User login
Pharmacomechanical thrombolysis does not reduce post-thrombotic syndrome risk
In patients with acute proximal deep vein thrombosis who were undergoing anticoagulation, adding pharmacomechanical catheter-directed thrombolysis did not reduce risk of the post-thrombotic syndrome, according to results of a phase 3, randomized, controlled trial.
Moreover, addition of pharmacomechanical thrombolysis increased risk of major bleeding risk, investigators wrote in a report published online Dec. 6 in the New England Journal of Medicine.
“Our trial, for uncertain reasons, did not confirm these findings,” wrote Suresh Vedantham, MD of Washington University, St. Louis, and his coauthors.
Post-thrombotic syndrome is associated with chronic limb swelling and pain, and can lead to leg ulcers, impaired quality of life, and major disability. About half of patients with proximal deep vein thrombosis (DVT) will develop the post-thrombotic syndrome within 2 years, despite use of anticoagulation therapy, Dr. Vedantham and his colleagues noted.
Pharmacomechanical thrombosis is the catheter-directed delivery of a fibrinolytic agent into the thrombus, along with aspiration or maceration of the thrombus. The goal of the treatment is to reduce the burden of thrombus, which in turn might reduce risk of the post-thrombotic syndrome.
However, in their randomized trial known as ATTRACT, which included 692 patients with an acute proximal DVT, rates of post-thrombotic syndrome between 6 to 24 months after intervention were 47% in the pharmacomechanical thrombolysis group and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56), according to the report (N Engl J Med. 2017;377:2240-52). Control group patients received no procedural intervention.
Major bleeds within 10 days of the intervention were 1.7% and 0.3% for the pharmacomechanical thrombolysis and control groups, respectively (P = .049).
By contrast, in the CAVENT trial, catheter-directed thrombolysis reduced the risk of the post-thrombotic syndrome over 5 years of follow-up (Lancet Haematol. 2016;3[2]:e64-71). Dr. Vedantham and his coauthors suggested that factors potentially explaining the difference in outcomes include the number of patients enrolled (692 in ATTRACT, versus 209 in CAVENT), or the greater use of mechanical therapies in ATTRACT versus longer recombinant tissue plasminogen activator infusions in CAVENT.
The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. Dr. Vedantham reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
In patients with acute proximal deep vein thrombosis who were undergoing anticoagulation, adding pharmacomechanical catheter-directed thrombolysis did not reduce risk of the post-thrombotic syndrome, according to results of a phase 3, randomized, controlled trial.
Moreover, addition of pharmacomechanical thrombolysis increased risk of major bleeding risk, investigators wrote in a report published online Dec. 6 in the New England Journal of Medicine.
“Our trial, for uncertain reasons, did not confirm these findings,” wrote Suresh Vedantham, MD of Washington University, St. Louis, and his coauthors.
Post-thrombotic syndrome is associated with chronic limb swelling and pain, and can lead to leg ulcers, impaired quality of life, and major disability. About half of patients with proximal deep vein thrombosis (DVT) will develop the post-thrombotic syndrome within 2 years, despite use of anticoagulation therapy, Dr. Vedantham and his colleagues noted.
Pharmacomechanical thrombosis is the catheter-directed delivery of a fibrinolytic agent into the thrombus, along with aspiration or maceration of the thrombus. The goal of the treatment is to reduce the burden of thrombus, which in turn might reduce risk of the post-thrombotic syndrome.
However, in their randomized trial known as ATTRACT, which included 692 patients with an acute proximal DVT, rates of post-thrombotic syndrome between 6 to 24 months after intervention were 47% in the pharmacomechanical thrombolysis group and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56), according to the report (N Engl J Med. 2017;377:2240-52). Control group patients received no procedural intervention.
Major bleeds within 10 days of the intervention were 1.7% and 0.3% for the pharmacomechanical thrombolysis and control groups, respectively (P = .049).
By contrast, in the CAVENT trial, catheter-directed thrombolysis reduced the risk of the post-thrombotic syndrome over 5 years of follow-up (Lancet Haematol. 2016;3[2]:e64-71). Dr. Vedantham and his coauthors suggested that factors potentially explaining the difference in outcomes include the number of patients enrolled (692 in ATTRACT, versus 209 in CAVENT), or the greater use of mechanical therapies in ATTRACT versus longer recombinant tissue plasminogen activator infusions in CAVENT.
The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. Dr. Vedantham reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
In patients with acute proximal deep vein thrombosis who were undergoing anticoagulation, adding pharmacomechanical catheter-directed thrombolysis did not reduce risk of the post-thrombotic syndrome, according to results of a phase 3, randomized, controlled trial.
Moreover, addition of pharmacomechanical thrombolysis increased risk of major bleeding risk, investigators wrote in a report published online Dec. 6 in the New England Journal of Medicine.
“Our trial, for uncertain reasons, did not confirm these findings,” wrote Suresh Vedantham, MD of Washington University, St. Louis, and his coauthors.
Post-thrombotic syndrome is associated with chronic limb swelling and pain, and can lead to leg ulcers, impaired quality of life, and major disability. About half of patients with proximal deep vein thrombosis (DVT) will develop the post-thrombotic syndrome within 2 years, despite use of anticoagulation therapy, Dr. Vedantham and his colleagues noted.
Pharmacomechanical thrombosis is the catheter-directed delivery of a fibrinolytic agent into the thrombus, along with aspiration or maceration of the thrombus. The goal of the treatment is to reduce the burden of thrombus, which in turn might reduce risk of the post-thrombotic syndrome.
However, in their randomized trial known as ATTRACT, which included 692 patients with an acute proximal DVT, rates of post-thrombotic syndrome between 6 to 24 months after intervention were 47% in the pharmacomechanical thrombolysis group and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56), according to the report (N Engl J Med. 2017;377:2240-52). Control group patients received no procedural intervention.
Major bleeds within 10 days of the intervention were 1.7% and 0.3% for the pharmacomechanical thrombolysis and control groups, respectively (P = .049).
By contrast, in the CAVENT trial, catheter-directed thrombolysis reduced the risk of the post-thrombotic syndrome over 5 years of follow-up (Lancet Haematol. 2016;3[2]:e64-71). Dr. Vedantham and his coauthors suggested that factors potentially explaining the difference in outcomes include the number of patients enrolled (692 in ATTRACT, versus 209 in CAVENT), or the greater use of mechanical therapies in ATTRACT versus longer recombinant tissue plasminogen activator infusions in CAVENT.
The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. Dr. Vedantham reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Rates of post-thrombotic syndrome were 47% in the pharmacomechanical thrombolysis group, and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56).
Data source: A phase 3, multicenter, randomized, open-label, assessor-blinded, controlled clinical trial, including 692 patients with acute proximal deep vein thrombosis.
Disclosures: The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. First author Suresh Vedantham, MD, reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
2017 MS Highlights: The Year in Review
Fenfluramine trials in Dravet syndrome yield highly positive results
WASHINGTON – The oral experimental agent fenfluramine, also known as ZX008, has been associated with a high degree of efficacy and good tolerability for the adjunctive treatment of Dravet syndrome, according to combined results of the first patients enrolled in two phase III trials.
“For me, a highlight of this study is the finding that 45% of patients on the higher dose achieved at least a 75% reduction from baseline in monthly convulsive seizures. This is a life-changing improvement,” reported Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco. He presented the results at the annual meeting of the American Epilepsy Society.
“If fenfluramine is approved as an adjunctive agent, it is likely to be introduced as the second or third medication in an effort to gain adequate symptom control,” Dr. Sullivan speculated.
Three phase 3 trials with fenfluramine are underway. The data presented at the American Epilepsy Society meeting were based on the first 119 patients who had participated in either of the two identical trials conducted in Europe and North America. The data from these two trials has now been combined, and the outcomes in the remaining patients in these two trials will be presented at a later time along with results from a third phase 3 study.
Patients between the ages of 2 and 18 years with a clinical diagnosis of Dravet syndrome were eligible for the European and North American trials if they were not controlled on current therapy, which could include multiple agents. However, patients had to be on stable therapies prior to enrollment for at least 4 weeks. Once enrolled, they were observed for 6 weeks prior to randomization.
After randomization to placebo, 0.2 mg/kg fenfluramine, or 0.8 mg/kg fenfluramine, patients completed a 2-week titration before they reached their maintenance dose. They were then evaluated over an additional 12-week treatment period. There were three withdrawals over the course of treatment in the placebo group, none in the lower-dose fenfluramine group, and six in the higher-dose fenfluramine group.
The primary endpoint was change in mean monthly convulsive seizure frequency from the observation period. When compared with placebo, these reductions were 63.9% (P less than .001) in the 0.8-mg/kg group and 33.7% (P = .019) in the 0.2-mg/kg group. When expressed as the median percent reduction in convulsive seizures from the observation period per 28 days, the reductions were 72.4% for the 0.8-mg/kg dose (P less than .001 vs. placebo), 37.6% for the 0.2-mg/kg group (P = .185 vs. placebo), and 17.4% for placebo.
Other efficacy measures supported the relative advantage of fenfluramine. For example, 70% and 41% of the patients in the 0.8-mg/kg and 0.2-mg/kg groups, respectively, versus 8% of placebo patients, had at least a 50% reduction in seizure frequency. Median seizure-free intervals for the three groups were 20.5, 14, and 9 days, respectively. Seizure activity was reduced to one or no seizures over the treatment period in 25% of the 0.8-mg/kg group, 12.8% of the 0.2-mg/kg group, and 0% of the placebo group.
The most common adverse events on the 0.8-mg/kg dose of fenfluramine, compared with placebo, were decreased appetite (37.5% vs. 5%) and lethargy (17.5% vs. 5%). The proportion of patients with weight loss was also greater on 0.8 mg/kg (5%) and 0.2 mg/kg (12.8%) versus placebo (0%). Diarrhea was more common in the 0.2-mg/kg group (30.8%) than in the 0.8-mg/kg group (17.5%) or in the placebo group (7.5%).
Although monitored closely, cardiotoxicity was not observed in this study. Concern about potential cardiotoxic effects was generated by the increased risk of valvular disease observed in patients taking fenfluramine with phentermine (fen-phen) for weight loss in the 1990s. This combination was withdrawn from the market in 1997.
“The potential for cardiotoxicity will continue to be monitored closely, but these initial results were reassuring,” reported Dr. Sullivan, who noted that a history of cardiovascular or cerebrovascular disease were exclusion criteria from this study.
Application for regulatory approval is not anticipated until all the phase 3 trial data are available, but Dr. Sullivan said that the results so far suggest that fenfluramine as an adjunctive agent “may represent a significant advance over existing treatment options for Dravet syndrome.”
The studies are funded by Zogenix. Dr. Sullivan reported financial relationships with Epygenix and Zogenix.
