thoracic Surgeons risk score of 8% or greater, and acute kidney injury of grade 2 or higher. There was also a trend for increased mortality in those with pulmonary hypertension.

Most of the devices (76%) were placed with a transfemoral approach. No difference in mortality was observed when a transfemoral approach was compared with a nontransfemoral approach.

According to the registry data, a 10%-20% oversizing of the THV was associated with a reduced risk of malpositioning, relative to devices with less than 10% oversizing or greater than 20% oversizing, reinforcing Dr. Dvir’s hypothesis that sizing is a variable affecting outcome in NAVR.

Although Dr. Dvir contended that these data raise issues about the suitability of current THV designs for use in the treatment of NAVR, not all experts were convinced by these data. Jeffrey Popma, MD, director of the interventional cardiology clinical service at Beth Israel Deaconess Hospital, Boston, questioned whether more experience is placing these devices for NAVR might lead to greater success.

“There are two variables to consider,” Dr. Popma said. “One is the valve and one is how much we’ve evolved our procedure over the past couple of years.” He indicated that these data do not preclude advances that would improve results in NAVR even without developing new valves specific for this indication.

Dr. Dvir reported financial relationships with Edwards Lifesciences, Medtronic, Abbott, and Jena.

SOURCE: Dvir D. CRT 2018.

WASHINGTON – Transcatheter heart valves (THV) developed for the treatment of symptomatic aortic stenosis have been used off label for the treatment of native aortic valve regurgitation (NAVR), but registry data suggest that outcomes have been disappointing, according to a presentation at CRT 2018 sponsored by the Cardiovascular Research Institute at Washington Hospital Center.

“Although significant improvement was seen with newer-generation THV devices, TAVR [transcatheter aortic valve replacement] for NAVR is a challenging approach associated with limited procedural efficacy,” reported Danny Dvir, MD, a prosthetic heart valve specialist and assistant professor of cardiology at the University of Washington, Seattle.

Ted Bosworth/Frontline Medical News

These improvements were reflected in clinical outcomes at 30 days. When second-generation devices were compared with first-generation devices, there was a reduction in all cause mortality (8% vs. 17%) and cardiac mortality (7% vs. 12%). There were also reductions from first- to second-generation devices in noncardiac mortality (1% vs. 5%), valve-related dysfunction (10% vs. 29%), and proportion of patients in New York Heart Association class III or IV (13% vs. 18%).

The improvement in outcomes from first- to second-generation devices is encouraging, but Dr. Dvir indicated that the main message is that TAVR for NAVR is producing success rates that “are suboptimal” and “not comparable to those being achieved when the indication is aortic stenosis.” The reasons cannot be derived from these data, but he suggested that optimal sizing of the device for NAVR might be different than it is for aortic stenosis.

“I wonder if we should have better devices designed specifically for aortic regurgitation,” Dr. Dvir said.

Despite the improved results with second-generation THV, receipt of a first-generation device was not a significant predictor of mortality at 1 year. Rather, in an analysis of predictors, mortality was significantly increased in those with moderate or worse aortic regurgitation, Society of Thoracic Surgeons risk score of 8% or greater, and acute kidney injury of grade 2 or higher. There was also a trend for increased mortality in those with pulmonary hypertension.

Most of the devices (76%) were placed with a transfemoral approach. No difference in mortality was observed when a transfemoral approach was compared with a nontransfemoral approach.

According to the registry data, a 10%-20% oversizing of the THV was associated with a reduced risk of malpositioning, relative to devices with less than 10% oversizing or greater than 20% oversizing, reinforcing Dr. Dvir’s hypothesis that sizing is a variable affecting outcome in NAVR.

Although Dr. Dvir contended that these data raise issues about the suitability of current THV designs for use in the treatment of NAVR, not all experts were convinced by these data. Jeffrey Popma, MD, director of the interventional cardiology clinical service at Beth Israel Deaconess Hospital, Boston, questioned whether more experience is placing these devices for NAVR might lead to greater success.

