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A Very Special Issue
Since 2011, Federal Practitioner and the Association of VA Hematology/Oncology have teamed up to create the “Advances in Hematology and Oncology” special issues. The collaboration has been a rewarding one for everyone involved, and we trust it will continue for years to come.
The issues have showcased the broad experience and expertise of VA hematology and oncology care providers. Over the years, we’ve highlighted the important research often coming out of the VA and have brought that knowledge to an audience that goes well beyond the 900 or so AVAHO members.
Still, that doesn’t seem like enough. More often than not, primary care providers are the first line of defense for patients. More important, as survivorship expands and new therapies continue to increase overall survival, all providers across the federal health care systems are treating patients after their diagnosis. There have been significant developments recently in hematology and oncology, and primary care providers are caring for more patients than ever who have cancer and leukemia, not only at the VA, but also at the PHS and DoD. This research is relevant to the entire Federal Practitioner audience, and we felt it was important to share as widely as possible.
The 7 articles included in this special issue are broad and diverse, illustrating the high degree of specialization that is occurring in the fields of hematology and oncology. These features cover breast cancer, chronic myelogenous leukemia, prostate cancer, mantle cell lymphoma, chronic lymphocytic leukemia, pancreatic cancer, and melanoma. Sometimes, the articles focus on highly specific topics for specialists, such as the role of autologous hematopoietic stem cell transplantation in mantle cell lymphoma. Other times, the articles are aimed at a primary care audience, providing an essential update on prostate cancer survivorship care. In either case, we hope you will find these articles valuable and worthwhile.
To compliment the features, we added a new Patient Information handout on hospice care as well as some recent news updates in our Clinical Digest department. We also wanted to echo these important research updates with audio interviews, blogs, and other online exclusive features.
We would like to thank the Association of VA Hematology/Oncology (AVAHO) for their cooperation and help in putting together this series. The AVAHO mission is to facilitate interaction and cooperation among VA hematology and oncology health care providers and to enhance professional careers and improve patient care, and we are honored to be able to help carry out that mission. The AVAHO Annual Meeting will be September 12-14, 2014, in Portland, Oregon. For more information visit avaho.org.
We would also like to thank Paulette Mehta, MD, MPH, and Peter Silberstein, MD, for their significant efforts and the time they put into making this special issue possible. Their commitment to creating this issue and to ensuring that Federal Practitioner remains on top of the latest advances in trends and practices in these quickly changing fields cannot be understated.
Since 2011, Federal Practitioner and the Association of VA Hematology/Oncology have teamed up to create the “Advances in Hematology and Oncology” special issues. The collaboration has been a rewarding one for everyone involved, and we trust it will continue for years to come.
The issues have showcased the broad experience and expertise of VA hematology and oncology care providers. Over the years, we’ve highlighted the important research often coming out of the VA and have brought that knowledge to an audience that goes well beyond the 900 or so AVAHO members.
Still, that doesn’t seem like enough. More often than not, primary care providers are the first line of defense for patients. More important, as survivorship expands and new therapies continue to increase overall survival, all providers across the federal health care systems are treating patients after their diagnosis. There have been significant developments recently in hematology and oncology, and primary care providers are caring for more patients than ever who have cancer and leukemia, not only at the VA, but also at the PHS and DoD. This research is relevant to the entire Federal Practitioner audience, and we felt it was important to share as widely as possible.
The 7 articles included in this special issue are broad and diverse, illustrating the high degree of specialization that is occurring in the fields of hematology and oncology. These features cover breast cancer, chronic myelogenous leukemia, prostate cancer, mantle cell lymphoma, chronic lymphocytic leukemia, pancreatic cancer, and melanoma. Sometimes, the articles focus on highly specific topics for specialists, such as the role of autologous hematopoietic stem cell transplantation in mantle cell lymphoma. Other times, the articles are aimed at a primary care audience, providing an essential update on prostate cancer survivorship care. In either case, we hope you will find these articles valuable and worthwhile.
To compliment the features, we added a new Patient Information handout on hospice care as well as some recent news updates in our Clinical Digest department. We also wanted to echo these important research updates with audio interviews, blogs, and other online exclusive features.