WASHINGTON – The oral experimental agent fenfluramine, also known as ZX008, has been associated with a high degree of efficacy and good tolerability for the adjunctive treatment of Dravet syndrome, according to combined results of the first patients enrolled in two phase III trials.
“For me, a highlight of this study is the finding that 45% of patients on the higher dose achieved at least a 75% reduction from baseline in monthly convulsive seizures. This is a life-changing improvement,” reported Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco. He presented the results at the annual meeting of the American Epilepsy Society.
“If fenfluramine is approved as an adjunctive agent, it is likely to be introduced as the second or third medication in an effort to gain adequate symptom control,” Dr. Sullivan speculated.
Three phase 3 trials with fenfluramine are underway. The data presented at the American Epilepsy Society meeting were based on the first 119 patients who had participated in either of the two identical trials conducted in Europe and North America. The data from these two trials has now been combined, and the outcomes in the remaining patients in these two trials will be presented at a later time along with results from a third phase 3 study.
Patients between the ages of 2 and 18 years with a clinical diagnosis of Dravet syndrome were eligible for the European and North American trials if they were not controlled on current therapy, which could include multiple agents. However, patients had to be on stable therapies prior to enrollment for at least 4 weeks. Once enrolled, they were observed for 6 weeks prior to randomization.
After randomization to placebo, 0.2 mg/kg fenfluramine, or 0.8 mg/kg fenfluramine, patients completed a 2-week titration before they reached their maintenance dose. They were then evaluated over an additional 12-week treatment period. There were three withdrawals over the course of treatment in the placebo group, none in the lower-dose fenfluramine group, and six in the higher-dose fenfluramine group.
The primary endpoint was change in mean monthly convulsive seizure frequency from the observation period. When compared with placebo, these reductions were 63.9% (P less than .001) in the 0.8-mg/kg group and 33.7% (P = .019) in the 0.2-mg/kg group. When expressed as the median percent reduction in convulsive seizures from the observation period per 28 days, the reductions were 72.4% for the 0.8-mg/kg dose (P less than .001 vs. placebo), 37.6% for the 0.2-mg/kg group (P = .185 vs. placebo), and 17.4% for placebo.
Other efficacy measures supported the relative advantage of fenfluramine. For example, 70% and 41% of the patients in the 0.8-mg/kg and 0.2-mg/kg groups, respectively, versus 8% of placebo patients, had at least a 50% reduction in seizure frequency. Median seizure-free intervals for the three groups were 20.5, 14, and 9 days, respectively. Seizure activity was reduced to one or no seizures over the treatment period in 25% of the 0.8-mg/kg group, 12.8% of the 0.2-mg/kg group, and 0% of the placebo group.
The most common adverse events on the 0.8-mg/kg dose of fenfluramine, compared with placebo, were decreased appetite (37.5% vs. 5%) and lethargy (17.5% vs. 5%). The proportion of patients with weight loss was also greater on 0.8 mg/kg (5%) and 0.2 mg/kg (12.8%) versus placebo (0%). Diarrhea was more common in the 0.2-mg/kg group (30.8%) than in the 0.8-mg/kg group (17.5%) or in the placebo group (7.5%).
Although monitored closely, cardiotoxicity was not observed in this study. Concern about potential cardiotoxic effects was generated by the increased risk of valvular disease observed in patients taking fenfluramine with phentermine (fen-phen) for weight loss in the 1990s. This combination was withdrawn from the market in 1997.
“The potential for cardiotoxicity will continue to be monitored closely, but these initial results were reassuring,” reported Dr. Sullivan, who noted that a history of cardiovascular or cerebrovascular disease were exclusion criteria from this study.
Application for regulatory approval is not anticipated until all the phase 3 trial data are available, but Dr. Sullivan said that the results so far suggest that fenfluramine as an adjunctive agent “may represent a significant advance over existing treatment options for Dravet syndrome.”
The studies are funded by Zogenix. Dr. Sullivan reported financial relationships with Epygenix and Zogenix.
WASHINGTON – The oral experimental agent fenfluramine, also known as ZX008, has been associated with a high degree of efficacy and good tolerability for the adjunctive treatment of Dravet syndrome, according to combined results of the first patients enrolled in two phase III trials.
“For me, a highlight of this study is the finding that 45% of patients on the higher dose achieved at least a 75% reduction from baseline in monthly convulsive seizures. This is a life-changing improvement,” reported Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco. He presented the results at the annual meeting of the American Epilepsy Society.
“If fenfluramine is approved as an adjunctive agent, it is likely to be introduced as the second or third medication in an effort to gain adequate symptom control,” Dr. Sullivan speculated.
Three phase 3 trials with fenfluramine are underway. The data presented at the American Epilepsy Society meeting were based on the first 119 patients who had participated in either of the two identical trials conducted in Europe and North America. The data from these two trials has now been combined, and the outcomes in the remaining patients in these two trials will be presented at a later time along with results from a third phase 3 study.
Patients between the ages of 2 and 18 years with a clinical diagnosis of Dravet syndrome were eligible for the European and North American trials if they were not controlled on current therapy, which could include multiple agents. However, patients had to be on stable therapies prior to enrollment for at least 4 weeks. Once enrolled, they were observed for 6 weeks prior to randomization.
After randomization to placebo, 0.2 mg/kg fenfluramine, or 0.8 mg/kg fenfluramine, patients completed a 2-week titration before they reached their maintenance dose. They were then evaluated over an additional 12-week treatment period. There were three withdrawals over the course of treatment in the placebo group, none in the lower-dose fenfluramine group, and six in the higher-dose fenfluramine group.
The primary endpoint was change in mean monthly convulsive seizure frequency from the observation period. When compared with placebo, these reductions were 63.9% (P less than .001) in the 0.8-mg/kg group and 33.7% (P = .019) in the 0.2-mg/kg group. When expressed as the median percent reduction in convulsive seizures from the observation period per 28 days, the reductions were 72.4% for the 0.8-mg/kg dose (P less than .001 vs. placebo), 37.6% for the 0.2-mg/kg group (P = .185 vs. placebo), and 17.4% for placebo.
Other efficacy measures supported the relative advantage of fenfluramine. For example, 70% and 41% of the patients in the 0.8-mg/kg and 0.2-mg/kg groups, respectively, versus 8% of placebo patients, had at least a 50% reduction in seizure frequency. Median seizure-free intervals for the three groups were 20.5, 14, and 9 days, respectively. Seizure activity was reduced to one or no seizures over the treatment period in 25% of the 0.8-mg/kg group, 12.8% of the 0.2-mg/kg group, and 0% of the placebo group.
The most common adverse events on the 0.8-mg/kg dose of fenfluramine, compared with placebo, were decreased appetite (37.5% vs. 5%) and lethargy (17.5% vs. 5%). The proportion of patients with weight loss was also greater on 0.8 mg/kg (5%) and 0.2 mg/kg (12.8%) versus placebo (0%). Diarrhea was more common in the 0.2-mg/kg group (30.8%) than in the 0.8-mg/kg group (17.5%) or in the placebo group (7.5%).
Although monitored closely, cardiotoxicity was not observed in this study. Concern about potential cardiotoxic effects was generated by the increased risk of valvular disease observed in patients taking fenfluramine with phentermine (fen-phen) for weight loss in the 1990s. This combination was withdrawn from the market in 1997.
“The potential for cardiotoxicity will continue to be monitored closely, but these initial results were reassuring,” reported Dr. Sullivan, who noted that a history of cardiovascular or cerebrovascular disease were exclusion criteria from this study.
Application for regulatory approval is not anticipated until all the phase 3 trial data are available, but Dr. Sullivan said that the results so far suggest that fenfluramine as an adjunctive agent “may represent a significant advance over existing treatment options for Dravet syndrome.”
The studies are funded by Zogenix. Dr. Sullivan reported financial relationships with Epygenix and Zogenix.
REPORTING FROM AES 2017
Key clinical point:
Major finding: For the highest dose, the mean reduction in convulsive seizure frequency was 63.9% (P less than .001) versus placebo over a 14-week treatment period.
Data source: An analysis of the first 119 patients with Dravet syndrome enrolled in two ongoing randomized, double-blind, multicenter, phase 3 trials.
Disclosures: The studies are funded by Zogenix. The presenter reported financial relationships with Epygenix and Zogenix.
Source: L Lagae et al. AES 2017 Abstract 2.434
Clostridium difficile in the ICU: A “fluid” issue
In critically ill patients admitted to the ICU, diarrhea (defined as three or more watery loose stools within 24 hours) is a common problem. The etiologies of diarrhea are many, with infectious and noninfectious causes encountered.
Clostridium difficile infection (CDI) is the most common infectious cause of diarrhea in the hospital, including the ICU. The Centers for Disease Control and Prevention estimates the number of overall CDI cases to number about a half-million per year, of which 1 in 5 patients will have a recurrence, and 1 in 11 people aged ≥65 years will die within a month of CDI diagnosis. Age is a poor prognostic risk; greater than 80% of C difficile deaths occur in people 65 and older.
The increased use of electronic sepsis screening tools and aggressive antibiotic treatment, often done through protocols, has recently been identified as paradoxically increasing CDI occurrence (Hiensch R et al. Am J Infect Control. 2017;45[10]:1091). However, similar rapid identification and management of CDI can result in improved patient outcomes.
Issues with diagnosing CDI
Episodes of CDI can be rapid and severe, especially if due to hyper-toxin producing–strains of C difficile, such as BI/NAP1/027, which produces significantly higher levels of Toxin A, Toxin B, and binary toxin CDT (Denève C, et al. Int J Antimicrob Agents. 2009;33:S24). Testing for CDI has been controversial; several methods have been employed to aid in the diagnosis of CDI. Currently, many institutions use either nucleic acid amplification tests (NAATs) for toxigenic C difficile or direct detection of the toxin produced by the bacteria. NAATs and past culture-based methods are more sensitive but less specific than toxin assays, whereas toxin assays are less sensitive but more specific than NAATs. However, detection of C difficile colonization due to high-sensitivity NAATs has caused a rise in the apparent rate of hospital-acquired CDI (Polage CR, et al. JAMA Intern Med. 2015;175[11]:4114).
To counter this, multi-step algorithmic approaches to CDI diagnosis have been recommended, including the use of glutamate dehydrogenase (GDH) antigen, toxin detection, and NAATs for toxin-producing C difficile. These multistep pathways attempt to minimize false-positive test results while affirming the presence or absence of true CDI (Fang F, et al. J Clin Microbiol. 2017; 55[3]:670).
