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OSA home testing less expensive than polysomnography
Home respiratory polygraphy had similar efficacy with substantially lower per-patient cost, compared with traditional polysomnography for diagnosing obstructive sleep apnea, a study showed.
Obstructive sleep apnea (OSA) is a common chronic disease associated with higher risk of cardiovascular disease and traffic accidents and a lower quality of life. Although expensive and time intensive, the polysomnography (PSG) has been the preferred test for diagnosing OSA. Home respiratory polygraphy (HRP) uses portable devices that are less complex than polysomnography and has been shown to have similar effectiveness in diagnosing OSA, compared with PSG, in patients with a high clinical suspicion of OSA. However, there is limited evidence for the cost effectiveness of HRP, compared with PSG (Am J Respir Crit Care Med. 2017 Nov 1;196[9]:1181-90).
The investigators conducted a multicenter, randomized controlled, noninferiority trial and cost-effectiveness analysis comparing PSG with HRP. Inclusion criteria included snoring or observed sleep apnea, Epworth Sleepiness Scale (ESS)of 10 or higher, and no suspicion of alternative causes for daytime sleepiness. Patients with a suspicion for OSA were randomized to polysomnography or respiratory polygraphy protocols. Both arms received counseling on proper sleep hygiene; counseling on weight loss, if overweight; and auto-CPAP titration if continuous positive airway pressure (CPAP) was clinically indicated.
Assessment of CPAP compliance or dietary and sleep hygiene compliance was assessed at months 1 and 3. ESS, quality of life measures, well-being measures, 24-hour blood pressure monitoring, auto accidents, and cardiovascular events were assessed at baseline and at month 6.
CPAP treatment was indicated in 68% of the PSG arm, compared with 53% of the HRP arm. After intention-to-treat analysis, there was no statistically significant difference between the two groups for ESS improvement (HRP mean, –4.2, vs. PSG mean, –4.9; P = .14). The groups demonstrated similar results for quality of life, blood pressure, polysomnographic assessment at 6 months, CPAP compliance, and rates of cardiovascular events and accidents at follow-up.
The cost-effective analysis demonstrated respiratory polygraphy was less expensive, saving more than 400 euros/patient. “Because the effectiveness (ESS and QALYs [quality-adjusted life-years]) was similar between arms, the HRP protocol is preferable due to its lower cost,” the authors wrote.
In all, 430 patients were randomized to HRP or PSG and consisted mostly of men (70.5%) with a mean body mass index of 30.7 kg/m2. The groups had similar rates of alcohol consumption and hypertension.
Limitations of the study included unblinded randomization to the participants and researchers and the possibility of variability in therapeutic decisions. However, the authors noted that intraobserver variability was minimized by using the Spanish Sleep Network guidelines and centralized assessment.
“[The] HRP management protocol is not inferior to PSG and presents substantially lower costs. Therefore, PSG is not necessary for most patients with suspicion of OSA. This finding could change established clinical practice, with a clear economic benefit,” the authors concluded.
Home respiratory polygraphy continues to impress
This study adds strong evidence to support the use of home respiratory polygraphy for the diagnosis of obstructive sleep apnea in patients without major comorbidities such as severe chronic restrictive or obstructive lung disease, heart failure or unstable cardiovascular disease, major psychiatric diagnoses, and neuromuscular conditions, noted Ching Li Chai-Coetzer, MBBS, PhD, and R.
Doug McEvoy, MBBS, MD, in an accompanying editorial (Am J Respir Crit Care Med. 2017 Nov 1;196[9]:1096-8). However, lower-cost methods to diagnose OSA would still not address unmet needs such as the cost of continuous positive airway pressure and scarcity of sleep physicians to assess patients with OSA, and still may be too expensive for underresourced populations, they said.
Dr. Chai-Coetzer and Dr. McEvoy are affiliated with the Adelaide Institute for Sleep Health at Flinders University and the Sleep Health Service, Southern Adelaide Local Health Network, both in South Australia.
The study was supported by Sociedad Española de Neumología, Air Liquide (Spain), Asociacion de Neumologos del Sur, and Sociedad Extremeña de Neumología. The investigators report no disclosures.
Dr. Chai-Coetzer reported grants from National Health and Medical Research Council of Australia and nonfinancial support from Biotech Pharmaceuticals. Dr. McEvoy reported grants and nonfinancial support from Philips Respironics, nonfinancial support from ResMed, and grants from Fisher & Paykel.
Home respiratory polygraphy had similar efficacy with substantially lower per-patient cost, compared with traditional polysomnography for diagnosing obstructive sleep apnea, a study showed.
Obstructive sleep apnea (OSA) is a common chronic disease associated with higher risk of cardiovascular disease and traffic accidents and a lower quality of life. Although expensive and time intensive, the polysomnography (PSG) has been the preferred test for diagnosing OSA. Home respiratory polygraphy (HRP) uses portable devices that are less complex than polysomnography and has been shown to have similar effectiveness in diagnosing OSA, compared with PSG, in patients with a high clinical suspicion of OSA. However, there is limited evidence for the cost effectiveness of HRP, compared with PSG (Am J Respir Crit Care Med. 2017 Nov 1;196[9]:1181-90).
The investigators conducted a multicenter, randomized controlled, noninferiority trial and cost-effectiveness analysis comparing PSG with HRP. Inclusion criteria included snoring or observed sleep apnea, Epworth Sleepiness Scale (ESS)of 10 or higher, and no suspicion of alternative causes for daytime sleepiness. Patients with a suspicion for OSA were randomized to polysomnography or respiratory polygraphy protocols. Both arms received counseling on proper sleep hygiene; counseling on weight loss, if overweight; and auto-CPAP titration if continuous positive airway pressure (CPAP) was clinically indicated.
Assessment of CPAP compliance or dietary and sleep hygiene compliance was assessed at months 1 and 3. ESS, quality of life measures, well-being measures, 24-hour blood pressure monitoring, auto accidents, and cardiovascular events were assessed at baseline and at month 6.
CPAP treatment was indicated in 68% of the PSG arm, compared with 53% of the HRP arm. After intention-to-treat analysis, there was no statistically significant difference between the two groups for ESS improvement (HRP mean, –4.2, vs. PSG mean, –4.9; P = .14). The groups demonstrated similar results for quality of life, blood pressure, polysomnographic assessment at 6 months, CPAP compliance, and rates of cardiovascular events and accidents at follow-up.
The cost-effective analysis demonstrated respiratory polygraphy was less expensive, saving more than 400 euros/patient. “Because the effectiveness (ESS and QALYs [quality-adjusted life-years]) was similar between arms, the HRP protocol is preferable due to its lower cost,” the authors wrote.
In all, 430 patients were randomized to HRP or PSG and consisted mostly of men (70.5%) with a mean body mass index of 30.7 kg/m2. The groups had similar rates of alcohol consumption and hypertension.
Limitations of the study included unblinded randomization to the participants and researchers and the possibility of variability in therapeutic decisions. However, the authors noted that intraobserver variability was minimized by using the Spanish Sleep Network guidelines and centralized assessment.
“[The] HRP management protocol is not inferior to PSG and presents substantially lower costs. Therefore, PSG is not necessary for most patients with suspicion of OSA. This finding could change established clinical practice, with a clear economic benefit,” the authors concluded.
Home respiratory polygraphy continues to impress
This study adds strong evidence to support the use of home respiratory polygraphy for the diagnosis of obstructive sleep apnea in patients without major comorbidities such as severe chronic restrictive or obstructive lung disease, heart failure or unstable cardiovascular disease, major psychiatric diagnoses, and neuromuscular conditions, noted Ching Li Chai-Coetzer, MBBS, PhD, and R.
Doug McEvoy, MBBS, MD, in an accompanying editorial (Am J Respir Crit Care Med. 2017 Nov 1;196[9]:1096-8). However, lower-cost methods to diagnose OSA would still not address unmet needs such as the cost of continuous positive airway pressure and scarcity of sleep physicians to assess patients with OSA, and still may be too expensive for underresourced populations, they said.
Dr. Chai-Coetzer and Dr. McEvoy are affiliated with the Adelaide Institute for Sleep Health at Flinders University and the Sleep Health Service, Southern Adelaide Local Health Network, both in South Australia.
The study was supported by Sociedad Española de Neumología, Air Liquide (Spain), Asociacion de Neumologos del Sur, and Sociedad Extremeña de Neumología. The investigators report no disclosures.
Dr. Chai-Coetzer reported grants from National Health and Medical Research Council of Australia and nonfinancial support from Biotech Pharmaceuticals. Dr. McEvoy reported grants and nonfinancial support from Philips Respironics, nonfinancial support from ResMed, and grants from Fisher & Paykel.
Home respiratory polygraphy had similar efficacy with substantially lower per-patient cost, compared with traditional polysomnography for diagnosing obstructive sleep apnea, a study showed.
Obstructive sleep apnea (OSA) is a common chronic disease associated with higher risk of cardiovascular disease and traffic accidents and a lower quality of life. Although expensive and time intensive, the polysomnography (PSG) has been the preferred test for diagnosing OSA. Home respiratory polygraphy (HRP) uses portable devices that are less complex than polysomnography and has been shown to have similar effectiveness in diagnosing OSA, compared with PSG, in patients with a high clinical suspicion of OSA. However, there is limited evidence for the cost effectiveness of HRP, compared with PSG (Am J Respir Crit Care Med. 2017 Nov 1;196[9]:1181-90).
The investigators conducted a multicenter, randomized controlled, noninferiority trial and cost-effectiveness analysis comparing PSG with HRP. Inclusion criteria included snoring or observed sleep apnea, Epworth Sleepiness Scale (ESS)of 10 or higher, and no suspicion of alternative causes for daytime sleepiness. Patients with a suspicion for OSA were randomized to polysomnography or respiratory polygraphy protocols. Both arms received counseling on proper sleep hygiene; counseling on weight loss, if overweight; and auto-CPAP titration if continuous positive airway pressure (CPAP) was clinically indicated.
Assessment of CPAP compliance or dietary and sleep hygiene compliance was assessed at months 1 and 3. ESS, quality of life measures, well-being measures, 24-hour blood pressure monitoring, auto accidents, and cardiovascular events were assessed at baseline and at month 6.
CPAP treatment was indicated in 68% of the PSG arm, compared with 53% of the HRP arm. After intention-to-treat analysis, there was no statistically significant difference between the two groups for ESS improvement (HRP mean, –4.2, vs. PSG mean, –4.9; P = .14). The groups demonstrated similar results for quality of life, blood pressure, polysomnographic assessment at 6 months, CPAP compliance, and rates of cardiovascular events and accidents at follow-up.
The cost-effective analysis demonstrated respiratory polygraphy was less expensive, saving more than 400 euros/patient. “Because the effectiveness (ESS and QALYs [quality-adjusted life-years]) was similar between arms, the HRP protocol is preferable due to its lower cost,” the authors wrote.
In all, 430 patients were randomized to HRP or PSG and consisted mostly of men (70.5%) with a mean body mass index of 30.7 kg/m2. The groups had similar rates of alcohol consumption and hypertension.