We would like to thank the Association of VA Hematology/Oncology (AVAHO) for their cooperation and help in putting together this series. The AVAHO mission is to facilitate interaction and cooperation among VA hematology and oncology health care providers and to enhance professional careers and improve patient care, and we are honored to be able to help carry out that mission. The AVAHO Annual Meeting will be September 12-14, 2014, in Portland, Oregon. For more information visit avaho.org.
We would also like to thank Paulette Mehta, MD, MPH, and Peter Silberstein, MD, for their significant efforts and the time they put into making this special issue possible. Their commitment to creating this issue and to ensuring that Federal Practitioner remains on top of the latest advances in trends and practices in these quickly changing fields cannot be understated.
Since 2011, Federal Practitioner and the Association of VA Hematology/Oncology have teamed up to create the “Advances in Hematology and Oncology” special issues. The collaboration has been a rewarding one for everyone involved, and we trust it will continue for years to come.
The issues have showcased the broad experience and expertise of VA hematology and oncology care providers. Over the years, we’ve highlighted the important research often coming out of the VA and have brought that knowledge to an audience that goes well beyond the 900 or so AVAHO members.
Still, that doesn’t seem like enough. More often than not, primary care providers are the first line of defense for patients. More important, as survivorship expands and new therapies continue to increase overall survival, all providers across the federal health care systems are treating patients after their diagnosis. There have been significant developments recently in hematology and oncology, and primary care providers are caring for more patients than ever who have cancer and leukemia, not only at the VA, but also at the PHS and DoD. This research is relevant to the entire Federal Practitioner audience, and we felt it was important to share as widely as possible.
The 7 articles included in this special issue are broad and diverse, illustrating the high degree of specialization that is occurring in the fields of hematology and oncology. These features cover breast cancer, chronic myelogenous leukemia, prostate cancer, mantle cell lymphoma, chronic lymphocytic leukemia, pancreatic cancer, and melanoma. Sometimes, the articles focus on highly specific topics for specialists, such as the role of autologous hematopoietic stem cell transplantation in mantle cell lymphoma. Other times, the articles are aimed at a primary care audience, providing an essential update on prostate cancer survivorship care. In either case, we hope you will find these articles valuable and worthwhile.
To compliment the features, we added a new Patient Information handout on hospice care as well as some recent news updates in our Clinical Digest department. We also wanted to echo these important research updates with audio interviews, blogs, and other online exclusive features.
We would like to thank the Association of VA Hematology/Oncology (AVAHO) for their cooperation and help in putting together this series. The AVAHO mission is to facilitate interaction and cooperation among VA hematology and oncology health care providers and to enhance professional careers and improve patient care, and we are honored to be able to help carry out that mission. The AVAHO Annual Meeting will be September 12-14, 2014, in Portland, Oregon. For more information visit avaho.org.
We would also like to thank Paulette Mehta, MD, MPH, and Peter Silberstein, MD, for their significant efforts and the time they put into making this special issue possible. Their commitment to creating this issue and to ensuring that Federal Practitioner remains on top of the latest advances in trends and practices in these quickly changing fields cannot be understated.
Caring for an expectant mother
"Mrs. Jones in ED room 12? Septic with severe multilobar pneumonia and hypoxemic respiratory failure? Got it. I’m on my way down to the ED now." The heart races in anticipation of caring for this critically ill patient near death’s door. But it’s okay. You know exactly what you have to do. You have done it many times before. No problem. Just as you are about to hang up the phone you learn more ...
"What’s that? She is 22 weeks pregnant? Uh, all right."
Suddenly, what initially seemed to be a routine case takes a complicated twist. You are no longer caring for one life, you are caring for two (or more), and one of those is extremely frail and vulnerable. The bugs, the drugs, maintaining adequate perfusion of vital organs – both hers and her baby’s – the questions of "What if ... ?" and "Should I ... ?" race through your mind. Should you get infectious disease and pulmonary consultations for an added layer of protection or should you treat her as you have treated so many others before her, the caveat, of course, being the need to check every single drug for its teratogenicity.