However, controversy continues regarding which testing modalities are optimal, as some patients with positive toxin assays have asymptomatic colonization while some patients with negative toxin assays have CDI. The hope is that emerging, higher sensitivity toxin assays will decrease the number of CDI cases missed by negative toxin tests. Because C difficile toxins are labile at body temperature and susceptible to inactivation by digestive enzymes, stool samples must be expeditiously transported to the lab (time is of the essence), so as not to lose toxin or NAAT target detection. Repeat CDI testing for a “test for cure” is not recommended.
Management of CDI
The initial management of CDI has been discussed in many publications, including the current SHEA/IDSA Guidelines (Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31[5]:431).
Briefly, this involves stratifying CDI patients by clinical severity (mild, moderate, severe) and objective data (leukocytosis >15,000, septic shock, serum creatinine level > 1.5 times premorbid level) to guide initial antibiotic therapy. For mild/moderate first episode of CDI, oral or IV metronidazole is generally recommended; more severe disease is generally treated with oral vancomycin.
Complicated CDI in patients (hypotension/shock, ileus, toxic megacolon) requires aggressive management with both IV metronidazole and oral vancomycin (if ileus is present, consider vancomycin enemas). Additionally, fidaxomicin is available for oral CDI treatment and has been associated with decreased first-episode CDI recurrence.
The management of CDI recurrence commonly involves using oral vancomycin as a taper (or taper/pulse regimen) or using fidaxomicin. A recent publication (Sirbu et al. Clin Infect Dis. 2017;65[8]:1396) retrospectively compared vancomycin taper and pulse treatment strategies for 100 consecutive patients with CDI.
After taper, patents who received every other day (QOD) dosing had a cure rate of 61%, while those who received QOD dosing followed by every third day dosing achieved an 81% cure rate. A clinical trial comparing vancomycin standard therapy vs vancomycin taper with pulse vs fidaxomicin for first- and second-recurrence of CDI is underway.
Last year, the FDA approved bezlotoxumab, a monoclonal antibody that binds to C difficile toxin B. Bezlotoxumab treatment is indicated to reduce CDI recurrence in patients >18 years of age and is administered while CDI antibiotic therapy is ongoing.
When comparing 12-week efficacy using standard of care (SoC) CDI treatment vs SoC plus bezlotoxumab (SoC+Bmab), recurrence rates in SoC and SoC+Bmab were 27.6% vs1 7.4%, respectively, in one trial, and 25.7% vs 15.7% in another. While generally well-tolerated, bezlotoxumab is associated with increased risk for exacerbating heart failure. Data relating to the cost-effectiveness of bezlotoxumab are currently pending.
Fecal microbiota transplant (FMT)— duodenal or colonic instillation of donor fecal microbiota to “restore” normal flora— is an evolving CDI therapy with promising results but difficult administration. Although FMT has high published success rates, the FDA’s policy of “enforcement discretion” permits practitioners to proceed with FMT only as an Investigational New Drug. This requires signed, informed consent to FMT as an investigational therapy with unknown long-term risks.
The FDA deemed these protections necessary as ongoing studies of the human microbiome have yet to define what constitutes “normal flora,” and some investigators highlight the possibility of transmitting flora or gut factors associated with obesity, metabolic syndrome, or malignancy.
Experimental CDI preventive modalities include new antibiotics, monoclonal antibodies, probiotics, select other novel agents, and C. difficile vaccinations. These vaccines include recombinant fusion proteins and adjuvant toxoids, both of which have generally favorable tolerance profiles, as well as robust immune responses in clinical trial subjects. However, the efficacy of these vaccines at preventing clinical disease is still to be demonstrated.
Lastly, the ubiquitous use of proton pump inhibitors (PPI) in ICUs plays a role in promoting CDI incidence, severity, and recurrence. Accordingly, the pros and cons of PPI use must be weighed in each patient.
CDI prevention in the hospital environment
Hospital-acquired CDIs (HA-CDI) and nosocomial transmission clearly occur. A recent study of electronic health record data demonstrated that patients who passed through the hospital’s emergency department CT scanner within 24 hours after a patient with C difficile were twice as likely to become infected (Murray SG, et al. JAMA Internal Medicine. published online October 23, 2017. doi:10.1001). Receipt of antibiotics by prior bed occupants was associated with increased risk for CDI in subsequent patients, implying that antibiotics can directly affect the risk for CDI in patients who do not themselves receive antibiotics. As such, aggressive environmental cleaning in conjunction with hospital antimicrobial stewardship efforts, such as appropriate use of antibiotics known to increase CDI occurrence, are required to minimize HA-CDI.
Contact precautions should be strictly enforced; wearing gloves and gowns is necessary for every encounter when treating patients with C difficile, even during short visits. Hand sanitizer does not kill C difficile, and although soap-and-water hand washing works better, it may be insufficient alone, reinforcing the importance of using gloves with all patient encounters.
The strain placed on ICUs by CDI has been increasing over the past several years. Physicians and hospitals are at risk for lower performance scores and reduced reimbursement due to CDI relapses. As such, burgeoning areas of debate and research include efforts to quickly and accurately diagnose CDI along with reducing recurrence rates. Yet, with all the capital investment, the most significant and cost-effective method to reduce CDI rates remains proper and frequent hand washing with soap and water. Prevention of disease remains the cornerstone to treatment.
In critically ill patients admitted to the ICU, diarrhea (defined as three or more watery loose stools within 24 hours) is a common problem. The etiologies of diarrhea are many, with infectious and noninfectious causes encountered.
Clostridium difficile infection (CDI) is the most common infectious cause of diarrhea in the hospital, including the ICU. The Centers for Disease Control and Prevention estimates the number of overall CDI cases to number about a half-million per year, of which 1 in 5 patients will have a recurrence, and 1 in 11 people aged ≥65 years will die within a month of CDI diagnosis. Age is a poor prognostic risk; greater than 80% of C difficile deaths occur in people 65 and older.
The increased use of electronic sepsis screening tools and aggressive antibiotic treatment, often done through protocols, has recently been identified as paradoxically increasing CDI occurrence (Hiensch R et al. Am J Infect Control. 2017;45[10]:1091). However, similar rapid identification and management of CDI can result in improved patient outcomes.
Issues with diagnosing CDI
Episodes of CDI can be rapid and severe, especially if due to hyper-toxin producing–strains of C difficile, such as BI/NAP1/027, which produces significantly higher levels of Toxin A, Toxin B, and binary toxin CDT (Denève C, et al. Int J Antimicrob Agents. 2009;33:S24). Testing for CDI has been controversial; several methods have been employed to aid in the diagnosis of CDI. Currently, many institutions use either nucleic acid amplification tests (NAATs) for toxigenic C difficile or direct detection of the toxin produced by the bacteria. NAATs and past culture-based methods are more sensitive but less specific than toxin assays, whereas toxin assays are less sensitive but more specific than NAATs. However, detection of C difficile colonization due to high-sensitivity NAATs has caused a rise in the apparent rate of hospital-acquired CDI (Polage CR, et al. JAMA Intern Med. 2015;175[11]:4114).
To counter this, multi-step algorithmic approaches to CDI diagnosis have been recommended, including the use of glutamate dehydrogenase (GDH) antigen, toxin detection, and NAATs for toxin-producing C difficile. These multistep pathways attempt to minimize false-positive test results while affirming the presence or absence of true CDI (Fang F, et al. J Clin Microbiol. 2017; 55[3]:670).
However, controversy continues regarding which testing modalities are optimal, as some patients with positive toxin assays have asymptomatic colonization while some patients with negative toxin assays have CDI. The hope is that emerging, higher sensitivity toxin assays will decrease the number of CDI cases missed by negative toxin tests. Because C difficile toxins are labile at body temperature and susceptible to inactivation by digestive enzymes, stool samples must be expeditiously transported to the lab (time is of the essence), so as not to lose toxin or NAAT target detection. Repeat CDI testing for a “test for cure” is not recommended.
Management of CDI
The initial management of CDI has been discussed in many publications, including the current SHEA/IDSA Guidelines (Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31[5]:431).
Briefly, this involves stratifying CDI patients by clinical severity (mild, moderate, severe) and objective data (leukocytosis >15,000, septic shock, serum creatinine level > 1.5 times premorbid level) to guide initial antibiotic therapy. For mild/moderate first episode of CDI, oral or IV metronidazole is generally recommended; more severe disease is generally treated with oral vancomycin.
Complicated CDI in patients (hypotension/shock, ileus, toxic megacolon) requires aggressive management with both IV metronidazole and oral vancomycin (if ileus is present, consider vancomycin enemas). Additionally, fidaxomicin is available for oral CDI treatment and has been associated with decreased first-episode CDI recurrence.
The management of CDI recurrence commonly involves using oral vancomycin as a taper (or taper/pulse regimen) or using fidaxomicin. A recent publication (Sirbu et al. Clin Infect Dis. 2017;65[8]:1396) retrospectively compared vancomycin taper and pulse treatment strategies for 100 consecutive patients with CDI.
After taper, patents who received every other day (QOD) dosing had a cure rate of 61%, while those who received QOD dosing followed by every third day dosing achieved an 81% cure rate. A clinical trial comparing vancomycin standard therapy vs vancomycin taper with pulse vs fidaxomicin for first- and second-recurrence of CDI is underway.
Last year, the FDA approved bezlotoxumab, a monoclonal antibody that binds to C difficile toxin B. Bezlotoxumab treatment is indicated to reduce CDI recurrence in patients >18 years of age and is administered while CDI antibiotic therapy is ongoing.
When comparing 12-week efficacy using standard of care (SoC) CDI treatment vs SoC plus bezlotoxumab (SoC+Bmab), recurrence rates in SoC and SoC+Bmab were 27.6% vs1 7.4%, respectively, in one trial, and 25.7% vs 15.7% in another. While generally well-tolerated, bezlotoxumab is associated with increased risk for exacerbating heart failure. Data relating to the cost-effectiveness of bezlotoxumab are currently pending.
Fecal microbiota transplant (FMT)— duodenal or colonic instillation of donor fecal microbiota to “restore” normal flora— is an evolving CDI therapy with promising results but difficult administration. Although FMT has high published success rates, the FDA’s policy of “enforcement discretion” permits practitioners to proceed with FMT only as an Investigational New Drug. This requires signed, informed consent to FMT as an investigational therapy with unknown long-term risks.
The FDA deemed these protections necessary as ongoing studies of the human microbiome have yet to define what constitutes “normal flora,” and some investigators highlight the possibility of transmitting flora or gut factors associated with obesity, metabolic syndrome, or malignancy.
Experimental CDI preventive modalities include new antibiotics, monoclonal antibodies, probiotics, select other novel agents, and C. difficile vaccinations. These vaccines include recombinant fusion proteins and adjuvant toxoids, both of which have generally favorable tolerance profiles, as well as robust immune responses in clinical trial subjects. However, the efficacy of these vaccines at preventing clinical disease is still to be demonstrated.