Limitations of the study included unblinded randomization to the participants and researchers and the possibility of variability in therapeutic decisions. However, the authors noted that intraobserver variability was minimized by using the Spanish Sleep Network guidelines and centralized assessment.
“[The] HRP management protocol is not inferior to PSG and presents substantially lower costs. Therefore, PSG is not necessary for most patients with suspicion of OSA. This finding could change established clinical practice, with a clear economic benefit,” the authors concluded.
Home respiratory polygraphy continues to impress
This study adds strong evidence to support the use of home respiratory polygraphy for the diagnosis of obstructive sleep apnea in patients without major comorbidities such as severe chronic restrictive or obstructive lung disease, heart failure or unstable cardiovascular disease, major psychiatric diagnoses, and neuromuscular conditions, noted Ching Li Chai-Coetzer, MBBS, PhD, and R.
Doug McEvoy, MBBS, MD, in an accompanying editorial (Am J Respir Crit Care Med. 2017 Nov 1;196[9]:1096-8). However, lower-cost methods to diagnose OSA would still not address unmet needs such as the cost of continuous positive airway pressure and scarcity of sleep physicians to assess patients with OSA, and still may be too expensive for underresourced populations, they said.
Dr. Chai-Coetzer and Dr. McEvoy are affiliated with the Adelaide Institute for Sleep Health at Flinders University and the Sleep Health Service, Southern Adelaide Local Health Network, both in South Australia.
The study was supported by Sociedad Española de Neumología, Air Liquide (Spain), Asociacion de Neumologos del Sur, and Sociedad Extremeña de Neumología. The investigators report no disclosures.
Dr. Chai-Coetzer reported grants from National Health and Medical Research Council of Australia and nonfinancial support from Biotech Pharmaceuticals. Dr. McEvoy reported grants and nonfinancial support from Philips Respironics, nonfinancial support from ResMed, and grants from Fisher & Paykel.
FROM THE AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Key clinical point: Home obstructive sleep apnea testing was less costly and noninferior to polysomnography.
Major finding: Using respiratory polygraphy instead of polysomnography results in savings of more than 400 euros/patient.
Data source: A multicenter, randomized controlled, noninferiority trial and cost-effectiveness analysis of 430 patients suspected of having OSA.
Disclosures: The study was supported by Sociedad Española de Neumología, Air Liquide (Spain), Asociacion de Neumologos del Sur, and Sociedad Extremeña de Neumología. The authors report no disclosures.
Neoantigen profiling predicts response to immunotherapy
In antitumor immunity and immunotherapy, quality and fitness count.
Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.
In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.
Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).
In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.
“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
Proof of concept
The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.
“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.
One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.
“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
Melanoma and lung cancer survivors
In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).
They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.
“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
Pancreatic cancer survivors
Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.
Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.
When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.
They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.
“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.
When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.
“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.
The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.
“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.
The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
In antitumor immunity and immunotherapy, quality and fitness count.
Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.
In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.
Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).
In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.
“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
Proof of concept
The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.
“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.
One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.
“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
Melanoma and lung cancer survivors
In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).
They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.
“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
Pancreatic cancer survivors
Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.
Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.
When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.
They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.
“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.
When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.
“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.
The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.
“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.
The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
In antitumor immunity and immunotherapy, quality and fitness count.
Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.
In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.
Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).
In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.
“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
Proof of concept
The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.
“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.
One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.
“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
Melanoma and lung cancer survivors
In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).
They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.
“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
Pancreatic cancer survivors
Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.
Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.
When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.
They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.
“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.
When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.
“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.
The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.
“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.
The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
FROM NATURE
Key clinical point: Proof-of-concept studies show that mathematical modeling of neoantigens can be used to predict tumor responses to immune checkpoint inhibitors.
Major finding: Neoantigen quality may be a better biomarker for guiding immunotherapy than tumor genomic profiling.
Data source: Basic science reports focusing on neoantigens and their potential influence on tumor interactions with the immune system.
Disclosures: The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
MedPAC offers more details of MIPS replacement
WASHINGTON – The Medicare Payment Advisory Commission continues to mull the specifics of its proposed recommendation to scrap the Quality Payment Program’s MIPS component.
The basics of the MIPS (Merit-based Incentive Payment System) replacement have not changed. The proposal calls for creation of a voluntary value program (VVP) that would withhold a percentage – currently 2% – of Medicare payments for physicians who are not part of an advanced alternative payment model (APM) under the Quality Payment Program of the Medicare Access and CHIP Reauthorization Act of 2015.
There would be two ways to recapture the withheld pay. The first would be to join an APM. The second would be to participate in a VVP by entering a voluntary reporting group. Under the proposal, VVPs would be at least 10 providers who would report together on population-based measures, patient experience, and cost measures, according to staff presentations given Nov. 2 at a meeting of the Medicare Payment Advisory Commission (MedPAC).
Proposed measures would be patient oriented, would encourage coordination across all providers, would promote positive change in the delivery system, and would be less burdensome to providers. Measures would be more in line with those employed by APMs – important because the overall goal would be encouraging participation in an APM rather than permanently lingering in the VVP.
To that end, MedPAC staff member Kate Bloniarz noted during the presentation of the VVP proposal that the total payments in the program “should be capped to be less attractive than joining an [advanced] APM. This comes from a general sense among commissioners that clinicians should not be able to receive large bonuses” for remaining in Medicare fee-for-service.
MedPAC staff recommended that the Centers for Medicare & Medicaid Services offer a fallback group that would provide an option to providers that would otherwise not have access to other groups to join.
Commission member Kathy Buto, former vice president of global health policy at Johnson & Johnson, suggested withholding be increased to perhaps 3%, with providers able to recoup 2% in the VVP and 3% in an APM, to further incentivize APM participation.
Staff noted that certain quality measures and process measures would be lost if MIPS were to go away, but they could be accounted for in other channels, such as through electronic health records and registries.
Most commissioners expressed support for both the repeal of MIPS and the conceptual framework for the new VVP, although many sought more details, particularly in the handling of specialists.
“I don’t know that we want to try to make the VVP do too much, especially when you get into the specialties that are very, very episodic,” said commission member Brian DeBusk, PhD, CEO of DeRoyal Industries. “The classic example would be a joint replacement. … I hope to see some specialist APMs developed in parallel and I think that is going to take some pressure off to try to make the VVP be all things to all people.”
Commission member Pat Wang, CEO of Healthfirst, offered a possible solution.
“I would suggest that we try to think about doing that in the context of something that is a little bit, perhaps, not full bore APM, but a VVP for specialists with their own metrics that are not big, gigantic readmissions,” she said. “Those are very broad population health metrics [that may not work for specialists].”
But at least two commission members voiced their dissent to the proposal as presented, with one going so far as to saying that MIPS should not be repealed.
David Nerenz, PhD, of the Henry Ford Health System, said that he had “very serious concerns about the VVP part of this proposal [and] they are such that if it comes to us as a recommendation in more or less its current form I will not support it.”
He called it “pretty significant social engineering in the structure of medical practice and I think we are doing it in the absence of what to me would be compelling evidence that this large group structure we are talking about is good.
“I also don’t see any evidence that beneficiaries find value in the set of measures we are talking about,” Dr. Nerenz added. He is on the record as supporting the repeal of MIPS.
Commission member Alice Coombs, MD, of Weymouth, Mass., was the lone voice speaking in support of MIPS: “I think MIPS has a lot of problems … but there are some things that are coming out of MIPS that are actually good.”
She called the VVP proposal “inadequate” and took issue with the measures. As a practicing physician, she said that she favors more population health measures that will affect patient outcomes.
MedPAC staff expect to have a draft recommendation prepared for discussion at the December meeting, with a final vote on what will be presented to Congress coming as soon as January.
WASHINGTON – The Medicare Payment Advisory Commission continues to mull the specifics of its proposed recommendation to scrap the Quality Payment Program’s MIPS component.
The basics of the MIPS (Merit-based Incentive Payment System) replacement have not changed. The proposal calls for creation of a voluntary value program (VVP) that would withhold a percentage – currently 2% – of Medicare payments for physicians who are not part of an advanced alternative payment model (APM) under the Quality Payment Program of the Medicare Access and CHIP Reauthorization Act of 2015.
There would be two ways to recapture the withheld pay. The first would be to join an APM. The second would be to participate in a VVP by entering a voluntary reporting group. Under the proposal, VVPs would be at least 10 providers who would report together on population-based measures, patient experience, and cost measures, according to staff presentations given Nov. 2 at a meeting of the Medicare Payment Advisory Commission (MedPAC).
Proposed measures would be patient oriented, would encourage coordination across all providers, would promote positive change in the delivery system, and would be less burdensome to providers. Measures would be more in line with those employed by APMs – important because the overall goal would be encouraging participation in an APM rather than permanently lingering in the VVP.
To that end, MedPAC staff member Kate Bloniarz noted during the presentation of the VVP proposal that the total payments in the program “should be capped to be less attractive than joining an [advanced] APM. This comes from a general sense among commissioners that clinicians should not be able to receive large bonuses” for remaining in Medicare fee-for-service.
MedPAC staff recommended that the Centers for Medicare & Medicaid Services offer a fallback group that would provide an option to providers that would otherwise not have access to other groups to join.
Commission member Kathy Buto, former vice president of global health policy at Johnson & Johnson, suggested withholding be increased to perhaps 3%, with providers able to recoup 2% in the VVP and 3% in an APM, to further incentivize APM participation.
Staff noted that certain quality measures and process measures would be lost if MIPS were to go away, but they could be accounted for in other channels, such as through electronic health records and registries.
Most commissioners expressed support for both the repeal of MIPS and the conceptual framework for the new VVP, although many sought more details, particularly in the handling of specialists.
“I don’t know that we want to try to make the VVP do too much, especially when you get into the specialties that are very, very episodic,” said commission member Brian DeBusk, PhD, CEO of DeRoyal Industries. “The classic example would be a joint replacement. … I hope to see some specialist APMs developed in parallel and I think that is going to take some pressure off to try to make the VVP be all things to all people.”
Commission member Pat Wang, CEO of Healthfirst, offered a possible solution.
“I would suggest that we try to think about doing that in the context of something that is a little bit, perhaps, not full bore APM, but a VVP for specialists with their own metrics that are not big, gigantic readmissions,” she said. “Those are very broad population health metrics [that may not work for specialists].”
But at least two commission members voiced their dissent to the proposal as presented, with one going so far as to saying that MIPS should not be repealed.
David Nerenz, PhD, of the Henry Ford Health System, said that he had “very serious concerns about the VVP part of this proposal [and] they are such that if it comes to us as a recommendation in more or less its current form I will not support it.”
He called it “pretty significant social engineering in the structure of medical practice and I think we are doing it in the absence of what to me would be compelling evidence that this large group structure we are talking about is good.
“I also don’t see any evidence that beneficiaries find value in the set of measures we are talking about,” Dr. Nerenz added. He is on the record as supporting the repeal of MIPS.