If you have ever felt at least a little queasiness in the pit of your stomach when called upon to care for an expectant mother, you are notalone. I think it is natural to feel a bit uneasy when we care for pregnant patients because most of us do it rather infrequently and there may not be room for a do-over even if you make the tiniest mistake. Each drug we order has the potential to do harm and any missed or delayed diagnosis may be tolerated well by mom, but maybe not much by the tiny baby growing inside her. Get it right and the family may live a storybook fantasy. Yet, a single miscalculation, an honest mistake, and that innocent child’s future may be compromised or destroyed.
Fortunately, these days, horror stories seem to be less frequent than in the past. But we must remain vigilant to not only optimally treat our patient (mommy), but also to protect our patients (mommy and baby) from future complications of treatment. If there is any doubt, go ahead and call an infectious disease and pulmonary consultation. Sometimes, everyone sleeps better when we do.
Dr. A. Maria Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.
"Mrs. Jones in ED room 12? Septic with severe multilobar pneumonia and hypoxemic respiratory failure? Got it. I’m on my way down to the ED now." The heart races in anticipation of caring for this critically ill patient near death’s door. But it’s okay. You know exactly what you have to do. You have done it many times before. No problem. Just as you are about to hang up the phone you learn more ...
"What’s that? She is 22 weeks pregnant? Uh, all right."
Suddenly, what initially seemed to be a routine case takes a complicated twist. You are no longer caring for one life, you are caring for two (or more), and one of those is extremely frail and vulnerable. The bugs, the drugs, maintaining adequate perfusion of vital organs – both hers and her baby’s – the questions of "What if ... ?" and "Should I ... ?" race through your mind. Should you get infectious disease and pulmonary consultations for an added layer of protection or should you treat her as you have treated so many others before her, the caveat, of course, being the need to check every single drug for its teratogenicity.
If you have ever felt at least a little queasiness in the pit of your stomach when called upon to care for an expectant mother, you are notalone. I think it is natural to feel a bit uneasy when we care for pregnant patients because most of us do it rather infrequently and there may not be room for a do-over even if you make the tiniest mistake. Each drug we order has the potential to do harm and any missed or delayed diagnosis may be tolerated well by mom, but maybe not much by the tiny baby growing inside her. Get it right and the family may live a storybook fantasy. Yet, a single miscalculation, an honest mistake, and that innocent child’s future may be compromised or destroyed.
Fortunately, these days, horror stories seem to be less frequent than in the past. But we must remain vigilant to not only optimally treat our patient (mommy), but also to protect our patients (mommy and baby) from future complications of treatment. If there is any doubt, go ahead and call an infectious disease and pulmonary consultation. Sometimes, everyone sleeps better when we do.
Dr. A. Maria Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.
"Mrs. Jones in ED room 12? Septic with severe multilobar pneumonia and hypoxemic respiratory failure? Got it. I’m on my way down to the ED now." The heart races in anticipation of caring for this critically ill patient near death’s door. But it’s okay. You know exactly what you have to do. You have done it many times before. No problem. Just as you are about to hang up the phone you learn more ...
"What’s that? She is 22 weeks pregnant? Uh, all right."
Suddenly, what initially seemed to be a routine case takes a complicated twist. You are no longer caring for one life, you are caring for two (or more), and one of those is extremely frail and vulnerable. The bugs, the drugs, maintaining adequate perfusion of vital organs – both hers and her baby’s – the questions of "What if ... ?" and "Should I ... ?" race through your mind. Should you get infectious disease and pulmonary consultations for an added layer of protection or should you treat her as you have treated so many others before her, the caveat, of course, being the need to check every single drug for its teratogenicity.
If you have ever felt at least a little queasiness in the pit of your stomach when called upon to care for an expectant mother, you are notalone. I think it is natural to feel a bit uneasy when we care for pregnant patients because most of us do it rather infrequently and there may not be room for a do-over even if you make the tiniest mistake. Each drug we order has the potential to do harm and any missed or delayed diagnosis may be tolerated well by mom, but maybe not much by the tiny baby growing inside her. Get it right and the family may live a storybook fantasy. Yet, a single miscalculation, an honest mistake, and that innocent child’s future may be compromised or destroyed.