Lastly, the ubiquitous use of proton pump inhibitors (PPI) in ICUs plays a role in promoting CDI incidence, severity, and recurrence. Accordingly, the pros and cons of PPI use must be weighed in each patient.
CDI prevention in the hospital environment
Hospital-acquired CDIs (HA-CDI) and nosocomial transmission clearly occur. A recent study of electronic health record data demonstrated that patients who passed through the hospital’s emergency department CT scanner within 24 hours after a patient with C difficile were twice as likely to become infected (Murray SG, et al. JAMA Internal Medicine. published online October 23, 2017. doi:10.1001). Receipt of antibiotics by prior bed occupants was associated with increased risk for CDI in subsequent patients, implying that antibiotics can directly affect the risk for CDI in patients who do not themselves receive antibiotics. As such, aggressive environmental cleaning in conjunction with hospital antimicrobial stewardship efforts, such as appropriate use of antibiotics known to increase CDI occurrence, are required to minimize HA-CDI.
Contact precautions should be strictly enforced; wearing gloves and gowns is necessary for every encounter when treating patients with C difficile, even during short visits. Hand sanitizer does not kill C difficile, and although soap-and-water hand washing works better, it may be insufficient alone, reinforcing the importance of using gloves with all patient encounters.
The strain placed on ICUs by CDI has been increasing over the past several years. Physicians and hospitals are at risk for lower performance scores and reduced reimbursement due to CDI relapses. As such, burgeoning areas of debate and research include efforts to quickly and accurately diagnose CDI along with reducing recurrence rates. Yet, with all the capital investment, the most significant and cost-effective method to reduce CDI rates remains proper and frequent hand washing with soap and water. Prevention of disease remains the cornerstone to treatment.
In critically ill patients admitted to the ICU, diarrhea (defined as three or more watery loose stools within 24 hours) is a common problem. The etiologies of diarrhea are many, with infectious and noninfectious causes encountered.
Clostridium difficile infection (CDI) is the most common infectious cause of diarrhea in the hospital, including the ICU. The Centers for Disease Control and Prevention estimates the number of overall CDI cases to number about a half-million per year, of which 1 in 5 patients will have a recurrence, and 1 in 11 people aged ≥65 years will die within a month of CDI diagnosis. Age is a poor prognostic risk; greater than 80% of C difficile deaths occur in people 65 and older.
The increased use of electronic sepsis screening tools and aggressive antibiotic treatment, often done through protocols, has recently been identified as paradoxically increasing CDI occurrence (Hiensch R et al. Am J Infect Control. 2017;45[10]:1091). However, similar rapid identification and management of CDI can result in improved patient outcomes.
Issues with diagnosing CDI
Episodes of CDI can be rapid and severe, especially if due to hyper-toxin producing–strains of C difficile, such as BI/NAP1/027, which produces significantly higher levels of Toxin A, Toxin B, and binary toxin CDT (Denève C, et al. Int J Antimicrob Agents. 2009;33:S24). Testing for CDI has been controversial; several methods have been employed to aid in the diagnosis of CDI. Currently, many institutions use either nucleic acid amplification tests (NAATs) for toxigenic C difficile or direct detection of the toxin produced by the bacteria. NAATs and past culture-based methods are more sensitive but less specific than toxin assays, whereas toxin assays are less sensitive but more specific than NAATs. However, detection of C difficile colonization due to high-sensitivity NAATs has caused a rise in the apparent rate of hospital-acquired CDI (Polage CR, et al. JAMA Intern Med. 2015;175[11]:4114).
To counter this, multi-step algorithmic approaches to CDI diagnosis have been recommended, including the use of glutamate dehydrogenase (GDH) antigen, toxin detection, and NAATs for toxin-producing C difficile. These multistep pathways attempt to minimize false-positive test results while affirming the presence or absence of true CDI (Fang F, et al. J Clin Microbiol. 2017; 55[3]:670).
However, controversy continues regarding which testing modalities are optimal, as some patients with positive toxin assays have asymptomatic colonization while some patients with negative toxin assays have CDI. The hope is that emerging, higher sensitivity toxin assays will decrease the number of CDI cases missed by negative toxin tests. Because C difficile toxins are labile at body temperature and susceptible to inactivation by digestive enzymes, stool samples must be expeditiously transported to the lab (time is of the essence), so as not to lose toxin or NAAT target detection. Repeat CDI testing for a “test for cure” is not recommended.
Management of CDI
The initial management of CDI has been discussed in many publications, including the current SHEA/IDSA Guidelines (Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31[5]:431).
Briefly, this involves stratifying CDI patients by clinical severity (mild, moderate, severe) and objective data (leukocytosis >15,000, septic shock, serum creatinine level > 1.5 times premorbid level) to guide initial antibiotic therapy. For mild/moderate first episode of CDI, oral or IV metronidazole is generally recommended; more severe disease is generally treated with oral vancomycin.
Complicated CDI in patients (hypotension/shock, ileus, toxic megacolon) requires aggressive management with both IV metronidazole and oral vancomycin (if ileus is present, consider vancomycin enemas). Additionally, fidaxomicin is available for oral CDI treatment and has been associated with decreased first-episode CDI recurrence.
The management of CDI recurrence commonly involves using oral vancomycin as a taper (or taper/pulse regimen) or using fidaxomicin. A recent publication (Sirbu et al. Clin Infect Dis. 2017;65[8]:1396) retrospectively compared vancomycin taper and pulse treatment strategies for 100 consecutive patients with CDI.
After taper, patents who received every other day (QOD) dosing had a cure rate of 61%, while those who received QOD dosing followed by every third day dosing achieved an 81% cure rate. A clinical trial comparing vancomycin standard therapy vs vancomycin taper with pulse vs fidaxomicin for first- and second-recurrence of CDI is underway.
Last year, the FDA approved bezlotoxumab, a monoclonal antibody that binds to C difficile toxin B. Bezlotoxumab treatment is indicated to reduce CDI recurrence in patients >18 years of age and is administered while CDI antibiotic therapy is ongoing.
When comparing 12-week efficacy using standard of care (SoC) CDI treatment vs SoC plus bezlotoxumab (SoC+Bmab), recurrence rates in SoC and SoC+Bmab were 27.6% vs1 7.4%, respectively, in one trial, and 25.7% vs 15.7% in another. While generally well-tolerated, bezlotoxumab is associated with increased risk for exacerbating heart failure. Data relating to the cost-effectiveness of bezlotoxumab are currently pending.
Fecal microbiota transplant (FMT)— duodenal or colonic instillation of donor fecal microbiota to “restore” normal flora— is an evolving CDI therapy with promising results but difficult administration. Although FMT has high published success rates, the FDA’s policy of “enforcement discretion” permits practitioners to proceed with FMT only as an Investigational New Drug. This requires signed, informed consent to FMT as an investigational therapy with unknown long-term risks.
The FDA deemed these protections necessary as ongoing studies of the human microbiome have yet to define what constitutes “normal flora,” and some investigators highlight the possibility of transmitting flora or gut factors associated with obesity, metabolic syndrome, or malignancy.
Experimental CDI preventive modalities include new antibiotics, monoclonal antibodies, probiotics, select other novel agents, and C. difficile vaccinations. These vaccines include recombinant fusion proteins and adjuvant toxoids, both of which have generally favorable tolerance profiles, as well as robust immune responses in clinical trial subjects. However, the efficacy of these vaccines at preventing clinical disease is still to be demonstrated.
Lastly, the ubiquitous use of proton pump inhibitors (PPI) in ICUs plays a role in promoting CDI incidence, severity, and recurrence. Accordingly, the pros and cons of PPI use must be weighed in each patient.
CDI prevention in the hospital environment
Hospital-acquired CDIs (HA-CDI) and nosocomial transmission clearly occur. A recent study of electronic health record data demonstrated that patients who passed through the hospital’s emergency department CT scanner within 24 hours after a patient with C difficile were twice as likely to become infected (Murray SG, et al. JAMA Internal Medicine. published online October 23, 2017. doi:10.1001). Receipt of antibiotics by prior bed occupants was associated with increased risk for CDI in subsequent patients, implying that antibiotics can directly affect the risk for CDI in patients who do not themselves receive antibiotics. As such, aggressive environmental cleaning in conjunction with hospital antimicrobial stewardship efforts, such as appropriate use of antibiotics known to increase CDI occurrence, are required to minimize HA-CDI.
Contact precautions should be strictly enforced; wearing gloves and gowns is necessary for every encounter when treating patients with C difficile, even during short visits. Hand sanitizer does not kill C difficile, and although soap-and-water hand washing works better, it may be insufficient alone, reinforcing the importance of using gloves with all patient encounters.
The strain placed on ICUs by CDI has been increasing over the past several years. Physicians and hospitals are at risk for lower performance scores and reduced reimbursement due to CDI relapses. As such, burgeoning areas of debate and research include efforts to quickly and accurately diagnose CDI along with reducing recurrence rates. Yet, with all the capital investment, the most significant and cost-effective method to reduce CDI rates remains proper and frequent hand washing with soap and water. Prevention of disease remains the cornerstone to treatment.
This month in CHEST Editor’s picks
Original Research
Pharmacotherapy for Non-Cystic Fibrosis Bronchiectasis: Results From an NTM Info and Research Patient Survey and the Bronchiectasis and NTM Research Registry.
By Dr. E. Henkle, et al.
By Dr. A. Lautenbach, et al.
Commentary
Crotalaria (Monocrotaline) Pulmonary Hypertension: The Fiftieth Anniversary.
By Dr. J. Kay.
Original Research
Pharmacotherapy for Non-Cystic Fibrosis Bronchiectasis: Results From an NTM Info and Research Patient Survey and the Bronchiectasis and NTM Research Registry.
By Dr. E. Henkle, et al.
By Dr. A. Lautenbach, et al.
Commentary
Crotalaria (Monocrotaline) Pulmonary Hypertension: The Fiftieth Anniversary.
By Dr. J. Kay.
Original Research
Pharmacotherapy for Non-Cystic Fibrosis Bronchiectasis: Results From an NTM Info and Research Patient Survey and the Bronchiectasis and NTM Research Registry.
By Dr. E. Henkle, et al.
By Dr. A. Lautenbach, et al.
Commentary
Crotalaria (Monocrotaline) Pulmonary Hypertension: The Fiftieth Anniversary.
By Dr. J. Kay.
NAMDRC Report
In mid-September, NAMDRC, along with the American Thoracic Society, the American Association for Respiratory Care, the COPD Foundation, the American Lung Association, and others met to discuss the components of a legislative agenda for the coming years. The primary purpose behind the meeting was the premise that IF the current Republican majority would shift in either the House or Senate after the 2018 election, the community should be prepared to move an already agreed upon legislative agenda. CHEST was involved in the preliminary discussions, as well as follow-up, but was not in attendance at the meeting due to a scheduling conflict. There was also tacit agreement that as these policies are fleshed out and crafted into specific legislative language, the community would re-evaluate the current political climate to determine the value of pushing an agreed upon agenda prior to the 2018 elections.