Commission member Alice Coombs, MD, of Weymouth, Mass., was the lone voice speaking in support of MIPS: “I think MIPS has a lot of problems … but there are some things that are coming out of MIPS that are actually good.”
She called the VVP proposal “inadequate” and took issue with the measures. As a practicing physician, she said that she favors more population health measures that will affect patient outcomes.
MedPAC staff expect to have a draft recommendation prepared for discussion at the December meeting, with a final vote on what will be presented to Congress coming as soon as January.
WASHINGTON – The Medicare Payment Advisory Commission continues to mull the specifics of its proposed recommendation to scrap the Quality Payment Program’s MIPS component.
The basics of the MIPS (Merit-based Incentive Payment System) replacement have not changed. The proposal calls for creation of a voluntary value program (VVP) that would withhold a percentage – currently 2% – of Medicare payments for physicians who are not part of an advanced alternative payment model (APM) under the Quality Payment Program of the Medicare Access and CHIP Reauthorization Act of 2015.
There would be two ways to recapture the withheld pay. The first would be to join an APM. The second would be to participate in a VVP by entering a voluntary reporting group. Under the proposal, VVPs would be at least 10 providers who would report together on population-based measures, patient experience, and cost measures, according to staff presentations given Nov. 2 at a meeting of the Medicare Payment Advisory Commission (MedPAC).
Proposed measures would be patient oriented, would encourage coordination across all providers, would promote positive change in the delivery system, and would be less burdensome to providers. Measures would be more in line with those employed by APMs – important because the overall goal would be encouraging participation in an APM rather than permanently lingering in the VVP.
To that end, MedPAC staff member Kate Bloniarz noted during the presentation of the VVP proposal that the total payments in the program “should be capped to be less attractive than joining an [advanced] APM. This comes from a general sense among commissioners that clinicians should not be able to receive large bonuses” for remaining in Medicare fee-for-service.
MedPAC staff recommended that the Centers for Medicare & Medicaid Services offer a fallback group that would provide an option to providers that would otherwise not have access to other groups to join.
Commission member Kathy Buto, former vice president of global health policy at Johnson & Johnson, suggested withholding be increased to perhaps 3%, with providers able to recoup 2% in the VVP and 3% in an APM, to further incentivize APM participation.
Staff noted that certain quality measures and process measures would be lost if MIPS were to go away, but they could be accounted for in other channels, such as through electronic health records and registries.
Most commissioners expressed support for both the repeal of MIPS and the conceptual framework for the new VVP, although many sought more details, particularly in the handling of specialists.
“I don’t know that we want to try to make the VVP do too much, especially when you get into the specialties that are very, very episodic,” said commission member Brian DeBusk, PhD, CEO of DeRoyal Industries. “The classic example would be a joint replacement. … I hope to see some specialist APMs developed in parallel and I think that is going to take some pressure off to try to make the VVP be all things to all people.”
Commission member Pat Wang, CEO of Healthfirst, offered a possible solution.
“I would suggest that we try to think about doing that in the context of something that is a little bit, perhaps, not full bore APM, but a VVP for specialists with their own metrics that are not big, gigantic readmissions,” she said. “Those are very broad population health metrics [that may not work for specialists].”
But at least two commission members voiced their dissent to the proposal as presented, with one going so far as to saying that MIPS should not be repealed.
David Nerenz, PhD, of the Henry Ford Health System, said that he had “very serious concerns about the VVP part of this proposal [and] they are such that if it comes to us as a recommendation in more or less its current form I will not support it.”
He called it “pretty significant social engineering in the structure of medical practice and I think we are doing it in the absence of what to me would be compelling evidence that this large group structure we are talking about is good.
“I also don’t see any evidence that beneficiaries find value in the set of measures we are talking about,” Dr. Nerenz added. He is on the record as supporting the repeal of MIPS.
Commission member Alice Coombs, MD, of Weymouth, Mass., was the lone voice speaking in support of MIPS: “I think MIPS has a lot of problems … but there are some things that are coming out of MIPS that are actually good.”
She called the VVP proposal “inadequate” and took issue with the measures. As a practicing physician, she said that she favors more population health measures that will affect patient outcomes.
MedPAC staff expect to have a draft recommendation prepared for discussion at the December meeting, with a final vote on what will be presented to Congress coming as soon as January.
AT A PUBLIC MEETING OF MEDPAC
FDA approves alectinib as frontline therapy for ALK-positive metastatic NSCLC
The Food and Drug Administration has approved frontline alectinib for the treatment of anaplastic lymphoma kinase (ALK)–positive metastatic non–small cell lung cancer (NSCLC) that has been detected by an FDA-approved test.
The drug previously received accelerated approval for treatment of patients with ALK-positive metastatic NSCLC whose disease progressed while receiving crizotinib or who were intolerant of that treatment.
There was also a lower incidence of progression to the central nervous system as first site of disease progression with alectinib: Incidence of progression to the CNS was 12% for patients receiving alectinib and 45% for patients receiving crizotinib.
The most common adverse events in patients receiving alectinib were fatigue, constipation, edema, myalgia, and anemia. Serious adverse events occurred in 28% of patients. Adverse events resulting in discontinuation occurred in 11% of patients.
“All patients in the trial were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) CDx Assay performed through central laboratory testing,” the FDA said in a press statement.
The recommended dose is 600 mg orally taken twice daily with food.
The Food and Drug Administration has approved frontline alectinib for the treatment of anaplastic lymphoma kinase (ALK)–positive metastatic non–small cell lung cancer (NSCLC) that has been detected by an FDA-approved test.
The drug previously received accelerated approval for treatment of patients with ALK-positive metastatic NSCLC whose disease progressed while receiving crizotinib or who were intolerant of that treatment.
There was also a lower incidence of progression to the central nervous system as first site of disease progression with alectinib: Incidence of progression to the CNS was 12% for patients receiving alectinib and 45% for patients receiving crizotinib.
The most common adverse events in patients receiving alectinib were fatigue, constipation, edema, myalgia, and anemia. Serious adverse events occurred in 28% of patients. Adverse events resulting in discontinuation occurred in 11% of patients.
“All patients in the trial were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) CDx Assay performed through central laboratory testing,” the FDA said in a press statement.
The recommended dose is 600 mg orally taken twice daily with food.
The Food and Drug Administration has approved frontline alectinib for the treatment of anaplastic lymphoma kinase (ALK)–positive metastatic non–small cell lung cancer (NSCLC) that has been detected by an FDA-approved test.
The drug previously received accelerated approval for treatment of patients with ALK-positive metastatic NSCLC whose disease progressed while receiving crizotinib or who were intolerant of that treatment.
There was also a lower incidence of progression to the central nervous system as first site of disease progression with alectinib: Incidence of progression to the CNS was 12% for patients receiving alectinib and 45% for patients receiving crizotinib.
The most common adverse events in patients receiving alectinib were fatigue, constipation, edema, myalgia, and anemia. Serious adverse events occurred in 28% of patients. Adverse events resulting in discontinuation occurred in 11% of patients.
“All patients in the trial were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) CDx Assay performed through central laboratory testing,” the FDA said in a press statement.
The recommended dose is 600 mg orally taken twice daily with food.
Warfarin may protect against cancer
Warfarin, the most frequently used anticoagulant worldwide, may be associated with a lower incidence of cancer incidence across a broad range of cancer types, according to results of a large, retrospective population-based cohort study.
Compared with non-users, warfarin users had a significantly lower rate of cancer overall (age- and sex-adjusted incidence rate ratio [IRR], .84; 95% CI, 0.82-0.86) and in common organ-specific cancer sites, according to the study, which included nearly 1.3 million individuals over 50 years of age in the Norwegian National Registry.
“An unintended consequence of this switch to new oral anticoagulants may be an increased incidence of cancer, which is an important consideration for public health,” Gry S. Haaland, MD, Department of Biomedicine, University of Bergen, Norway and her colleagues wrote in the report.
The study included population registry data on nearly 1.3 million Norwegians, correlated with more data from a prescription database and cancer registry in that country.
While there was no correlation between warfarin use and colon cancer, there were significantly reduced age- and sex-adjusted IRRs associated with other common organ-specific sites such as lung (.80); prostate (.69); and breast (.90), Dr. Haaland and her colleagues reported.
A subgroup analysis of the 33,313 patients (35.8%) with atrial fibrillation showed a significantly lower IRR for all cancer sites (IRR, .625) and most prevalent sites (compared with nonusers): IRR for prostate was.60; lung was.39; and the IRR for female breast cancer was .72.
The potential anticancer effects of warfarin have been suggested in various experimental cancer models. In particular, warfarin at doses not reaching anticoagulation levels has been shown to inhibits AXL receptor tyrosine kinase–dependent tumorigenesis, the authors said.
Beyond those models, there have been “conflicting conclusions” in the medical literature regarding whether warfarin protects against cancer, they added.
While some studies have shown no such association, Dr. Haaland and colleagues say they used a “stricter definition” of warfarin use that included at least 6 months of a warfarin prescription. Moreover, they only counted cancer cases that were diagnosed at least 2 years after the first prescription.
“Our data indicate that warfarin provides a possible cancer protection, a finding that may have important implications for choosing medications for patients who need anticoagulation,” the authors concluded.
However, further study is needed to better understand the mechanisms by which warfarin exerts this protective effect, they added.
Warfarin, the most frequently used anticoagulant worldwide, may be associated with a lower incidence of cancer incidence across a broad range of cancer types, according to results of a large, retrospective population-based cohort study.
Compared with non-users, warfarin users had a significantly lower rate of cancer overall (age- and sex-adjusted incidence rate ratio [IRR], .84; 95% CI, 0.82-0.86) and in common organ-specific cancer sites, according to the study, which included nearly 1.3 million individuals over 50 years of age in the Norwegian National Registry.
“An unintended consequence of this switch to new oral anticoagulants may be an increased incidence of cancer, which is an important consideration for public health,” Gry S. Haaland, MD, Department of Biomedicine, University of Bergen, Norway and her colleagues wrote in the report.
The study included population registry data on nearly 1.3 million Norwegians, correlated with more data from a prescription database and cancer registry in that country.
While there was no correlation between warfarin use and colon cancer, there were significantly reduced age- and sex-adjusted IRRs associated with other common organ-specific sites such as lung (.80); prostate (.69); and breast (.90), Dr. Haaland and her colleagues reported.
A subgroup analysis of the 33,313 patients (35.8%) with atrial fibrillation showed a significantly lower IRR for all cancer sites (IRR, .625) and most prevalent sites (compared with nonusers): IRR for prostate was.60; lung was.39; and the IRR for female breast cancer was .72.
The potential anticancer effects of warfarin have been suggested in various experimental cancer models. In particular, warfarin at doses not reaching anticoagulation levels has been shown to inhibits AXL receptor tyrosine kinase–dependent tumorigenesis, the authors said.
Beyond those models, there have been “conflicting conclusions” in the medical literature regarding whether warfarin protects against cancer, they added.