Fortunately, these days, horror stories seem to be less frequent than in the past. But we must remain vigilant to not only optimally treat our patient (mommy), but also to protect our patients (mommy and baby) from future complications of treatment. If there is any doubt, go ahead and call an infectious disease and pulmonary consultation. Sometimes, everyone sleeps better when we do.
Dr. A. Maria Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.
File it under fiction
Doctors once received a free pass when it came to penmanship. We wrote our prescriptions in Latin. So, it was okay that everything else we scribbled looked like Greek. Referrals and consultations occurred in hospital corridors or doctors’ lounges. Documentation was spotty if it happened at all. Our handwriting was a joke. As long as we could sort of decipher our own scribbling, that was okay. But, the laughing stopped when third-party payers began to ask for proof that they were getting their money’s worth for our services – a proof that they could read.
Dictation with transcription was the obvious solution. It was efficient and produced a legible result. Whatever was lost in transcription resulted in humorous and usually harmless errors. As a card-carrying cheapskate, I typed my own letters. My typos added a kind of homey touch to my communications, and they were certainly more readable than my scrawl.
Dictated and transcribed reports seemed to be a relatively accurate reflection of what had occurred at an office visit, and it kept the payers happy for a while. Most physicians continued to handwrite their office notes. But, it was clear that handwriting was coming off the walls. Insurance companies, the government, quality control folks, and risk assessment managers all wanted more documentation. Computerization seemed to offer a reasonable compromise. The payers got the data, and physicians could take advantage of the efficiencies that electronic records promised.
The software vendors’ sales pitch went like this, "Doc, aren’t most of your visits pretty much the same? History, physical, lab, diagnosis, plan? And, you do pretty much the same exam on everyone? And most of the stuff is normal, right? We’ll show you how to make some templates that will save you a ton of time without all that repetition – done in just a couple of mouse clicks."
So, the templates were made, sometimes with the physician’s help, but often without. And accuracy was sacrificed in the name of legibility and efficiency. The problem is that patients with the same diagnosis aren’t all the same. Their examinations are as different as snowflakes.
What makes a normal ENT exam normal? Is the absence of tonsils worth noting? A bifid uvula? It depends. What does the template include in its definition of normal? More importantly, does the physician remember or did he ever know what his computer considers normal? With a single mouse click, he can create a crisp, laser-printable document that because of its legibility and level of detail appears to be the gospel truth.
But of course, sometimes and certainly too often, it’s not the truth. I recently received an e-mail from a pediatrician who said that he files the EHR records from specialists, emergency departments, and urgent care centers in the "fiction section." He cited an example of a report from a neurologist about a 10-month-old that included a "normal sense of smell" and a warning against driving while taking the medicine prescribed. I can’t top that; maybe you can. But I certainly have received numerous reports that clearly bore little relationship to what had transpired in the clinic or specialist’s office – complete neurologic exams that would have taken 30 minutes to perform, normal tympanic membranes in children with PE (pressure equalization) tubes or cavernous perforations.
Although I frequently complain about the sad state of the physical examination, a bigger problem may be the reliance on the EHR to document the result of the exam. I fear there is little incentive to correct the problem because of the malpractice lawyers’ mantra, "if you didn’t document it, it wasn’t done." Unfortunately, that has come to mean that if it’s legible and detailed, it must be the truth. I would enjoy hearing from you some examples in which you know this clearly wasn’t the case.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including "How to Say No to Your Toddler." E-mail him at [email protected].
Doctors once received a free pass when it came to penmanship. We wrote our prescriptions in Latin. So, it was okay that everything else we scribbled looked like Greek. Referrals and consultations occurred in hospital corridors or doctors’ lounges. Documentation was spotty if it happened at all. Our handwriting was a joke. As long as we could sort of decipher our own scribbling, that was okay. But, the laughing stopped when third-party payers began to ask for proof that they were getting their money’s worth for our services – a proof that they could read.
Dictation with transcription was the obvious solution. It was efficient and produced a legible result. Whatever was lost in transcription resulted in humorous and usually harmless errors. As a card-carrying cheapskate, I typed my own letters. My typos added a kind of homey touch to my communications, and they were certainly more readable than my scrawl.