Various patient groups were also invited to participate, but scheduling conflicts precluded some societies from participating but signaled their desire to work with the broad pulmonary medicine community to pursue common goals.
Each society brought its legislative priorities to the table, and there was active discussion on issues ranging from funding for NIH/NHLBI, to CDC and its COPD Action Plan, to a range of Medicare-related issues.
NAMDRC brought three specific Medicare coverage and payment issues to the discussion: home mechanical ventilation, payment for high flow oxygen therapy, and site of service/Section 603 issues.
Home mechanical ventilation is admittedly a complex issue, but it is moving forward in at least two political directions. First, Senator Bill Cassidy (R-LA) and a physician by training, has signaled his desire to move this issue forward, either legislatively or giving CMS one last chance to move forward through the regulatory structure. He agrees that a payment system that inhibits access to appropriate bi-level mechanical ventilators and encourages access to more complex life-sustaining ventilators, regardless of documented medical need, is appropriate. While CMS does have the authority to act, it has chosen to ignore repeated requests for action over the past 4 years.
Ironically, the House Energy and Commerce Committee, which shares jurisdiction on the House of Representatives with the Ways and Means Committee on Medicare issues, has sent a request to the Congressional Budget Office to provide a cost estimate (a “score” in Washington vernacular) of likely savings from a legislative solution to this matter. In the current political climate, a legislative proposal that actually saves $$$ is politically attractive, and we are working both the regulatory and legislative pathway to seek a workable solution.
On the oxygen therapy issue, there is growing evidence that, for a small group of Medicare beneficiaries who need high flow oxygen therapy as their disease progresses (pulmonary fibrosis, end-stage COPD, etc), there are no oxygen systems readily available to meet that need outside the home. At home, numerous concentrators can meet that need, but outside the home, the ideal solution, liquid systems, is not readily available because of the payment system tied to competitive bidding. CMS payment data indicate that a very low percentage of oxygen users need more than 4 liters per minute, and current law would make a payment adjustment unique to certain patients a very difficult hurdle, particularly in the era of competitive bidding, a legislative change is the best solution facing the community. The challenge is to craft legislative language that addresses the need but would preclude abuse by suppliers who might jump at the chance for higher payment for liquid, well above current payment levels. And because liquid systems fit into a “delivery model” business plan, contrary to portable oxygen concentrators and transfill systems, the solution is not as easy as a payment bump to make provision of liquid systems more attractive.
Site of service regulations are hitting pulmonary rehabilitation particularly hard, and CMS concedes that the only solution is a legislative one. Under current policy, a pulmonary rehab program that is located off campus but needs to expand or move from its current location (losing a lease, for example), if the expanded program is NOT within 250 yards of the main hospital campus, the program is then reimbursed at the physician fee schedule rate, a rate cut of approximately 50%. Needless to say, hospitals are not pursuing that approach. Likewise, a hospital that chooses to open a NEW program is also constrained, needing to locate within 250 yards of the main campus or face the dramatic cut in payment.
As these issues evolve and the political climate perhaps opens unique opportunities, we can expect the broad pulmonary community to pursue these and other issues.
In mid-September, NAMDRC, along with the American Thoracic Society, the American Association for Respiratory Care, the COPD Foundation, the American Lung Association, and others met to discuss the components of a legislative agenda for the coming years. The primary purpose behind the meeting was the premise that IF the current Republican majority would shift in either the House or Senate after the 2018 election, the community should be prepared to move an already agreed upon legislative agenda. CHEST was involved in the preliminary discussions, as well as follow-up, but was not in attendance at the meeting due to a scheduling conflict. There was also tacit agreement that as these policies are fleshed out and crafted into specific legislative language, the community would re-evaluate the current political climate to determine the value of pushing an agreed upon agenda prior to the 2018 elections.
Various patient groups were also invited to participate, but scheduling conflicts precluded some societies from participating but signaled their desire to work with the broad pulmonary medicine community to pursue common goals.
Each society brought its legislative priorities to the table, and there was active discussion on issues ranging from funding for NIH/NHLBI, to CDC and its COPD Action Plan, to a range of Medicare-related issues.
NAMDRC brought three specific Medicare coverage and payment issues to the discussion: home mechanical ventilation, payment for high flow oxygen therapy, and site of service/Section 603 issues.
Home mechanical ventilation is admittedly a complex issue, but it is moving forward in at least two political directions. First, Senator Bill Cassidy (R-LA) and a physician by training, has signaled his desire to move this issue forward, either legislatively or giving CMS one last chance to move forward through the regulatory structure. He agrees that a payment system that inhibits access to appropriate bi-level mechanical ventilators and encourages access to more complex life-sustaining ventilators, regardless of documented medical need, is appropriate. While CMS does have the authority to act, it has chosen to ignore repeated requests for action over the past 4 years.
Ironically, the House Energy and Commerce Committee, which shares jurisdiction on the House of Representatives with the Ways and Means Committee on Medicare issues, has sent a request to the Congressional Budget Office to provide a cost estimate (a “score” in Washington vernacular) of likely savings from a legislative solution to this matter. In the current political climate, a legislative proposal that actually saves $$$ is politically attractive, and we are working both the regulatory and legislative pathway to seek a workable solution.
On the oxygen therapy issue, there is growing evidence that, for a small group of Medicare beneficiaries who need high flow oxygen therapy as their disease progresses (pulmonary fibrosis, end-stage COPD, etc), there are no oxygen systems readily available to meet that need outside the home. At home, numerous concentrators can meet that need, but outside the home, the ideal solution, liquid systems, is not readily available because of the payment system tied to competitive bidding. CMS payment data indicate that a very low percentage of oxygen users need more than 4 liters per minute, and current law would make a payment adjustment unique to certain patients a very difficult hurdle, particularly in the era of competitive bidding, a legislative change is the best solution facing the community. The challenge is to craft legislative language that addresses the need but would preclude abuse by suppliers who might jump at the chance for higher payment for liquid, well above current payment levels. And because liquid systems fit into a “delivery model” business plan, contrary to portable oxygen concentrators and transfill systems, the solution is not as easy as a payment bump to make provision of liquid systems more attractive.
Site of service regulations are hitting pulmonary rehabilitation particularly hard, and CMS concedes that the only solution is a legislative one. Under current policy, a pulmonary rehab program that is located off campus but needs to expand or move from its current location (losing a lease, for example), if the expanded program is NOT within 250 yards of the main hospital campus, the program is then reimbursed at the physician fee schedule rate, a rate cut of approximately 50%. Needless to say, hospitals are not pursuing that approach. Likewise, a hospital that chooses to open a NEW program is also constrained, needing to locate within 250 yards of the main campus or face the dramatic cut in payment.
As these issues evolve and the political climate perhaps opens unique opportunities, we can expect the broad pulmonary community to pursue these and other issues.
In mid-September, NAMDRC, along with the American Thoracic Society, the American Association for Respiratory Care, the COPD Foundation, the American Lung Association, and others met to discuss the components of a legislative agenda for the coming years. The primary purpose behind the meeting was the premise that IF the current Republican majority would shift in either the House or Senate after the 2018 election, the community should be prepared to move an already agreed upon legislative agenda. CHEST was involved in the preliminary discussions, as well as follow-up, but was not in attendance at the meeting due to a scheduling conflict. There was also tacit agreement that as these policies are fleshed out and crafted into specific legislative language, the community would re-evaluate the current political climate to determine the value of pushing an agreed upon agenda prior to the 2018 elections.
Various patient groups were also invited to participate, but scheduling conflicts precluded some societies from participating but signaled their desire to work with the broad pulmonary medicine community to pursue common goals.
Each society brought its legislative priorities to the table, and there was active discussion on issues ranging from funding for NIH/NHLBI, to CDC and its COPD Action Plan, to a range of Medicare-related issues.
NAMDRC brought three specific Medicare coverage and payment issues to the discussion: home mechanical ventilation, payment for high flow oxygen therapy, and site of service/Section 603 issues.
Home mechanical ventilation is admittedly a complex issue, but it is moving forward in at least two political directions. First, Senator Bill Cassidy (R-LA) and a physician by training, has signaled his desire to move this issue forward, either legislatively or giving CMS one last chance to move forward through the regulatory structure. He agrees that a payment system that inhibits access to appropriate bi-level mechanical ventilators and encourages access to more complex life-sustaining ventilators, regardless of documented medical need, is appropriate. While CMS does have the authority to act, it has chosen to ignore repeated requests for action over the past 4 years.
Ironically, the House Energy and Commerce Committee, which shares jurisdiction on the House of Representatives with the Ways and Means Committee on Medicare issues, has sent a request to the Congressional Budget Office to provide a cost estimate (a “score” in Washington vernacular) of likely savings from a legislative solution to this matter. In the current political climate, a legislative proposal that actually saves $$$ is politically attractive, and we are working both the regulatory and legislative pathway to seek a workable solution.
On the oxygen therapy issue, there is growing evidence that, for a small group of Medicare beneficiaries who need high flow oxygen therapy as their disease progresses (pulmonary fibrosis, end-stage COPD, etc), there are no oxygen systems readily available to meet that need outside the home. At home, numerous concentrators can meet that need, but outside the home, the ideal solution, liquid systems, is not readily available because of the payment system tied to competitive bidding. CMS payment data indicate that a very low percentage of oxygen users need more than 4 liters per minute, and current law would make a payment adjustment unique to certain patients a very difficult hurdle, particularly in the era of competitive bidding, a legislative change is the best solution facing the community. The challenge is to craft legislative language that addresses the need but would preclude abuse by suppliers who might jump at the chance for higher payment for liquid, well above current payment levels. And because liquid systems fit into a “delivery model” business plan, contrary to portable oxygen concentrators and transfill systems, the solution is not as easy as a payment bump to make provision of liquid systems more attractive.
Site of service regulations are hitting pulmonary rehabilitation particularly hard, and CMS concedes that the only solution is a legislative one. Under current policy, a pulmonary rehab program that is located off campus but needs to expand or move from its current location (losing a lease, for example), if the expanded program is NOT within 250 yards of the main hospital campus, the program is then reimbursed at the physician fee schedule rate, a rate cut of approximately 50%. Needless to say, hospitals are not pursuing that approach. Likewise, a hospital that chooses to open a NEW program is also constrained, needing to locate within 250 yards of the main campus or face the dramatic cut in payment.
As these issues evolve and the political climate perhaps opens unique opportunities, we can expect the broad pulmonary community to pursue these and other issues.