While some studies have shown no such association, Dr. Haaland and colleagues say they used a “stricter definition” of warfarin use that included at least 6 months of a warfarin prescription. Moreover, they only counted cancer cases that were diagnosed at least 2 years after the first prescription.
“Our data indicate that warfarin provides a possible cancer protection, a finding that may have important implications for choosing medications for patients who need anticoagulation,” the authors concluded.
However, further study is needed to better understand the mechanisms by which warfarin exerts this protective effect, they added.
Warfarin, the most frequently used anticoagulant worldwide, may be associated with a lower incidence of cancer incidence across a broad range of cancer types, according to results of a large, retrospective population-based cohort study.
Compared with non-users, warfarin users had a significantly lower rate of cancer overall (age- and sex-adjusted incidence rate ratio [IRR], .84; 95% CI, 0.82-0.86) and in common organ-specific cancer sites, according to the study, which included nearly 1.3 million individuals over 50 years of age in the Norwegian National Registry.
“An unintended consequence of this switch to new oral anticoagulants may be an increased incidence of cancer, which is an important consideration for public health,” Gry S. Haaland, MD, Department of Biomedicine, University of Bergen, Norway and her colleagues wrote in the report.
The study included population registry data on nearly 1.3 million Norwegians, correlated with more data from a prescription database and cancer registry in that country.
While there was no correlation between warfarin use and colon cancer, there were significantly reduced age- and sex-adjusted IRRs associated with other common organ-specific sites such as lung (.80); prostate (.69); and breast (.90), Dr. Haaland and her colleagues reported.
A subgroup analysis of the 33,313 patients (35.8%) with atrial fibrillation showed a significantly lower IRR for all cancer sites (IRR, .625) and most prevalent sites (compared with nonusers): IRR for prostate was.60; lung was.39; and the IRR for female breast cancer was .72.
The potential anticancer effects of warfarin have been suggested in various experimental cancer models. In particular, warfarin at doses not reaching anticoagulation levels has been shown to inhibits AXL receptor tyrosine kinase–dependent tumorigenesis, the authors said.
Beyond those models, there have been “conflicting conclusions” in the medical literature regarding whether warfarin protects against cancer, they added.
While some studies have shown no such association, Dr. Haaland and colleagues say they used a “stricter definition” of warfarin use that included at least 6 months of a warfarin prescription. Moreover, they only counted cancer cases that were diagnosed at least 2 years after the first prescription.
“Our data indicate that warfarin provides a possible cancer protection, a finding that may have important implications for choosing medications for patients who need anticoagulation,” the authors concluded.
However, further study is needed to better understand the mechanisms by which warfarin exerts this protective effect, they added.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Warfarin may have broad anticancer effects, a finding which could have implications for choice of anticoagulant.
Major finding: Compared with warfarin non-users, warfarin users had a significantly lower rate of cancer overall (age- and sex-adjusted incidence rate ratio [IRR], 0.84) and in common organ-specific cancer sites.
Data source: A retrospective population-based cohort study of nearly 1.3 million individuals over 50 years of age in the Norwegian National Registry.
Disclosures: James B. Lorens, PhD, reported ownership interest in BerGenBio ASA.
Type of headwear worn during surgery had no impact on SSI rates
SAN DIEGO – Surgeon preference for bouffant versus skull caps does not significantly impact superficial surgical site infection rates after accounting for surgical procedure type, results from a an analysis of a previously randomized, prospective trial showed.
“We are all aware of the current battle that is taking place over operating room attire based on the differences between the AORN [Association of periOperative Nurses] recommendations and ACS guidelines,” lead study author Shanu N. Kothari, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
In 2016, Dr. Kothari, director of minimally invasive bariatric surgery at Gundersen Health System, La Crosse, Wisc., and his associates published results from a prospective, randomized non-inferiority trial on the impact of hair removal on surgical site infection rates (J Am Coll Surg 2016;223[5]:704-11). Patients were grouped by the attending surgeons’ preferred cap choice into either bouffant or skull cap groups. Their analysis concluded that hair left on the abdomen had no impact on surgical site infection rates. “What is unique about this study is that two independent certified research nurses independently assessed every wound in that trial,” he said.
For the current study, the researchers re-examined the data by conducting a multivariate analysis to determine the influence of surgical cap choice on SSIs. Overall, 1,543 patients were included in the trial. Attending surgeons wore bouffant caps and skull caps in 39% and 61% of cases, respectively. Bouffant caps were used in 71% of colon/intestine, 42% of hernia/other, 40% of biliary cases and only 1% of foregut cases. Overall, SSIs occurred in 8% and 5% of cases in which attending surgeons wore a bouffant and skull cap, respectively (P = .016), with 6% vs. 4% classified as superficial (P = .041), 0.8% vs. 0.2% deep (P = .120), and 1% vs. 0.9% organ space (P = .790). However, when the researchers adjusted for the type of surgery and surgical approach (laparoscopic vs. open), they observed no difference in SSI rates for skull cap, compared with bouffant cap.
“Surgeon preference should dictate the choice of headwear in the operating room,” Dr. Kothari commented. “What I would encourage is perhaps a summit between thought leaders in the ACS and the AORN, [to conduct] a true review of evidence and come up with a universal guideline. There are many other issues we need to be focusing on in surgery, and this probably doesn’t have to be one of them.”
“In general, there is a complete and utter absence of any scientific evidence whatsoever for most of the things we are told to do in terms of wearing what we do in the OR,” said invited discussant E. Patchen Dellinger, MD, FACS, FIDSA, professor of surgery at the University of Washington, Seattle. “In fact, there are prospective randomized trials showing that wearing a [face] mask does not reduce surgical site infection, although I’ve been wearing a mask in the OR for approximately 48 years.”
Dr. Kothari reported having no relevant financial disclosures.
SAN DIEGO – Surgeon preference for bouffant versus skull caps does not significantly impact superficial surgical site infection rates after accounting for surgical procedure type, results from a an analysis of a previously randomized, prospective trial showed.
“We are all aware of the current battle that is taking place over operating room attire based on the differences between the AORN [Association of periOperative Nurses] recommendations and ACS guidelines,” lead study author Shanu N. Kothari, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
In 2016, Dr. Kothari, director of minimally invasive bariatric surgery at Gundersen Health System, La Crosse, Wisc., and his associates published results from a prospective, randomized non-inferiority trial on the impact of hair removal on surgical site infection rates (J Am Coll Surg 2016;223[5]:704-11). Patients were grouped by the attending surgeons’ preferred cap choice into either bouffant or skull cap groups. Their analysis concluded that hair left on the abdomen had no impact on surgical site infection rates. “What is unique about this study is that two independent certified research nurses independently assessed every wound in that trial,” he said.
For the current study, the researchers re-examined the data by conducting a multivariate analysis to determine the influence of surgical cap choice on SSIs. Overall, 1,543 patients were included in the trial. Attending surgeons wore bouffant caps and skull caps in 39% and 61% of cases, respectively. Bouffant caps were used in 71% of colon/intestine, 42% of hernia/other, 40% of biliary cases and only 1% of foregut cases. Overall, SSIs occurred in 8% and 5% of cases in which attending surgeons wore a bouffant and skull cap, respectively (P = .016), with 6% vs. 4% classified as superficial (P = .041), 0.8% vs. 0.2% deep (P = .120), and 1% vs. 0.9% organ space (P = .790). However, when the researchers adjusted for the type of surgery and surgical approach (laparoscopic vs. open), they observed no difference in SSI rates for skull cap, compared with bouffant cap.
“Surgeon preference should dictate the choice of headwear in the operating room,” Dr. Kothari commented. “What I would encourage is perhaps a summit between thought leaders in the ACS and the AORN, [to conduct] a true review of evidence and come up with a universal guideline. There are many other issues we need to be focusing on in surgery, and this probably doesn’t have to be one of them.”
“In general, there is a complete and utter absence of any scientific evidence whatsoever for most of the things we are told to do in terms of wearing what we do in the OR,” said invited discussant E. Patchen Dellinger, MD, FACS, FIDSA, professor of surgery at the University of Washington, Seattle. “In fact, there are prospective randomized trials showing that wearing a [face] mask does not reduce surgical site infection, although I’ve been wearing a mask in the OR for approximately 48 years.”
Dr. Kothari reported having no relevant financial disclosures.
SAN DIEGO – Surgeon preference for bouffant versus skull caps does not significantly impact superficial surgical site infection rates after accounting for surgical procedure type, results from a an analysis of a previously randomized, prospective trial showed.
“We are all aware of the current battle that is taking place over operating room attire based on the differences between the AORN [Association of periOperative Nurses] recommendations and ACS guidelines,” lead study author Shanu N. Kothari, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
In 2016, Dr. Kothari, director of minimally invasive bariatric surgery at Gundersen Health System, La Crosse, Wisc., and his associates published results from a prospective, randomized non-inferiority trial on the impact of hair removal on surgical site infection rates (J Am Coll Surg 2016;223[5]:704-11). Patients were grouped by the attending surgeons’ preferred cap choice into either bouffant or skull cap groups. Their analysis concluded that hair left on the abdomen had no impact on surgical site infection rates. “What is unique about this study is that two independent certified research nurses independently assessed every wound in that trial,” he said.
For the current study, the researchers re-examined the data by conducting a multivariate analysis to determine the influence of surgical cap choice on SSIs. Overall, 1,543 patients were included in the trial. Attending surgeons wore bouffant caps and skull caps in 39% and 61% of cases, respectively. Bouffant caps were used in 71% of colon/intestine, 42% of hernia/other, 40% of biliary cases and only 1% of foregut cases. Overall, SSIs occurred in 8% and 5% of cases in which attending surgeons wore a bouffant and skull cap, respectively (P = .016), with 6% vs. 4% classified as superficial (P = .041), 0.8% vs. 0.2% deep (P = .120), and 1% vs. 0.9% organ space (P = .790). However, when the researchers adjusted for the type of surgery and surgical approach (laparoscopic vs. open), they observed no difference in SSI rates for skull cap, compared with bouffant cap.
“Surgeon preference should dictate the choice of headwear in the operating room,” Dr. Kothari commented. “What I would encourage is perhaps a summit between thought leaders in the ACS and the AORN, [to conduct] a true review of evidence and come up with a universal guideline. There are many other issues we need to be focusing on in surgery, and this probably doesn’t have to be one of them.”
“In general, there is a complete and utter absence of any scientific evidence whatsoever for most of the things we are told to do in terms of wearing what we do in the OR,” said invited discussant E. Patchen Dellinger, MD, FACS, FIDSA, professor of surgery at the University of Washington, Seattle. “In fact, there are prospective randomized trials showing that wearing a [face] mask does not reduce surgical site infection, although I’ve been wearing a mask in the OR for approximately 48 years.”
Dr. Kothari reported having no relevant financial disclosures.
AT THE ACS CLINICAL CONGRESS
Key clinical point: Surgeon preference should dictate choice of headwear in the OR.
Major finding: There was no significant difference in the rate of SSI, regardless of whether a skull cap or a bouffant cap was used during surgery.