“There are two variables to consider,” Dr. Popma said. “One is the valve and one is how much we’ve evolved our procedure over the past couple of years.” He indicated that these data do not preclude advances that would improve results in NAVR even without developing new valves specific for this indication.

Dr. Dvir reported financial relationships with Edwards Lifesciences, Medtronic, Abbott, and Jena.

SOURCE: Dvir D. CRT 2018.

WASHINGTON – Transcatheter heart valves (THV) developed for the treatment of symptomatic aortic stenosis have been used off label for the treatment of native aortic valve regurgitation (NAVR), but registry data suggest that outcomes have been disappointing, according to a presentation at CRT 2018 sponsored by the Cardiovascular Research Institute at Washington Hospital Center.

“Although significant improvement was seen with newer-generation THV devices, TAVR [transcatheter aortic valve replacement] for NAVR is a challenging approach associated with limited procedural efficacy,” reported Danny Dvir, MD, a prosthetic heart valve specialist and assistant professor of cardiology at the University of Washington, Seattle.

Ted Bosworth/Frontline Medical News

These improvements were reflected in clinical outcomes at 30 days. When second-generation devices were compared with first-generation devices, there was a reduction in all cause mortality (8% vs. 17%) and cardiac mortality (7% vs. 12%). There were also reductions from first- to second-generation devices in noncardiac mortality (1% vs. 5%), valve-related dysfunction (10% vs. 29%), and proportion of patients in New York Heart Association class III or IV (13% vs. 18%).

The improvement in outcomes from first- to second-generation devices is encouraging, but Dr. Dvir indicated that the main message is that TAVR for NAVR is producing success rates that “are suboptimal” and “not comparable to those being achieved when the indication is aortic stenosis.” The reasons cannot be derived from these data, but he suggested that optimal sizing of the device for NAVR might be different than it is for aortic stenosis.

“I wonder if we should have better devices designed specifically for aortic regurgitation,” Dr. Dvir said.

Despite the improved results with second-generation THV, receipt of a first-generation device was not a significant predictor of mortality at 1 year. Rather, in an analysis of predictors, mortality was significantly increased in those with moderate or worse aortic regurgitation, Society of Thoracic Surgeons risk score of 8% or greater, and acute kidney injury of grade 2 or higher. There was also a trend for increased mortality in those with pulmonary hypertension.

Most of the devices (76%) were placed with a transfemoral approach. No difference in mortality was observed when a transfemoral approach was compared with a nontransfemoral approach.

According to the registry data, a 10%-20% oversizing of the THV was associated with a reduced risk of malpositioning, relative to devices with less than 10% oversizing or greater than 20% oversizing, reinforcing Dr. Dvir’s hypothesis that sizing is a variable affecting outcome in NAVR.

Although Dr. Dvir contended that these data raise issues about the suitability of current THV designs for use in the treatment of NAVR, not all experts were convinced by these data. Jeffrey Popma, MD, director of the interventional cardiology clinical service at Beth Israel Deaconess Hospital, Boston, questioned whether more experience is placing these devices for NAVR might lead to greater success.

“There are two variables to consider,” Dr. Popma said. “One is the valve and one is how much we’ve evolved our procedure over the past couple of years.” He indicated that these data do not preclude advances that would improve results in NAVR even without developing new valves specific for this indication.

Dr. Dvir reported financial relationships with Edwards Lifesciences, Medtronic, Abbott, and Jena.

SOURCE: Dvir D. CRT 2018.

In October 2017, in support of the Federal Emergency Management Agency’s response to assist the Governor and people of Puerto Rico, three Department of Defense (DOD) military hospital platforms were deployed; one each, by the US Army, Navy, and Air Force. They arrived on the island at different times with predominantly wartime surgical capabilities and augmented the Federal Emergency Management Agency (FEMA), US Public Health Service, National Guard, and Puerto Rico Department of Health efforts. My perspective is that of patient care and transport between the Centro Medico hospital complex in San Juan, the larger regional hospitals, the Veterans Administration hospital, the DOD response, FEMA Disaster Medical Assistance Teams (DMAT), and FEMA Federal Medical Shelters about 4 to 6 weeks after Hurricanes Maria and Irma struck. Based upon this experience, I would like to offer the following.