CHEST Foundation Champions
Champion…. You ARE A CHAMPION for your patients, and as a CHEST Foundation supporter, you are a Champion for Lung Health! These words are now staples in our foundation mission. To champion lung health through clinical research and community service grants, patient education, and community service, the impact your support can have is quite profound. You are a part of an elite group to be called “champions,” and you should be celebrated for all the ways that you have championed lung health in 2017.
- YOU funded more than a half-million dollars in community service grants awarded to the next generation of CHEST leaders.
- YOU educated MILLIONS by supporting nationwide disease awareness campaigns for COPD, asthma, sarcoidosis, and lung cancer.
- YOU brought the Lung Health Experience to communities where over 1,000 people received COPD and asthma education, as well as spirometry screening.
- YOU created awareness in rare disease spaces and raised crucial support by partnering with family foundations, such as the Irv Family Foundation.
- The reach of these activities in 2017 has been astounding, and YOU, as a champion for lung health, have generated a great impact on the chest medicine community and the patients we serve.
- Now, the CHEST Foundation asks YOU to join us and support our efforts for 2018 by giving to the CHEST Foundation Annual Fund today. We ask you to help:
- Meet our fundraising goal of $700,000 for new clinical research and community service grants.
- Support NEW lung health disease awareness campaigns.
- Expand family foundation partnerships to create NEW patient resources.
- Provide NEW e-learning modules to aide patients and caregivers in managing health.
Your support today makes possible tomorrow’s advances in lung health and chest medicine. YOU believe in patient outcomes and, for that commitment, we graciously thank you. YOU save lives by supporting clinical research, patient education, and community service.
Be THE Champion for Lung Health that patients and families count on, and make an impact today. YOU can be a champion and DONATE today through a new gift to the CHEST Foundation. We cannot meet our goals for the health professionals, patients, families, and caregivers we serve without you.
Thank you for your essential continued support!
Champion…. You ARE A CHAMPION for your patients, and as a CHEST Foundation supporter, you are a Champion for Lung Health! These words are now staples in our foundation mission. To champion lung health through clinical research and community service grants, patient education, and community service, the impact your support can have is quite profound. You are a part of an elite group to be called “champions,” and you should be celebrated for all the ways that you have championed lung health in 2017.
- YOU funded more than a half-million dollars in community service grants awarded to the next generation of CHEST leaders.
- YOU educated MILLIONS by supporting nationwide disease awareness campaigns for COPD, asthma, sarcoidosis, and lung cancer.
- YOU brought the Lung Health Experience to communities where over 1,000 people received COPD and asthma education, as well as spirometry screening.
- YOU created awareness in rare disease spaces and raised crucial support by partnering with family foundations, such as the Irv Family Foundation.
- The reach of these activities in 2017 has been astounding, and YOU, as a champion for lung health, have generated a great impact on the chest medicine community and the patients we serve.
- Now, the CHEST Foundation asks YOU to join us and support our efforts for 2018 by giving to the CHEST Foundation Annual Fund today. We ask you to help:
- Meet our fundraising goal of $700,000 for new clinical research and community service grants.
- Support NEW lung health disease awareness campaigns.
- Expand family foundation partnerships to create NEW patient resources.
- Provide NEW e-learning modules to aide patients and caregivers in managing health.
Your support today makes possible tomorrow’s advances in lung health and chest medicine. YOU believe in patient outcomes and, for that commitment, we graciously thank you. YOU save lives by supporting clinical research, patient education, and community service.
Be THE Champion for Lung Health that patients and families count on, and make an impact today. YOU can be a champion and DONATE today through a new gift to the CHEST Foundation. We cannot meet our goals for the health professionals, patients, families, and caregivers we serve without you.
Thank you for your essential continued support!
Champion…. You ARE A CHAMPION for your patients, and as a CHEST Foundation supporter, you are a Champion for Lung Health! These words are now staples in our foundation mission. To champion lung health through clinical research and community service grants, patient education, and community service, the impact your support can have is quite profound. You are a part of an elite group to be called “champions,” and you should be celebrated for all the ways that you have championed lung health in 2017.
- YOU funded more than a half-million dollars in community service grants awarded to the next generation of CHEST leaders.
- YOU educated MILLIONS by supporting nationwide disease awareness campaigns for COPD, asthma, sarcoidosis, and lung cancer.
- YOU brought the Lung Health Experience to communities where over 1,000 people received COPD and asthma education, as well as spirometry screening.
- YOU created awareness in rare disease spaces and raised crucial support by partnering with family foundations, such as the Irv Family Foundation.
- The reach of these activities in 2017 has been astounding, and YOU, as a champion for lung health, have generated a great impact on the chest medicine community and the patients we serve.
- Now, the CHEST Foundation asks YOU to join us and support our efforts for 2018 by giving to the CHEST Foundation Annual Fund today. We ask you to help:
- Meet our fundraising goal of $700,000 for new clinical research and community service grants.
- Support NEW lung health disease awareness campaigns.
- Expand family foundation partnerships to create NEW patient resources.
- Provide NEW e-learning modules to aide patients and caregivers in managing health.
Your support today makes possible tomorrow’s advances in lung health and chest medicine. YOU believe in patient outcomes and, for that commitment, we graciously thank you. YOU save lives by supporting clinical research, patient education, and community service.
Be THE Champion for Lung Health that patients and families count on, and make an impact today. YOU can be a champion and DONATE today through a new gift to the CHEST Foundation. We cannot meet our goals for the health professionals, patients, families, and caregivers we serve without you.
Thank you for your essential continued support!
The rise and fall of treatment trials in group 3 pulmonary hypertension: Where do we go from here?
Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).
Group 3 PH – The rationale to treat
Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.
Previous studies of pulmonary vasodilator therapy for group 3 PH
Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).
The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
Hot off the presses – RISE-IIP
The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.
To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.
The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
RISE’ing from the ashes – Where do we go from here?
So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.
The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.
Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).
Group 3 PH – The rationale to treat
Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.
Previous studies of pulmonary vasodilator therapy for group 3 PH
Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).
The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
Hot off the presses – RISE-IIP
The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.
To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.
The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
RISE’ing from the ashes – Where do we go from here?
So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.
The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.
Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).
Group 3 PH – The rationale to treat
Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.
Previous studies of pulmonary vasodilator therapy for group 3 PH
Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).
The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
Hot off the presses – RISE-IIP
The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.
To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.
The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
RISE’ing from the ashes – Where do we go from here?
So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.
The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.
ABIM to allow do-overs for all subspecialties with Knowledge Check-In
ABIM previously announced that, beginning in 2018, physicians taking the Knowledge Check-In in 2018 would get another chance to take it in 2 years if they were unsuccessful, even if they were due to pass the maintenance of certification (MOC) exam later that year. In 2018, Knowledge Check-Ins will be offered in internal medicine and nephrology.
“Based on feedback ABIM has received from the physician community, we are happy to let you know that we are extending this policy to include all other internal medicine subspecialties in the future,” ABIM said in a Dec. 4 announcement on its website. “This means that if a physician takes the Knowledge Check-In in the first year it is offered in their subspecialty and is unsuccessful, they will get at least one additional opportunity to take and pass it 2 years later.”
The Knowledge Check-In is an alternative to the traditional MOC process, and is administered every 2 years rather than the standard decade between MOC exams. ABIM noted that a single failure on a Knowledge Check-In will not result in a status change to a physician’s certification status.
Separately, ABIM also announced that it will continue to make practice assessment activities (part IV of the MOC program) a part of the portfolio of options that can be used to satisfy MOC requirements.
“Our intent is to support physicians completing MOC activities that are most meaningful to their practice, including those that enhance and improve medical knowledge, as well as many existing quality improvement activities, and those that blend both,” ABIM said in its announcement.
ABIM previously announced that, beginning in 2018, physicians taking the Knowledge Check-In in 2018 would get another chance to take it in 2 years if they were unsuccessful, even if they were due to pass the maintenance of certification (MOC) exam later that year. In 2018, Knowledge Check-Ins will be offered in internal medicine and nephrology.
“Based on feedback ABIM has received from the physician community, we are happy to let you know that we are extending this policy to include all other internal medicine subspecialties in the future,” ABIM said in a Dec. 4 announcement on its website. “This means that if a physician takes the Knowledge Check-In in the first year it is offered in their subspecialty and is unsuccessful, they will get at least one additional opportunity to take and pass it 2 years later.”
The Knowledge Check-In is an alternative to the traditional MOC process, and is administered every 2 years rather than the standard decade between MOC exams. ABIM noted that a single failure on a Knowledge Check-In will not result in a status change to a physician’s certification status.
Separately, ABIM also announced that it will continue to make practice assessment activities (part IV of the MOC program) a part of the portfolio of options that can be used to satisfy MOC requirements.
“Our intent is to support physicians completing MOC activities that are most meaningful to their practice, including those that enhance and improve medical knowledge, as well as many existing quality improvement activities, and those that blend both,” ABIM said in its announcement.
ABIM previously announced that, beginning in 2018, physicians taking the Knowledge Check-In in 2018 would get another chance to take it in 2 years if they were unsuccessful, even if they were due to pass the maintenance of certification (MOC) exam later that year. In 2018, Knowledge Check-Ins will be offered in internal medicine and nephrology.
“Based on feedback ABIM has received from the physician community, we are happy to let you know that we are extending this policy to include all other internal medicine subspecialties in the future,” ABIM said in a Dec. 4 announcement on its website. “This means that if a physician takes the Knowledge Check-In in the first year it is offered in their subspecialty and is unsuccessful, they will get at least one additional opportunity to take and pass it 2 years later.”
The Knowledge Check-In is an alternative to the traditional MOC process, and is administered every 2 years rather than the standard decade between MOC exams. ABIM noted that a single failure on a Knowledge Check-In will not result in a status change to a physician’s certification status.
Separately, ABIM also announced that it will continue to make practice assessment activities (part IV of the MOC program) a part of the portfolio of options that can be used to satisfy MOC requirements.
“Our intent is to support physicians completing MOC activities that are most meaningful to their practice, including those that enhance and improve medical knowledge, as well as many existing quality improvement activities, and those that blend both,” ABIM said in its announcement.
Intranasal insulin, ketogenic diet may benefit Alzheimer’s patients
LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that
In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.
When that process goes awry, several pathologic processes linking insulin resistance (IR) and Alzheimer’s disease occur, including impaired proteostasis (oligomeric beta amyloid, microtubule-associated tau, and oligomeric insulin); hyperglycemia-induced toxicity and reduced glucose utilization; mitochondrial dysfunction; and vascular dysfunction, Dr. Craft continued.