Study details: Re-examination of a prospective, randomized non-inferiority trial of 1,543 patients, on the impact of hair removal on surgical site infection rates.
Disclosures: Dr. Kothari reporting having no relevant disclosures.
Female surgeons are responsible for more work at home
Female surgeons and trainees are more likely to be responsible for household activities such a childcare planning, grocery shopping, and meal planning, according to a pilot survey.
As the rates of women in the medical profession has increased so have the level of dual-professional/dual-physician relationships which presents unique challenges for working professionals including work-home conflicts which are frequently related to surgeon burnout and depression.
The survey found that female surgeons are significantly more likely to be responsible for household responsibilities such as childcare planning, grocery shopping, meal planning, and vacation planning. Conversely, the men surveyed were more likely to pass these responsibilities on to their spouses.
Women were significantly more likely than men to be married to a professional (90% versus 37%, for faculty; 82%versus 41% for trainees; they were also significantly more likely to be married to a spouse who was working full time.
Female surgeons also reported significantly lower personal (mean 3.1 vs. 3.7) and work life (mean 2.7 vs. 3.5) satisfaction compared to men, Dr. Baptiste and her colleagues reported. Although female surgeons are burdened with household responsibilities, they are still managing to produce a similar number of publications to their male colleagues. Despite having a similar number of publications, women were less likely to be on track for tenure (adjusted P less than.01) and be at a lower rank despite equivalent years of practice (interaction P less than.001) than their male colleagues.Due to the increased demands on female surgeons many are more likely to delay child-bearing until completion of medical school or residency. This leads to women surgeons having fewer children (P = .04) and younger children (P less than.001).Medical trainees appear to equally divide responsibilities. Childcare planning was a shared responsibility among female trainees as well as financial planning, although financial planning was often the primary responsibility of male surgical trainees (P = .004). Although female trainees were significantly more likely not to have children (82% vs. 33% and delay childbearing until after medical school (100% vs. 46%) or residency (77% vs. 19%) compared to men. Household chores were equally shared for female trainees, but were still seen by men trainees as a spousal responsibility (P less than.001). Vacation planning was seen as entirely sex neutral among trainees.
Similar to their surgeon counterparts, female trainees reported lower work satisfaction (mean 2.9 vs. 3.4, P = .009). But, there were no differences between male and female trainees for reported personal life or work-life balance.As the number of female surgeons rises, strategies must be implemented regarding recruitment of female faculty, according to the authors. Universities such as Stanford have implemented strategies to recruit and retain female surgeons which resulted in a 74% increase in female faculty and a 66% increase in promotion of female faculty members (Acad Med. 2014 Jun;89[6]:904-11).
“Implementation of research-driven changes in policies that facilitate successful career development and promotion will aid in equalizing [sex] disparities, lead to improvement in recruitment, and result in retention of the current and subsequent generations of surgeons” wrote Dr. Baptiste and her colleagues.All the authors of this study reported no financial conflicts of interest.
Female surgeons and trainees are more likely to be responsible for household activities such a childcare planning, grocery shopping, and meal planning, according to a pilot survey.
As the rates of women in the medical profession has increased so have the level of dual-professional/dual-physician relationships which presents unique challenges for working professionals including work-home conflicts which are frequently related to surgeon burnout and depression.
The survey found that female surgeons are significantly more likely to be responsible for household responsibilities such as childcare planning, grocery shopping, meal planning, and vacation planning. Conversely, the men surveyed were more likely to pass these responsibilities on to their spouses.
Women were significantly more likely than men to be married to a professional (90% versus 37%, for faculty; 82%versus 41% for trainees; they were also significantly more likely to be married to a spouse who was working full time.
Female surgeons also reported significantly lower personal (mean 3.1 vs. 3.7) and work life (mean 2.7 vs. 3.5) satisfaction compared to men, Dr. Baptiste and her colleagues reported. Although female surgeons are burdened with household responsibilities, they are still managing to produce a similar number of publications to their male colleagues. Despite having a similar number of publications, women were less likely to be on track for tenure (adjusted P less than.01) and be at a lower rank despite equivalent years of practice (interaction P less than.001) than their male colleagues.Due to the increased demands on female surgeons many are more likely to delay child-bearing until completion of medical school or residency. This leads to women surgeons having fewer children (P = .04) and younger children (P less than.001).Medical trainees appear to equally divide responsibilities. Childcare planning was a shared responsibility among female trainees as well as financial planning, although financial planning was often the primary responsibility of male surgical trainees (P = .004). Although female trainees were significantly more likely not to have children (82% vs. 33% and delay childbearing until after medical school (100% vs. 46%) or residency (77% vs. 19%) compared to men. Household chores were equally shared for female trainees, but were still seen by men trainees as a spousal responsibility (P less than.001). Vacation planning was seen as entirely sex neutral among trainees.
Similar to their surgeon counterparts, female trainees reported lower work satisfaction (mean 2.9 vs. 3.4, P = .009). But, there were no differences between male and female trainees for reported personal life or work-life balance.As the number of female surgeons rises, strategies must be implemented regarding recruitment of female faculty, according to the authors. Universities such as Stanford have implemented strategies to recruit and retain female surgeons which resulted in a 74% increase in female faculty and a 66% increase in promotion of female faculty members (Acad Med. 2014 Jun;89[6]:904-11).
“Implementation of research-driven changes in policies that facilitate successful career development and promotion will aid in equalizing [sex] disparities, lead to improvement in recruitment, and result in retention of the current and subsequent generations of surgeons” wrote Dr. Baptiste and her colleagues.All the authors of this study reported no financial conflicts of interest.
Female surgeons and trainees are more likely to be responsible for household activities such a childcare planning, grocery shopping, and meal planning, according to a pilot survey.
As the rates of women in the medical profession has increased so have the level of dual-professional/dual-physician relationships which presents unique challenges for working professionals including work-home conflicts which are frequently related to surgeon burnout and depression.
The survey found that female surgeons are significantly more likely to be responsible for household responsibilities such as childcare planning, grocery shopping, meal planning, and vacation planning. Conversely, the men surveyed were more likely to pass these responsibilities on to their spouses.
Women were significantly more likely than men to be married to a professional (90% versus 37%, for faculty; 82%versus 41% for trainees; they were also significantly more likely to be married to a spouse who was working full time.
Female surgeons also reported significantly lower personal (mean 3.1 vs. 3.7) and work life (mean 2.7 vs. 3.5) satisfaction compared to men, Dr. Baptiste and her colleagues reported. Although female surgeons are burdened with household responsibilities, they are still managing to produce a similar number of publications to their male colleagues. Despite having a similar number of publications, women were less likely to be on track for tenure (adjusted P less than.01) and be at a lower rank despite equivalent years of practice (interaction P less than.001) than their male colleagues.Due to the increased demands on female surgeons many are more likely to delay child-bearing until completion of medical school or residency. This leads to women surgeons having fewer children (P = .04) and younger children (P less than.001).Medical trainees appear to equally divide responsibilities. Childcare planning was a shared responsibility among female trainees as well as financial planning, although financial planning was often the primary responsibility of male surgical trainees (P = .004). Although female trainees were significantly more likely not to have children (82% vs. 33% and delay childbearing until after medical school (100% vs. 46%) or residency (77% vs. 19%) compared to men. Household chores were equally shared for female trainees, but were still seen by men trainees as a spousal responsibility (P less than.001). Vacation planning was seen as entirely sex neutral among trainees.
Similar to their surgeon counterparts, female trainees reported lower work satisfaction (mean 2.9 vs. 3.4, P = .009). But, there were no differences between male and female trainees for reported personal life or work-life balance.As the number of female surgeons rises, strategies must be implemented regarding recruitment of female faculty, according to the authors. Universities such as Stanford have implemented strategies to recruit and retain female surgeons which resulted in a 74% increase in female faculty and a 66% increase in promotion of female faculty members (Acad Med. 2014 Jun;89[6]:904-11).
“Implementation of research-driven changes in policies that facilitate successful career development and promotion will aid in equalizing [sex] disparities, lead to improvement in recruitment, and result in retention of the current and subsequent generations of surgeons” wrote Dr. Baptiste and her colleagues.All the authors of this study reported no financial conflicts of interest.
FROM THE JOURNAL OF SURGICAL RESEARCH
Key clinical point:
Major finding: Childcare planning, grocery shopping, and meal planning were all significantly more likely to be managed by women.
Data source: Pilot survey of 127 faculty surgeons and 116 trainees in the Department of Surgery at a single, large academic medical center.
Disclosures: All the authors of this study reported no financial conflicts of interest.
Heart surgery halves in-hospital mortality in trisomy 13 and 18
For infants with trisomy 13 or trisomy 18, congenital heart surgery is associated with a significant decrease in in-hospital mortality, according to results of a large, retrospective, multicenter cohort study.
In-hospital mortality was 45% lower in trisomy 13 patients (P = .003) and 64% lower in trisomy 18 patients (P less than.001) who underwent surgery, data show (Pediatrics 140(5); 2017. doi: https://doi.org/10.1542/peds.2017-0772).
The study, based on records from the 44 participating children’s hospitals represented in the Pediatric Health Information System (PHIS) database, included 1,668 newborns with trisomy 13 or 18 who were admitted within 14 days of birth. Median age at admission was less than 1 day for both groups.
Congenital heart disease was present in 925 out of 1,020 infants with trisomy 18 (91%) and 555 out of 648 with trisomy 13 (86%), the report stated.
For those infants with congenital heart disease, overall mortality was highest during the first hospital admission (63%), investigators wrote. However, for those undergoing congenital heart surgery, multivariate analysis showed decreased in-hospital mortality vs. those who had no surgery for both the trisomy 13 (30% vs. 55%, respectively, P = .003) and the trisomy 18 groups (16% vs. 44%, P less than .001).
This is not only the largest-ever study of trisomy 13 and 18 ever reported, according to the investigators, but also the first to show that higher weight, female sex, and older age at admission are associated with improved survival following congenital heart surgery among these patients. Multiple logistic regression analysis showed significant effects of these risk factors on mortality for both the trisomy 13 and 18 infant subsets, according to Dr. Kosiv and her colleagues.
These findings come at a time when many centers elect not to perform congenital heart surgery in trisomy 13 and 18 patients, the investigators wrote, noting that management is typically limited to medical strategies due to the “markedly short life expectancy” and grave prognosis associated with the condition.
Mortality was markedly decreased, but still considerably higher than what would be expected for congenital heart surgery in the general population, which is an important consideration for families and practitioners who are considering the procedure, investigators said in their report.
Nevertheless, the present findings suggest that “CHS may not be futile, at least not in the short-term, in patients with T13 and T18,” Dr. Kosiv and colleagues wrote. “Additionally, these results suggest that CHS may allow families to be able to take their children home and avoid [them] dying in the hospital.”
The article by Kosiv and colleagues provides “compelling evidence that congenital heart surgery can be considered” in infants with trisomy 13 or 18, according Kathy J. Jenkins, MD, MPH, and Amy E. Roberts, MD in their accompanying editorial. The decision, however, should be made as part of a comprehensive treatment plan, they said.