Pre-Disaster: All clinicians have a few patients that teeter “on the edge.” When basic services go away, these patients fall over that edge and become inpatients. Establish a list of patients who require oxygen and devices such as vests, cough-assist, or ventilation. If evacuation before the disaster is possible, those patients need to leave. If they refuse, or are unable to leave, they need to be able to supply their own generated power for a prolonged period of time, as batteries will run out prior to power restoration. They must be able to use oxygen concentrators, as tank re-supply may not be readily available. By law, FEMA cannot give generators to individuals, so individuals must prepare for themselves. In a hurricane-prone area where seasonal risk can be established, planning medication refills at the beginning of the season or giving a larger than normal supply may prove useful. In an area prone to sudden disaster, such as earthquake or tornado, then counseling patients to request refills at least 2 weeks early may be adequate.

In October 2017, in support of the Federal Emergency Management Agency’s response to assist the Governor and people of Puerto Rico, three Department of Defense (DOD) military hospital platforms were deployed; one each, by the US Army, Navy, and Air Force. They arrived on the island at different times with predominantly wartime surgical capabilities and augmented the Federal Emergency Management Agency (FEMA), US Public Health Service, National Guard, and Puerto Rico Department of Health efforts. My perspective is that of patient care and transport between the Centro Medico hospital complex in San Juan, the larger regional hospitals, the Veterans Administration hospital, the DOD response, FEMA Disaster Medical Assistance Teams (DMAT), and FEMA Federal Medical Shelters about 4 to 6 weeks after Hurricanes Maria and Irma struck. Based upon this experience, I would like to offer the following.

Pre-Disaster: All clinicians have a few patients that teeter “on the edge.” When basic services go away, these patients fall over that edge and become inpatients. Establish a list of patients who require oxygen and devices such as vests, cough-assist, or ventilation. If evacuation before the disaster is possible, those patients need to leave. If they refuse, or are unable to leave, they need to be able to supply their own generated power for a prolonged period of time, as batteries will run out prior to power restoration. They must be able to use oxygen concentrators, as tank re-supply may not be readily available. By law, FEMA cannot give generators to individuals, so individuals must prepare for themselves. In a hurricane-prone area where seasonal risk can be established, planning medication refills at the beginning of the season or giving a larger than normal supply may prove useful. In an area prone to sudden disaster, such as earthquake or tornado, then counseling patients to request refills at least 2 weeks early may be adequate.

In October 2017, in support of the Federal Emergency Management Agency’s response to assist the Governor and people of Puerto Rico, three Department of Defense (DOD) military hospital platforms were deployed; one each, by the US Army, Navy, and Air Force. They arrived on the island at different times with predominantly wartime surgical capabilities and augmented the Federal Emergency Management Agency (FEMA), US Public Health Service, National Guard, and Puerto Rico Department of Health efforts. My perspective is that of patient care and transport between the Centro Medico hospital complex in San Juan, the larger regional hospitals, the Veterans Administration hospital, the DOD response, FEMA Disaster Medical Assistance Teams (DMAT), and FEMA Federal Medical Shelters about 4 to 6 weeks after Hurricanes Maria and Irma struck. Based upon this experience, I would like to offer the following.

Pre-Disaster: All clinicians have a few patients that teeter “on the edge.” When basic services go away, these patients fall over that edge and become inpatients. Establish a list of patients who require oxygen and devices such as vests, cough-assist, or ventilation. If evacuation before the disaster is possible, those patients need to leave. If they refuse, or are unable to leave, they need to be able to supply their own generated power for a prolonged period of time, as batteries will run out prior to power restoration. They must be able to use oxygen concentrators, as tank re-supply may not be readily available. By law, FEMA cannot give generators to individuals, so individuals must prepare for themselves. In a hurricane-prone area where seasonal risk can be established, planning medication refills at the beginning of the season or giving a larger than normal supply may prove useful. In an area prone to sudden disaster, such as earthquake or tornado, then counseling patients to request refills at least 2 weeks early may be adequate.