In the past 5 years, researchers have developed ways to measure expression levels of insulin resistance markers like insulin receptor substrate 1 (IRS-1) pSer–positive neurons, Dr. Craft said. Others have found that increased IRS-1 pSer is associated with paired helical filaments (PHFs) tau in mild cognitive impairment (MCI) and AD, and that increased IRS-1 pSer in neutrally derived plasma exomes increased in AD years before onset and in type 2 diabetes. “We can look at the neurons themselves and what we see is that this IR marker colocalizes with tau,” Dr. Craft said. “It’s not very common in normal folks, but as you progress through the stages of MCI to AD, it becomes more common. So there’s a progressive increase in IR markers that associates with neurons in tau.” Other imaging studies have shown that homeostatic model assessment IR predicts gray matter atrophy, reduced blood flow, and amyloid deposition in middle-aged adults.
One way to overcome IR in AD is to increase insulin availability in the brain. Intranasal administration of insulin is a novel method being tested by Dr. Craft and her associates. “This is not inhaled insulin; it does not target the lungs,” she explained. “It’s insulin administered with a very specialized device that targets the olfactory cleft in the upper nasal passages. Virtually none of the insulin is deposited in the lungs or nasopharyngeally.” The approach is modeled on the notion that there are pathways from the olfactory perivascular spaces to the brain by which peptides can travel readily by bulk flow. “They reach the brain within minutes,” she said. “It’s a way of delivering peptides to the brain that bypasses the blood-brain barrier.”
In a published study, she and her associates randomized 104 adults with MCI or AD to receive 20 IU insulin, 40 IU insulin, or placebo twice daily for 4 months (Arch Neurol. 2012;61[1]:29-38). Tests performed at baseline and at 4 months included cognitive evaluation based on story recall and the ADAS-Cog (Alzheimer’s Disease Assessment Scale–Cognitive subscale); function based on the Dementia Rating Severity Scale, FDG-PET (positron emission tomography with 18fluorodeoxyglucose), and cerebrospinal fluid biomarkers. “We showed that the 20-IU dose of intranasal insulin improved memory quite substantially (P less than .05),” Dr. Craft said. “It also improved glucose utilization as assessed by FDG-PET. We also saw changes in spinal fluid biomarkers of amyloid in a favorable direction. Most recently, we looked at the exosomal indicator of IR (IRS-1 pSer), and what we saw quite remarkably was a reduction in the same condition that the memory improved. This gives us hope that we have a marker of whether or not we’re having a positive impact.”
She and her research team recently finished a phase 2 pilot study of regular insulin vs. long-acting insulin detemir, to determine if a longer-acting agent with longer exposure would have greater efficacy (J Alzheimers Dis. 2017;57[4]:1325–34). In all, 36 participants were randomized to receive placebo, 40 IU of insulin detemir, or 40 IU of regular insulin daily for 4 months, administered with a nasal delivery device. The investigators found that only the group treated with 40 IU regular insulin had better memory after 2 and 4 months, compared with placebo (P less than .03). Regular insulin treatment was also associated with preserved volume on MRI. “The normal pattern is for AD patients to lose brain volume rather rapidly,” Dr. Craft commented. “We see that abolished by the insulin treatment, which suggests to us that we’re able to stave off this disease-related mechanism.” She and her associates are currently conducting a phase 3 clinical trial with regular insulin and a phase 3 trial with rapid-acting insulin that are expected to be completed in the summer of 2018.
Dr. Craft spent the last few minutes of her presentation discussing the ketogenic diet as a nonpharmacologic approach to preventing or treating brain insulin resistance and AD. “I think the power of diet is underestimated, both in terms of causing disease and potentially modulating it,” she said. Her research team just completed a study of 87 middle-aged adults who were randomized to a Western diet or a healthy diet. The Western diet was high in saturated fat, sugar, and salt. The healthy diet was low in saturated fat, sugar, and salt, but the macronutrient composition of both diets was the same. “It was a eucaloric diet with normal calorie intake; no weight change, so trying to understand the integrated effect of the Western diet,” she said. “All food was prepared by us and delivered to the patients two times per week.” Patients with type 2 diabetes, patients with hypertension, and those who were on statins were excluded from the study.
The researchers observed pronounced diet-induced changes in cerebral blood flow, all which favored the healthy diet group. “The Western diet reduced blood flow, and the healthy diet increased blood blow in the hippocampus, which is critical for memory, as in some other regions that are known to be affected in AD,” Dr. Craft said. “We saw an effect on memory as well, with the healthy diet improving memory and the Western diet reducing it. Both of these effects were significant, so 4 weeks on a diet such as this is sufficient to modulate key aspects of brain function.”
More recently, Dr. Craft and her colleagues have been evaluating the effects of what they term the modified Mediterranean ketogenic diet (MMKD). “It does allow for higher carbohydrate consumption, compared with a traditional ketogenic diet, but they still have to stay under 10% a day,” she said. “We have an emphasis on healthy fats. We send everybody home with extra virgin olive oil. We think it gives us extra compliance and the potential for long-term nutrition.” She explained that the diet increases plasma and CNS ketone bodies, beta-hydroxybutyrate, acetoacetate, and acetone, which serves as preferred alternative fuel for the brain. “If the brain has a choice between glucose and ketones, it will choose ketones,” Dr. Craft said. “It can use them more easily.”
Ketone bodies are derived from hepatic fatty acid oxidation and readily diffuse across the blood-brain barrier into the brain. They are also synthesized in the brain by astrocytes, and they appear to have direct neuroprotective effects. “Ketone bodies may be beneficial because they may correct the hyperglycemic state and reduce glucose utilization in the brain in AD years prior to symptom onset,” Dr. Craft said. “They may correct neuronal hyperexcitability and preclinical seizures in presymptomatic and early stages of AD; they restore the balance between inhibitory and excitatory neurotransmitters like GABA [gamma-aminobutyric acid] and glutamate.”
In an unpublished, 16-week study, Dr. Craft and her associates randomized 16 patients to a Mediterranean ketogenic diet or to an American Heart Association low-fat diet. Lumbar punctures and brain imaging were performed before and after diet intervention. By the end of 6 weeks, they observed significant increases in ketones and in HDL cholesterol level in the MMKD group, compared with the AHA diet group, as well as significant decreases in trigylcerides and HbA1c level. “I would say that we improved the peripheral metabolic profile with the ketogenic diet,” Dr. Craft said. They also observed significant improvements from baseline in memory, spinal fluid AD biomarkers, and mitochondrial respiration.
“One of the things we’re appreciating is the role of insulin in a host of activities in the brain,” she concluded. “Disrupting those activities can have dire consequences on brain function that may lead to a neurological milieu that lends itself to pathological aging conditions like Alzheimer’s. Several large ongoing trials are poised to validate results of smaller studies, elucidate underlying mechanisms, and provide new therapeutic targets. It’s an exciting time.”
Dr. Craft’s research is supported by the National Institute on Aging and the Alzheimer’s Association Zenith Program. Intranasal delivery devices were provided by Kurve Technology.
LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that
In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.
When that process goes awry, several pathologic processes linking insulin resistance (IR) and Alzheimer’s disease occur, including impaired proteostasis (oligomeric beta amyloid, microtubule-associated tau, and oligomeric insulin); hyperglycemia-induced toxicity and reduced glucose utilization; mitochondrial dysfunction; and vascular dysfunction, Dr. Craft continued.
In the past 5 years, researchers have developed ways to measure expression levels of insulin resistance markers like insulin receptor substrate 1 (IRS-1) pSer–positive neurons, Dr. Craft said. Others have found that increased IRS-1 pSer is associated with paired helical filaments (PHFs) tau in mild cognitive impairment (MCI) and AD, and that increased IRS-1 pSer in neutrally derived plasma exomes increased in AD years before onset and in type 2 diabetes. “We can look at the neurons themselves and what we see is that this IR marker colocalizes with tau,” Dr. Craft said. “It’s not very common in normal folks, but as you progress through the stages of MCI to AD, it becomes more common. So there’s a progressive increase in IR markers that associates with neurons in tau.” Other imaging studies have shown that homeostatic model assessment IR predicts gray matter atrophy, reduced blood flow, and amyloid deposition in middle-aged adults.
One way to overcome IR in AD is to increase insulin availability in the brain. Intranasal administration of insulin is a novel method being tested by Dr. Craft and her associates. “This is not inhaled insulin; it does not target the lungs,” she explained. “It’s insulin administered with a very specialized device that targets the olfactory cleft in the upper nasal passages. Virtually none of the insulin is deposited in the lungs or nasopharyngeally.” The approach is modeled on the notion that there are pathways from the olfactory perivascular spaces to the brain by which peptides can travel readily by bulk flow. “They reach the brain within minutes,” she said. “It’s a way of delivering peptides to the brain that bypasses the blood-brain barrier.”
In a published study, she and her associates randomized 104 adults with MCI or AD to receive 20 IU insulin, 40 IU insulin, or placebo twice daily for 4 months (Arch Neurol. 2012;61[1]:29-38). Tests performed at baseline and at 4 months included cognitive evaluation based on story recall and the ADAS-Cog (Alzheimer’s Disease Assessment Scale–Cognitive subscale); function based on the Dementia Rating Severity Scale, FDG-PET (positron emission tomography with 18fluorodeoxyglucose), and cerebrospinal fluid biomarkers. “We showed that the 20-IU dose of intranasal insulin improved memory quite substantially (P less than .05),” Dr. Craft said. “It also improved glucose utilization as assessed by FDG-PET. We also saw changes in spinal fluid biomarkers of amyloid in a favorable direction. Most recently, we looked at the exosomal indicator of IR (IRS-1 pSer), and what we saw quite remarkably was a reduction in the same condition that the memory improved. This gives us hope that we have a marker of whether or not we’re having a positive impact.”
She and her research team recently finished a phase 2 pilot study of regular insulin vs. long-acting insulin detemir, to determine if a longer-acting agent with longer exposure would have greater efficacy (J Alzheimers Dis. 2017;57[4]:1325–34). In all, 36 participants were randomized to receive placebo, 40 IU of insulin detemir, or 40 IU of regular insulin daily for 4 months, administered with a nasal delivery device. The investigators found that only the group treated with 40 IU regular insulin had better memory after 2 and 4 months, compared with placebo (P less than .03). Regular insulin treatment was also associated with preserved volume on MRI. “The normal pattern is for AD patients to lose brain volume rather rapidly,” Dr. Craft commented. “We see that abolished by the insulin treatment, which suggests to us that we’re able to stave off this disease-related mechanism.” She and her associates are currently conducting a phase 3 clinical trial with regular insulin and a phase 3 trial with rapid-acting insulin that are expected to be completed in the summer of 2018.