“In our view, this should only occur when parents are fully informed of the still significant residual infant mortality risk with cardiac surgery … and unavoidable, severe neurocognitive delays,” they wrote in their editorial.
Caregivers helping families make the decision, they added, should be aware that delays in decision-making might make operations impossible or even more risky than they already are.
“The revolution in congenital heart surgery … has now changed the equation for infants with trisomy 18 and 13 just as it did for trisomy 21 in the past,” the authors wrote. “However, numerous factors must be taken into account to optimize decision-making for each infant and family.”
Dr. Jenkins, MD, MPH, and Dr. Roberts, MD are with the Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts. These comments are based on their editorial (Pediatrics 2017. doi: https://doi.org/10.1542/peds.2017-2809). The authors reported no potential conflicts of interest.
The article by Kosiv and colleagues provides “compelling evidence that congenital heart surgery can be considered” in infants with trisomy 13 or 18, according Kathy J. Jenkins, MD, MPH, and Amy E. Roberts, MD in their accompanying editorial. The decision, however, should be made as part of a comprehensive treatment plan, they said.
“In our view, this should only occur when parents are fully informed of the still significant residual infant mortality risk with cardiac surgery … and unavoidable, severe neurocognitive delays,” they wrote in their editorial.
Caregivers helping families make the decision, they added, should be aware that delays in decision-making might make operations impossible or even more risky than they already are.
“The revolution in congenital heart surgery … has now changed the equation for infants with trisomy 18 and 13 just as it did for trisomy 21 in the past,” the authors wrote. “However, numerous factors must be taken into account to optimize decision-making for each infant and family.”
Dr. Jenkins, MD, MPH, and Dr. Roberts, MD are with the Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts. These comments are based on their editorial (Pediatrics 2017. doi: https://doi.org/10.1542/peds.2017-2809). The authors reported no potential conflicts of interest.
The article by Kosiv and colleagues provides “compelling evidence that congenital heart surgery can be considered” in infants with trisomy 13 or 18, according Kathy J. Jenkins, MD, MPH, and Amy E. Roberts, MD in their accompanying editorial. The decision, however, should be made as part of a comprehensive treatment plan, they said.
“In our view, this should only occur when parents are fully informed of the still significant residual infant mortality risk with cardiac surgery … and unavoidable, severe neurocognitive delays,” they wrote in their editorial.
Caregivers helping families make the decision, they added, should be aware that delays in decision-making might make operations impossible or even more risky than they already are.
“The revolution in congenital heart surgery … has now changed the equation for infants with trisomy 18 and 13 just as it did for trisomy 21 in the past,” the authors wrote. “However, numerous factors must be taken into account to optimize decision-making for each infant and family.”
Dr. Jenkins, MD, MPH, and Dr. Roberts, MD are with the Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts. These comments are based on their editorial (Pediatrics 2017. doi: https://doi.org/10.1542/peds.2017-2809). The authors reported no potential conflicts of interest.
For infants with trisomy 13 or trisomy 18, congenital heart surgery is associated with a significant decrease in in-hospital mortality, according to results of a large, retrospective, multicenter cohort study.
In-hospital mortality was 45% lower in trisomy 13 patients (P = .003) and 64% lower in trisomy 18 patients (P less than.001) who underwent surgery, data show (Pediatrics 140(5); 2017. doi: https://doi.org/10.1542/peds.2017-0772).
The study, based on records from the 44 participating children’s hospitals represented in the Pediatric Health Information System (PHIS) database, included 1,668 newborns with trisomy 13 or 18 who were admitted within 14 days of birth. Median age at admission was less than 1 day for both groups.
Congenital heart disease was present in 925 out of 1,020 infants with trisomy 18 (91%) and 555 out of 648 with trisomy 13 (86%), the report stated.
For those infants with congenital heart disease, overall mortality was highest during the first hospital admission (63%), investigators wrote. However, for those undergoing congenital heart surgery, multivariate analysis showed decreased in-hospital mortality vs. those who had no surgery for both the trisomy 13 (30% vs. 55%, respectively, P = .003) and the trisomy 18 groups (16% vs. 44%, P less than .001).
This is not only the largest-ever study of trisomy 13 and 18 ever reported, according to the investigators, but also the first to show that higher weight, female sex, and older age at admission are associated with improved survival following congenital heart surgery among these patients. Multiple logistic regression analysis showed significant effects of these risk factors on mortality for both the trisomy 13 and 18 infant subsets, according to Dr. Kosiv and her colleagues.
These findings come at a time when many centers elect not to perform congenital heart surgery in trisomy 13 and 18 patients, the investigators wrote, noting that management is typically limited to medical strategies due to the “markedly short life expectancy” and grave prognosis associated with the condition.
Mortality was markedly decreased, but still considerably higher than what would be expected for congenital heart surgery in the general population, which is an important consideration for families and practitioners who are considering the procedure, investigators said in their report.
Nevertheless, the present findings suggest that “CHS may not be futile, at least not in the short-term, in patients with T13 and T18,” Dr. Kosiv and colleagues wrote. “Additionally, these results suggest that CHS may allow families to be able to take their children home and avoid [them] dying in the hospital.”
For infants with trisomy 13 or trisomy 18, congenital heart surgery is associated with a significant decrease in in-hospital mortality, according to results of a large, retrospective, multicenter cohort study.
In-hospital mortality was 45% lower in trisomy 13 patients (P = .003) and 64% lower in trisomy 18 patients (P less than.001) who underwent surgery, data show (Pediatrics 140(5); 2017. doi: https://doi.org/10.1542/peds.2017-0772).
The study, based on records from the 44 participating children’s hospitals represented in the Pediatric Health Information System (PHIS) database, included 1,668 newborns with trisomy 13 or 18 who were admitted within 14 days of birth. Median age at admission was less than 1 day for both groups.
Congenital heart disease was present in 925 out of 1,020 infants with trisomy 18 (91%) and 555 out of 648 with trisomy 13 (86%), the report stated.
For those infants with congenital heart disease, overall mortality was highest during the first hospital admission (63%), investigators wrote. However, for those undergoing congenital heart surgery, multivariate analysis showed decreased in-hospital mortality vs. those who had no surgery for both the trisomy 13 (30% vs. 55%, respectively, P = .003) and the trisomy 18 groups (16% vs. 44%, P less than .001).
This is not only the largest-ever study of trisomy 13 and 18 ever reported, according to the investigators, but also the first to show that higher weight, female sex, and older age at admission are associated with improved survival following congenital heart surgery among these patients. Multiple logistic regression analysis showed significant effects of these risk factors on mortality for both the trisomy 13 and 18 infant subsets, according to Dr. Kosiv and her colleagues.
These findings come at a time when many centers elect not to perform congenital heart surgery in trisomy 13 and 18 patients, the investigators wrote, noting that management is typically limited to medical strategies due to the “markedly short life expectancy” and grave prognosis associated with the condition.
Mortality was markedly decreased, but still considerably higher than what would be expected for congenital heart surgery in the general population, which is an important consideration for families and practitioners who are considering the procedure, investigators said in their report.
Nevertheless, the present findings suggest that “CHS may not be futile, at least not in the short-term, in patients with T13 and T18,” Dr. Kosiv and colleagues wrote. “Additionally, these results suggest that CHS may allow families to be able to take their children home and avoid [them] dying in the hospital.”
FROM PEDIATRICS
Key clinical point: Despite many centers choosing not to perform congenital heart surgery in infants with trisomy 13 and trisomy 18, doing so cuts in-hospital mortality by more than half.
Major finding: In-hospital mortality was 45% lower in trisomy 13 patients (P = 0.003) and 64% lower in trisomy 18 patients (P < 0.001) who underwent surgery.
Data source: A large, retrospective, multicenter cohort study of 1,668 newborns with trisomy 13 or 18 admitted within 14 days of birth.
Disclosures: The authors reported no potential conflicts of interest.
Docs to receive slightly better Medicare pay bump than originally proposed
Physicians will see a 0.41% increase to their payments under the Medicare physician fee schedule in 2018, a slight increase from the proposed 0.31% uptick but still short of the 0.5% increase promised under the Medicare Access and CHIP Reauthorization Act (MACRA).
Officials at the Centers for Medicare & Medicaid Services were unable to find adequate funding in so-called misvalued codes to back the larger increase, as required by law, according to the final version of the 2018 physician fee schedule, released Nov. 2 and scheduled for publication in the Federal Register on Nov. 15.
“We finalized these changes based on stakeholder feedback and to better align with the MIPS data submission requirements for the quality performance category,” CMS said in a fact sheet detailing the provisions of the final rule.
CMS also is delaying the start of the appropriate use criteria (AUC) for imaging services, a program that would deny payments for imaging services unless the ordering physician consulted appropriate use criteria. The program will begin with an educational and operational testing year in 2020. Physicians will be required to start using AUCs and reporting this information on claims, but CMS will pay claims regardless of whether they correctly contain the required AUC data.
“This allows both clinicians and the agency to prepare for this new program,” the agency said in the fact sheet, CMS had proposed 2019 be the educational and operational testing year.
In response to comments submitted to the agency, CMS is changing its policy on billing codes for biosimilars administered under Medicare Part B.
“Effective January 1, 2018, newly approved biosimilar products with a common reference product will no longer be grouped in the same billing code,” the agency said in the fact sheet. “By encouraging innovation and greater manufacturer participation in the marketplace, we believe that this policy change will result in the licensing of more biosimilar products, thus creating a stable and robust market, driving market competition, and decreasing uncertainty about access and payment.”
The final rule implements proposed expansion of the Medicare Diabetes Prevention Program from a demonstration project to a nationwide program in 2018, however the implementation will be delayed for three months until April 1, 2018, rather than at the beginning of the year. The program provides payments to physicians based on performance goals being met by patients, including meeting certain numbers of service and maintenance sessions with the program and achieving specific weight loss goals.
CMS also finalized a number of new telemedicine payment codes.
Mike Nelson, MD, FCCP, comments: One need not “google” too long to find that the United States performs quite poorly in overall health care when compared with other nations, despite spending more than any of the comparators…we’re 37th this year. This information from Avalere Health portends a further drop in our ranking next year. The privilege of good health is a responsibility of the individual, but the right to affordable health care is a responsibility of the government. It is time for our legislators to stop playing partisan politics and start communicating to propose a workable and affordable solution.
Mike Nelson, MD, FCCP, comments: One need not “google” too long to find that the United States performs quite poorly in overall health care when compared with other nations, despite spending more than any of the comparators…we’re 37th this year. This information from Avalere Health portends a further drop in our ranking next year. The privilege of good health is a responsibility of the individual, but the right to affordable health care is a responsibility of the government. It is time for our legislators to stop playing partisan politics and start communicating to propose a workable and affordable solution.
Mike Nelson, MD, FCCP, comments: One need not “google” too long to find that the United States performs quite poorly in overall health care when compared with other nations, despite spending more than any of the comparators…we’re 37th this year. This information from Avalere Health portends a further drop in our ranking next year. The privilege of good health is a responsibility of the individual, but the right to affordable health care is a responsibility of the government. It is time for our legislators to stop playing partisan politics and start communicating to propose a workable and affordable solution.
Physicians will see a 0.41% increase to their payments under the Medicare physician fee schedule in 2018, a slight increase from the proposed 0.31% uptick but still short of the 0.5% increase promised under the Medicare Access and CHIP Reauthorization Act (MACRA).
Officials at the Centers for Medicare & Medicaid Services were unable to find adequate funding in so-called misvalued codes to back the larger increase, as required by law, according to the final version of the 2018 physician fee schedule, released Nov. 2 and scheduled for publication in the Federal Register on Nov. 15.
“We finalized these changes based on stakeholder feedback and to better align with the MIPS data submission requirements for the quality performance category,” CMS said in a fact sheet detailing the provisions of the final rule.
CMS also is delaying the start of the appropriate use criteria (AUC) for imaging services, a program that would deny payments for imaging services unless the ordering physician consulted appropriate use criteria. The program will begin with an educational and operational testing year in 2020. Physicians will be required to start using AUCs and reporting this information on claims, but CMS will pay claims regardless of whether they correctly contain the required AUC data.
“This allows both clinicians and the agency to prepare for this new program,” the agency said in the fact sheet, CMS had proposed 2019 be the educational and operational testing year.
In response to comments submitted to the agency, CMS is changing its policy on billing codes for biosimilars administered under Medicare Part B.
“Effective January 1, 2018, newly approved biosimilar products with a common reference product will no longer be grouped in the same billing code,” the agency said in the fact sheet. “By encouraging innovation and greater manufacturer participation in the marketplace, we believe that this policy change will result in the licensing of more biosimilar products, thus creating a stable and robust market, driving market competition, and decreasing uncertainty about access and payment.”
The final rule implements proposed expansion of the Medicare Diabetes Prevention Program from a demonstration project to a nationwide program in 2018, however the implementation will be delayed for three months until April 1, 2018, rather than at the beginning of the year. The program provides payments to physicians based on performance goals being met by patients, including meeting certain numbers of service and maintenance sessions with the program and achieving specific weight loss goals.
CMS also finalized a number of new telemedicine payment codes.
Physicians will see a 0.41% increase to their payments under the Medicare physician fee schedule in 2018, a slight increase from the proposed 0.31% uptick but still short of the 0.5% increase promised under the Medicare Access and CHIP Reauthorization Act (MACRA).
Officials at the Centers for Medicare & Medicaid Services were unable to find adequate funding in so-called misvalued codes to back the larger increase, as required by law, according to the final version of the 2018 physician fee schedule, released Nov. 2 and scheduled for publication in the Federal Register on Nov. 15.
“We finalized these changes based on stakeholder feedback and to better align with the MIPS data submission requirements for the quality performance category,” CMS said in a fact sheet detailing the provisions of the final rule.
CMS also is delaying the start of the appropriate use criteria (AUC) for imaging services, a program that would deny payments for imaging services unless the ordering physician consulted appropriate use criteria. The program will begin with an educational and operational testing year in 2020. Physicians will be required to start using AUCs and reporting this information on claims, but CMS will pay claims regardless of whether they correctly contain the required AUC data.
“This allows both clinicians and the agency to prepare for this new program,” the agency said in the fact sheet, CMS had proposed 2019 be the educational and operational testing year.
In response to comments submitted to the agency, CMS is changing its policy on billing codes for biosimilars administered under Medicare Part B.
“Effective January 1, 2018, newly approved biosimilar products with a common reference product will no longer be grouped in the same billing code,” the agency said in the fact sheet. “By encouraging innovation and greater manufacturer participation in the marketplace, we believe that this policy change will result in the licensing of more biosimilar products, thus creating a stable and robust market, driving market competition, and decreasing uncertainty about access and payment.”
The final rule implements proposed expansion of the Medicare Diabetes Prevention Program from a demonstration project to a nationwide program in 2018, however the implementation will be delayed for three months until April 1, 2018, rather than at the beginning of the year. The program provides payments to physicians based on performance goals being met by patients, including meeting certain numbers of service and maintenance sessions with the program and achieving specific weight loss goals.
CMS also finalized a number of new telemedicine payment codes.
ORBITA: PCI no better than meds for stable angina
DENVER – The first-ever blinded, sham-controlled randomized trial of percutaneous coronary intervention for stable angina failed to show a significant improvement in exercise time for PCI, compared with placebo PCI, Rasha Al-Lamee, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The blockbuster results of the ORBITA trial, published online in the Lancet simultaneously with Dr. Al-Lamee’s presentation in Denver, quickly went viral, with a story splashed across the front page of the New York Times under the headline “‘Unbelievable’: Heart Stents Fail to Ease Chest Pain.” Interventional cardiology thought leaders at TCT said the newspaper piece, and a Lancet editorial commentary entitled “Last nail in the coffin for PCI in stable angina?” that accompanied publication of ORBITA, failed to convey the study’s major limitations, drawbacks that Dr. Al-Lamee readily acknowledged.
What ORBITA did
ORBITA (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina) included 200 patients referred to five U.K. cardiac catheterization labs for diagnostic angiography. Participants had to have stable angina, single-vessel disease, and at least one 70% or greater stenosis; in fact, their stenotic severity averaged 84.4% by quantitative coronary angiography.
The patients received 6 weeks of intensive medical therapy during which they were uptitrated to an average of three antianginal medications. They then underwent either real or sham PCI followed by 6 weeks of recovery, during which both the patients and care team remained blinded. Then the same assessments done before randomization were repeated, including exercise treadmill testing, the Seattle Angina Questionnaire, and dobutamine stress echocardiography, explained Dr. Al-Lamee of Imperial College London.
The primary outcome was achievement of at least a 30-second greater improvement in total exercise time following PCI, compared with sham PCI, an effect size chosen based on placebo-controlled studies of antianginal drugs. The PCI group improved by a mean of 28.4 seconds, the controls by 11.8 seconds, and the resultant 16.6-second difference made for a negative result (Lancet. 2017 Nov 2;doi: 10.1016/S0140-6736[17]32714-9).
PCI did, however, result in significant improvement in the secondary endpoint of ischemia reduction as assessed by blinded evaluation of dobutamine stress echocardiography results. The PCI group’s mean peak stress wall motion index score improved from 1.11 prerandomization to 1.03 – that is, normal – at follow-up 6 weeks post procedure while remaining unchanged in the sham PCI group, Dr. Al-Lamee noted at the meeting, sponsored by the Cardiovascular Research Foundation.
What the results mean
Dr. Al-Lamee said the ORBITA results should enable cardiologists to sit with patients similar to those in the trial and have a more informed, patient-centered discussion in which intensive medical management can be offered as an initial first-line option with an understanding that it will likely improve their symptoms to the same degree as angioplasty.
“There will be those patients who would rather avoid having to take high doses of antianginal medications with the side effects they involve, who may well prefer to have an upfront procedure with a small risk in order to reduce their pill count, and who also would rather have improved blood flow to the heart, which may have prognostic implications,” Dr. Al-Lamee said.
Carl L. Tommaso, MD, part of the panel of discussants at the late-breaking clinical trials session in which Dr. Al-Lamee presented the ORBITA findings, applauded the investigators for their ingenious study design, which included elaborate blinding techniques involving music played through headphones throughout the procedure, heavy sedation, separate angioplasty and clinical care teams, the same postprocedural instructions and discharge letter, and dual-antiplatelet therapy in both study arms.
“This is a great study. I don’t think any of us could get this study past an institutional review board in the United States,” commented Dr. Tommaso, director of the cardiac catheterization laboratory at Skokie (Ill.) Hospital.
He added, however, that he wouldn’t have performed PCI on the basis of angiographic findings alone in stable angina patients with a 9-minute treadmill exercise time.
Where OPTIMA fell short
Angiography vs. functional testing
“Twenty-nine percent of patients, we’d all agree, should not have had angioplasty because they had no ischemia,” said Dr. Stone, professor of medicine at Columbia University, New York, and director of the TCT conference.
All subjects in ORBITA did indeed undergo measurement of both FFR and instant Wave-Free Ratio (iFR) while on the table immediately before and after their real or sham PCI. The mean stenosis severity was 0.69 by FFR and 0.76 by iFR, readings indicative of significantly impaired flow. However, the operators were blinded as to those results. The rationale for withholding that information was that, even though it has been shown to be clinically useful, studies show that 80% of angioplasties are done based upon angiography alone, and the ORBITA investigators wanted the study to reflect routine clinical practice, Dr. Al-Lamee explained.
“I think one of the many lessons coming out of this trial is to see the discrepancy between the angiogram and functional testing. We cannot guide our therapy solely by the angiogram. We have to get physiologic data and consider that together with symptoms in the patient’s clinical context,” said panelist Allen Jeremias, MD, director of interventional cardiology research at St. Francis Hospital in Rosyln, N.Y.
Commentary goes too far
The “last-nail-in-the-coffin” Lancet commentary (2017 Nov 2. doi: 10.1016/S0140-6736[17]32757-5) penned by David L. Brown, MD, of Washington University in St. Louis and Rita F. Redberg, MD, of the University of California, San Francisco, emphatically declared that the ORBITA results mean all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite medical therapy. Dr. Al-Lamee was one of many at TCT 2017 who took strong exception to that.
“This is the first trial of its kind. I think it would be very easy to take the results of this trial and overextrapolate. To downgrade the guideline recommendations based on this study would be an incredibly large overreach,” she said.
Ajay J. Kirtane, MD, who chaired a press conference in which Dr. Al-Lamee presented the ORBITA results, had a further criticism of the editorial.
“Some of the risks of PCI as described in the editorial are just factually inaccurate. An MI rate of 15%, an acute kidney injury rate of 13% – those are simply factually incorrect,” said Dr. Kirtane, director of the cardiac catheterization laboratories at New York-Presbyterian/Columbia University Medical Center.
The ORBITA trial was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. Dr. Al-Lamee reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.
DENVER – The first-ever blinded, sham-controlled randomized trial of percutaneous coronary intervention for stable angina failed to show a significant improvement in exercise time for PCI, compared with placebo PCI, Rasha Al-Lamee, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The blockbuster results of the ORBITA trial, published online in the Lancet simultaneously with Dr. Al-Lamee’s presentation in Denver, quickly went viral, with a story splashed across the front page of the New York Times under the headline “‘Unbelievable’: Heart Stents Fail to Ease Chest Pain.” Interventional cardiology thought leaders at TCT said the newspaper piece, and a Lancet editorial commentary entitled “Last nail in the coffin for PCI in stable angina?” that accompanied publication of ORBITA, failed to convey the study’s major limitations, drawbacks that Dr. Al-Lamee readily acknowledged.