Dr. Craft spent the last few minutes of her presentation discussing the ketogenic diet as a nonpharmacologic approach to preventing or treating brain insulin resistance and AD. “I think the power of diet is underestimated, both in terms of causing disease and potentially modulating it,” she said. Her research team just completed a study of 87 middle-aged adults who were randomized to a Western diet or a healthy diet. The Western diet was high in saturated fat, sugar, and salt. The healthy diet was low in saturated fat, sugar, and salt, but the macronutrient composition of both diets was the same. “It was a eucaloric diet with normal calorie intake; no weight change, so trying to understand the integrated effect of the Western diet,” she said. “All food was prepared by us and delivered to the patients two times per week.” Patients with type 2 diabetes, patients with hypertension, and those who were on statins were excluded from the study.
The researchers observed pronounced diet-induced changes in cerebral blood flow, all which favored the healthy diet group. “The Western diet reduced blood flow, and the healthy diet increased blood blow in the hippocampus, which is critical for memory, as in some other regions that are known to be affected in AD,” Dr. Craft said. “We saw an effect on memory as well, with the healthy diet improving memory and the Western diet reducing it. Both of these effects were significant, so 4 weeks on a diet such as this is sufficient to modulate key aspects of brain function.”
More recently, Dr. Craft and her colleagues have been evaluating the effects of what they term the modified Mediterranean ketogenic diet (MMKD). “It does allow for higher carbohydrate consumption, compared with a traditional ketogenic diet, but they still have to stay under 10% a day,” she said. “We have an emphasis on healthy fats. We send everybody home with extra virgin olive oil. We think it gives us extra compliance and the potential for long-term nutrition.” She explained that the diet increases plasma and CNS ketone bodies, beta-hydroxybutyrate, acetoacetate, and acetone, which serves as preferred alternative fuel for the brain. “If the brain has a choice between glucose and ketones, it will choose ketones,” Dr. Craft said. “It can use them more easily.”
Ketone bodies are derived from hepatic fatty acid oxidation and readily diffuse across the blood-brain barrier into the brain. They are also synthesized in the brain by astrocytes, and they appear to have direct neuroprotective effects. “Ketone bodies may be beneficial because they may correct the hyperglycemic state and reduce glucose utilization in the brain in AD years prior to symptom onset,” Dr. Craft said. “They may correct neuronal hyperexcitability and preclinical seizures in presymptomatic and early stages of AD; they restore the balance between inhibitory and excitatory neurotransmitters like GABA [gamma-aminobutyric acid] and glutamate.”
In an unpublished, 16-week study, Dr. Craft and her associates randomized 16 patients to a Mediterranean ketogenic diet or to an American Heart Association low-fat diet. Lumbar punctures and brain imaging were performed before and after diet intervention. By the end of 6 weeks, they observed significant increases in ketones and in HDL cholesterol level in the MMKD group, compared with the AHA diet group, as well as significant decreases in trigylcerides and HbA1c level. “I would say that we improved the peripheral metabolic profile with the ketogenic diet,” Dr. Craft said. They also observed significant improvements from baseline in memory, spinal fluid AD biomarkers, and mitochondrial respiration.
“One of the things we’re appreciating is the role of insulin in a host of activities in the brain,” she concluded. “Disrupting those activities can have dire consequences on brain function that may lead to a neurological milieu that lends itself to pathological aging conditions like Alzheimer’s. Several large ongoing trials are poised to validate results of smaller studies, elucidate underlying mechanisms, and provide new therapeutic targets. It’s an exciting time.”
Dr. Craft’s research is supported by the National Institute on Aging and the Alzheimer’s Association Zenith Program. Intranasal delivery devices were provided by Kurve Technology.
LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that
In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.
When that process goes awry, several pathologic processes linking insulin resistance (IR) and Alzheimer’s disease occur, including impaired proteostasis (oligomeric beta amyloid, microtubule-associated tau, and oligomeric insulin); hyperglycemia-induced toxicity and reduced glucose utilization; mitochondrial dysfunction; and vascular dysfunction, Dr. Craft continued.
In the past 5 years, researchers have developed ways to measure expression levels of insulin resistance markers like insulin receptor substrate 1 (IRS-1) pSer–positive neurons, Dr. Craft said. Others have found that increased IRS-1 pSer is associated with paired helical filaments (PHFs) tau in mild cognitive impairment (MCI) and AD, and that increased IRS-1 pSer in neutrally derived plasma exomes increased in AD years before onset and in type 2 diabetes. “We can look at the neurons themselves and what we see is that this IR marker colocalizes with tau,” Dr. Craft said. “It’s not very common in normal folks, but as you progress through the stages of MCI to AD, it becomes more common. So there’s a progressive increase in IR markers that associates with neurons in tau.” Other imaging studies have shown that homeostatic model assessment IR predicts gray matter atrophy, reduced blood flow, and amyloid deposition in middle-aged adults.
One way to overcome IR in AD is to increase insulin availability in the brain. Intranasal administration of insulin is a novel method being tested by Dr. Craft and her associates. “This is not inhaled insulin; it does not target the lungs,” she explained. “It’s insulin administered with a very specialized device that targets the olfactory cleft in the upper nasal passages. Virtually none of the insulin is deposited in the lungs or nasopharyngeally.” The approach is modeled on the notion that there are pathways from the olfactory perivascular spaces to the brain by which peptides can travel readily by bulk flow. “They reach the brain within minutes,” she said. “It’s a way of delivering peptides to the brain that bypasses the blood-brain barrier.”
In a published study, she and her associates randomized 104 adults with MCI or AD to receive 20 IU insulin, 40 IU insulin, or placebo twice daily for 4 months (Arch Neurol. 2012;61[1]:29-38). Tests performed at baseline and at 4 months included cognitive evaluation based on story recall and the ADAS-Cog (Alzheimer’s Disease Assessment Scale–Cognitive subscale); function based on the Dementia Rating Severity Scale, FDG-PET (positron emission tomography with 18fluorodeoxyglucose), and cerebrospinal fluid biomarkers. “We showed that the 20-IU dose of intranasal insulin improved memory quite substantially (P less than .05),” Dr. Craft said. “It also improved glucose utilization as assessed by FDG-PET. We also saw changes in spinal fluid biomarkers of amyloid in a favorable direction. Most recently, we looked at the exosomal indicator of IR (IRS-1 pSer), and what we saw quite remarkably was a reduction in the same condition that the memory improved. This gives us hope that we have a marker of whether or not we’re having a positive impact.”
She and her research team recently finished a phase 2 pilot study of regular insulin vs. long-acting insulin detemir, to determine if a longer-acting agent with longer exposure would have greater efficacy (J Alzheimers Dis. 2017;57[4]:1325–34). In all, 36 participants were randomized to receive placebo, 40 IU of insulin detemir, or 40 IU of regular insulin daily for 4 months, administered with a nasal delivery device. The investigators found that only the group treated with 40 IU regular insulin had better memory after 2 and 4 months, compared with placebo (P less than .03). Regular insulin treatment was also associated with preserved volume on MRI. “The normal pattern is for AD patients to lose brain volume rather rapidly,” Dr. Craft commented. “We see that abolished by the insulin treatment, which suggests to us that we’re able to stave off this disease-related mechanism.” She and her associates are currently conducting a phase 3 clinical trial with regular insulin and a phase 3 trial with rapid-acting insulin that are expected to be completed in the summer of 2018.
Dr. Craft spent the last few minutes of her presentation discussing the ketogenic diet as a nonpharmacologic approach to preventing or treating brain insulin resistance and AD. “I think the power of diet is underestimated, both in terms of causing disease and potentially modulating it,” she said. Her research team just completed a study of 87 middle-aged adults who were randomized to a Western diet or a healthy diet. The Western diet was high in saturated fat, sugar, and salt. The healthy diet was low in saturated fat, sugar, and salt, but the macronutrient composition of both diets was the same. “It was a eucaloric diet with normal calorie intake; no weight change, so trying to understand the integrated effect of the Western diet,” she said. “All food was prepared by us and delivered to the patients two times per week.” Patients with type 2 diabetes, patients with hypertension, and those who were on statins were excluded from the study.
The researchers observed pronounced diet-induced changes in cerebral blood flow, all which favored the healthy diet group. “The Western diet reduced blood flow, and the healthy diet increased blood blow in the hippocampus, which is critical for memory, as in some other regions that are known to be affected in AD,” Dr. Craft said. “We saw an effect on memory as well, with the healthy diet improving memory and the Western diet reducing it. Both of these effects were significant, so 4 weeks on a diet such as this is sufficient to modulate key aspects of brain function.”
More recently, Dr. Craft and her colleagues have been evaluating the effects of what they term the modified Mediterranean ketogenic diet (MMKD). “It does allow for higher carbohydrate consumption, compared with a traditional ketogenic diet, but they still have to stay under 10% a day,” she said. “We have an emphasis on healthy fats. We send everybody home with extra virgin olive oil. We think it gives us extra compliance and the potential for long-term nutrition.” She explained that the diet increases plasma and CNS ketone bodies, beta-hydroxybutyrate, acetoacetate, and acetone, which serves as preferred alternative fuel for the brain. “If the brain has a choice between glucose and ketones, it will choose ketones,” Dr. Craft said. “It can use them more easily.”
Ketone bodies are derived from hepatic fatty acid oxidation and readily diffuse across the blood-brain barrier into the brain. They are also synthesized in the brain by astrocytes, and they appear to have direct neuroprotective effects. “Ketone bodies may be beneficial because they may correct the hyperglycemic state and reduce glucose utilization in the brain in AD years prior to symptom onset,” Dr. Craft said. “They may correct neuronal hyperexcitability and preclinical seizures in presymptomatic and early stages of AD; they restore the balance between inhibitory and excitatory neurotransmitters like GABA [gamma-aminobutyric acid] and glutamate.”
In an unpublished, 16-week study, Dr. Craft and her associates randomized 16 patients to a Mediterranean ketogenic diet or to an American Heart Association low-fat diet. Lumbar punctures and brain imaging were performed before and after diet intervention. By the end of 6 weeks, they observed significant increases in ketones and in HDL cholesterol level in the MMKD group, compared with the AHA diet group, as well as significant decreases in trigylcerides and HbA1c level. “I would say that we improved the peripheral metabolic profile with the ketogenic diet,” Dr. Craft said. They also observed significant improvements from baseline in memory, spinal fluid AD biomarkers, and mitochondrial respiration.
“One of the things we’re appreciating is the role of insulin in a host of activities in the brain,” she concluded. “Disrupting those activities can have dire consequences on brain function that may lead to a neurological milieu that lends itself to pathological aging conditions like Alzheimer’s. Several large ongoing trials are poised to validate results of smaller studies, elucidate underlying mechanisms, and provide new therapeutic targets. It’s an exciting time.”
Dr. Craft’s research is supported by the National Institute on Aging and the Alzheimer’s Association Zenith Program. Intranasal delivery devices were provided by Kurve Technology.
AT WCIRDC 2017