What ORBITA did
ORBITA (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina) included 200 patients referred to five U.K. cardiac catheterization labs for diagnostic angiography. Participants had to have stable angina, single-vessel disease, and at least one 70% or greater stenosis; in fact, their stenotic severity averaged 84.4% by quantitative coronary angiography.
The patients received 6 weeks of intensive medical therapy during which they were uptitrated to an average of three antianginal medications. They then underwent either real or sham PCI followed by 6 weeks of recovery, during which both the patients and care team remained blinded. Then the same assessments done before randomization were repeated, including exercise treadmill testing, the Seattle Angina Questionnaire, and dobutamine stress echocardiography, explained Dr. Al-Lamee of Imperial College London.
The primary outcome was achievement of at least a 30-second greater improvement in total exercise time following PCI, compared with sham PCI, an effect size chosen based on placebo-controlled studies of antianginal drugs. The PCI group improved by a mean of 28.4 seconds, the controls by 11.8 seconds, and the resultant 16.6-second difference made for a negative result (Lancet. 2017 Nov 2;doi: 10.1016/S0140-6736[17]32714-9).
PCI did, however, result in significant improvement in the secondary endpoint of ischemia reduction as assessed by blinded evaluation of dobutamine stress echocardiography results. The PCI group’s mean peak stress wall motion index score improved from 1.11 prerandomization to 1.03 – that is, normal – at follow-up 6 weeks post procedure while remaining unchanged in the sham PCI group, Dr. Al-Lamee noted at the meeting, sponsored by the Cardiovascular Research Foundation.
What the results mean
Dr. Al-Lamee said the ORBITA results should enable cardiologists to sit with patients similar to those in the trial and have a more informed, patient-centered discussion in which intensive medical management can be offered as an initial first-line option with an understanding that it will likely improve their symptoms to the same degree as angioplasty.
“There will be those patients who would rather avoid having to take high doses of antianginal medications with the side effects they involve, who may well prefer to have an upfront procedure with a small risk in order to reduce their pill count, and who also would rather have improved blood flow to the heart, which may have prognostic implications,” Dr. Al-Lamee said.
Carl L. Tommaso, MD, part of the panel of discussants at the late-breaking clinical trials session in which Dr. Al-Lamee presented the ORBITA findings, applauded the investigators for their ingenious study design, which included elaborate blinding techniques involving music played through headphones throughout the procedure, heavy sedation, separate angioplasty and clinical care teams, the same postprocedural instructions and discharge letter, and dual-antiplatelet therapy in both study arms.
“This is a great study. I don’t think any of us could get this study past an institutional review board in the United States,” commented Dr. Tommaso, director of the cardiac catheterization laboratory at Skokie (Ill.) Hospital.
He added, however, that he wouldn’t have performed PCI on the basis of angiographic findings alone in stable angina patients with a 9-minute treadmill exercise time.
Where OPTIMA fell short
Angiography vs. functional testing
“Twenty-nine percent of patients, we’d all agree, should not have had angioplasty because they had no ischemia,” said Dr. Stone, professor of medicine at Columbia University, New York, and director of the TCT conference.
All subjects in ORBITA did indeed undergo measurement of both FFR and instant Wave-Free Ratio (iFR) while on the table immediately before and after their real or sham PCI. The mean stenosis severity was 0.69 by FFR and 0.76 by iFR, readings indicative of significantly impaired flow. However, the operators were blinded as to those results. The rationale for withholding that information was that, even though it has been shown to be clinically useful, studies show that 80% of angioplasties are done based upon angiography alone, and the ORBITA investigators wanted the study to reflect routine clinical practice, Dr. Al-Lamee explained.
“I think one of the many lessons coming out of this trial is to see the discrepancy between the angiogram and functional testing. We cannot guide our therapy solely by the angiogram. We have to get physiologic data and consider that together with symptoms in the patient’s clinical context,” said panelist Allen Jeremias, MD, director of interventional cardiology research at St. Francis Hospital in Rosyln, N.Y.
Commentary goes too far
The “last-nail-in-the-coffin” Lancet commentary (2017 Nov 2. doi: 10.1016/S0140-6736[17]32757-5) penned by David L. Brown, MD, of Washington University in St. Louis and Rita F. Redberg, MD, of the University of California, San Francisco, emphatically declared that the ORBITA results mean all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite medical therapy. Dr. Al-Lamee was one of many at TCT 2017 who took strong exception to that.
“This is the first trial of its kind. I think it would be very easy to take the results of this trial and overextrapolate. To downgrade the guideline recommendations based on this study would be an incredibly large overreach,” she said.
Ajay J. Kirtane, MD, who chaired a press conference in which Dr. Al-Lamee presented the ORBITA results, had a further criticism of the editorial.
“Some of the risks of PCI as described in the editorial are just factually inaccurate. An MI rate of 15%, an acute kidney injury rate of 13% – those are simply factually incorrect,” said Dr. Kirtane, director of the cardiac catheterization laboratories at New York-Presbyterian/Columbia University Medical Center.
The ORBITA trial was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. Dr. Al-Lamee reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.
DENVER – The first-ever blinded, sham-controlled randomized trial of percutaneous coronary intervention for stable angina failed to show a significant improvement in exercise time for PCI, compared with placebo PCI, Rasha Al-Lamee, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The blockbuster results of the ORBITA trial, published online in the Lancet simultaneously with Dr. Al-Lamee’s presentation in Denver, quickly went viral, with a story splashed across the front page of the New York Times under the headline “‘Unbelievable’: Heart Stents Fail to Ease Chest Pain.” Interventional cardiology thought leaders at TCT said the newspaper piece, and a Lancet editorial commentary entitled “Last nail in the coffin for PCI in stable angina?” that accompanied publication of ORBITA, failed to convey the study’s major limitations, drawbacks that Dr. Al-Lamee readily acknowledged.
What ORBITA did
ORBITA (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina) included 200 patients referred to five U.K. cardiac catheterization labs for diagnostic angiography. Participants had to have stable angina, single-vessel disease, and at least one 70% or greater stenosis; in fact, their stenotic severity averaged 84.4% by quantitative coronary angiography.
The patients received 6 weeks of intensive medical therapy during which they were uptitrated to an average of three antianginal medications. They then underwent either real or sham PCI followed by 6 weeks of recovery, during which both the patients and care team remained blinded. Then the same assessments done before randomization were repeated, including exercise treadmill testing, the Seattle Angina Questionnaire, and dobutamine stress echocardiography, explained Dr. Al-Lamee of Imperial College London.
The primary outcome was achievement of at least a 30-second greater improvement in total exercise time following PCI, compared with sham PCI, an effect size chosen based on placebo-controlled studies of antianginal drugs. The PCI group improved by a mean of 28.4 seconds, the controls by 11.8 seconds, and the resultant 16.6-second difference made for a negative result (Lancet. 2017 Nov 2;doi: 10.1016/S0140-6736[17]32714-9).
PCI did, however, result in significant improvement in the secondary endpoint of ischemia reduction as assessed by blinded evaluation of dobutamine stress echocardiography results. The PCI group’s mean peak stress wall motion index score improved from 1.11 prerandomization to 1.03 – that is, normal – at follow-up 6 weeks post procedure while remaining unchanged in the sham PCI group, Dr. Al-Lamee noted at the meeting, sponsored by the Cardiovascular Research Foundation.
What the results mean
Dr. Al-Lamee said the ORBITA results should enable cardiologists to sit with patients similar to those in the trial and have a more informed, patient-centered discussion in which intensive medical management can be offered as an initial first-line option with an understanding that it will likely improve their symptoms to the same degree as angioplasty.
“There will be those patients who would rather avoid having to take high doses of antianginal medications with the side effects they involve, who may well prefer to have an upfront procedure with a small risk in order to reduce their pill count, and who also would rather have improved blood flow to the heart, which may have prognostic implications,” Dr. Al-Lamee said.
Carl L. Tommaso, MD, part of the panel of discussants at the late-breaking clinical trials session in which Dr. Al-Lamee presented the ORBITA findings, applauded the investigators for their ingenious study design, which included elaborate blinding techniques involving music played through headphones throughout the procedure, heavy sedation, separate angioplasty and clinical care teams, the same postprocedural instructions and discharge letter, and dual-antiplatelet therapy in both study arms.
“This is a great study. I don’t think any of us could get this study past an institutional review board in the United States,” commented Dr. Tommaso, director of the cardiac catheterization laboratory at Skokie (Ill.) Hospital.
He added, however, that he wouldn’t have performed PCI on the basis of angiographic findings alone in stable angina patients with a 9-minute treadmill exercise time.
Where OPTIMA fell short
Angiography vs. functional testing
“Twenty-nine percent of patients, we’d all agree, should not have had angioplasty because they had no ischemia,” said Dr. Stone, professor of medicine at Columbia University, New York, and director of the TCT conference.
All subjects in ORBITA did indeed undergo measurement of both FFR and instant Wave-Free Ratio (iFR) while on the table immediately before and after their real or sham PCI. The mean stenosis severity was 0.69 by FFR and 0.76 by iFR, readings indicative of significantly impaired flow. However, the operators were blinded as to those results. The rationale for withholding that information was that, even though it has been shown to be clinically useful, studies show that 80% of angioplasties are done based upon angiography alone, and the ORBITA investigators wanted the study to reflect routine clinical practice, Dr. Al-Lamee explained.
“I think one of the many lessons coming out of this trial is to see the discrepancy between the angiogram and functional testing. We cannot guide our therapy solely by the angiogram. We have to get physiologic data and consider that together with symptoms in the patient’s clinical context,” said panelist Allen Jeremias, MD, director of interventional cardiology research at St. Francis Hospital in Rosyln, N.Y.
Commentary goes too far
The “last-nail-in-the-coffin” Lancet commentary (2017 Nov 2. doi: 10.1016/S0140-6736[17]32757-5) penned by David L. Brown, MD, of Washington University in St. Louis and Rita F. Redberg, MD, of the University of California, San Francisco, emphatically declared that the ORBITA results mean all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite medical therapy. Dr. Al-Lamee was one of many at TCT 2017 who took strong exception to that.
“This is the first trial of its kind. I think it would be very easy to take the results of this trial and overextrapolate. To downgrade the guideline recommendations based on this study would be an incredibly large overreach,” she said.
Ajay J. Kirtane, MD, who chaired a press conference in which Dr. Al-Lamee presented the ORBITA results, had a further criticism of the editorial.
“Some of the risks of PCI as described in the editorial are just factually inaccurate. An MI rate of 15%, an acute kidney injury rate of 13% – those are simply factually incorrect,” said Dr. Kirtane, director of the cardiac catheterization laboratories at New York-Presbyterian/Columbia University Medical Center.
The ORBITA trial was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. Dr. Al-Lamee reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.
AT TCT 2017
Key clinical point:
Major finding: PCI on top of intensive antianginal medications was not significantly more effective at improving exercise tolerance than sham PCI.
Data source: ORBITA, a randomized, multicenter, blinded, sham-controlled study of 200 patients with mild angina and single-vessel CAD.
Disclosures: ORBITA was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. The presenter reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.