Dictated and transcribed reports seemed to be a relatively accurate reflection of what had occurred at an office visit, and it kept the payers happy for a while. Most physicians continued to handwrite their office notes. But, it was clear that handwriting was coming off the walls. Insurance companies, the government, quality control folks, and risk assessment managers all wanted more documentation. Computerization seemed to offer a reasonable compromise. The payers got the data, and physicians could take advantage of the efficiencies that electronic records promised.
The software vendors’ sales pitch went like this, "Doc, aren’t most of your visits pretty much the same? History, physical, lab, diagnosis, plan? And, you do pretty much the same exam on everyone? And most of the stuff is normal, right? We’ll show you how to make some templates that will save you a ton of time without all that repetition – done in just a couple of mouse clicks."
So, the templates were made, sometimes with the physician’s help, but often without. And accuracy was sacrificed in the name of legibility and efficiency. The problem is that patients with the same diagnosis aren’t all the same. Their examinations are as different as snowflakes.
What makes a normal ENT exam normal? Is the absence of tonsils worth noting? A bifid uvula? It depends. What does the template include in its definition of normal? More importantly, does the physician remember or did he ever know what his computer considers normal? With a single mouse click, he can create a crisp, laser-printable document that because of its legibility and level of detail appears to be the gospel truth.
But of course, sometimes and certainly too often, it’s not the truth. I recently received an e-mail from a pediatrician who said that he files the EHR records from specialists, emergency departments, and urgent care centers in the "fiction section." He cited an example of a report from a neurologist about a 10-month-old that included a "normal sense of smell" and a warning against driving while taking the medicine prescribed. I can’t top that; maybe you can. But I certainly have received numerous reports that clearly bore little relationship to what had transpired in the clinic or specialist’s office – complete neurologic exams that would have taken 30 minutes to perform, normal tympanic membranes in children with PE (pressure equalization) tubes or cavernous perforations.
Although I frequently complain about the sad state of the physical examination, a bigger problem may be the reliance on the EHR to document the result of the exam. I fear there is little incentive to correct the problem because of the malpractice lawyers’ mantra, "if you didn’t document it, it wasn’t done." Unfortunately, that has come to mean that if it’s legible and detailed, it must be the truth. I would enjoy hearing from you some examples in which you know this clearly wasn’t the case.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including "How to Say No to Your Toddler." E-mail him at [email protected].
Doctors once received a free pass when it came to penmanship. We wrote our prescriptions in Latin. So, it was okay that everything else we scribbled looked like Greek. Referrals and consultations occurred in hospital corridors or doctors’ lounges. Documentation was spotty if it happened at all. Our handwriting was a joke. As long as we could sort of decipher our own scribbling, that was okay. But, the laughing stopped when third-party payers began to ask for proof that they were getting their money’s worth for our services – a proof that they could read.
Dictation with transcription was the obvious solution. It was efficient and produced a legible result. Whatever was lost in transcription resulted in humorous and usually harmless errors. As a card-carrying cheapskate, I typed my own letters. My typos added a kind of homey touch to my communications, and they were certainly more readable than my scrawl.
Dictated and transcribed reports seemed to be a relatively accurate reflection of what had occurred at an office visit, and it kept the payers happy for a while. Most physicians continued to handwrite their office notes. But, it was clear that handwriting was coming off the walls. Insurance companies, the government, quality control folks, and risk assessment managers all wanted more documentation. Computerization seemed to offer a reasonable compromise. The payers got the data, and physicians could take advantage of the efficiencies that electronic records promised.
The software vendors’ sales pitch went like this, "Doc, aren’t most of your visits pretty much the same? History, physical, lab, diagnosis, plan? And, you do pretty much the same exam on everyone? And most of the stuff is normal, right? We’ll show you how to make some templates that will save you a ton of time without all that repetition – done in just a couple of mouse clicks."
So, the templates were made, sometimes with the physician’s help, but often without. And accuracy was sacrificed in the name of legibility and efficiency. The problem is that patients with the same diagnosis aren’t all the same. Their examinations are as different as snowflakes.
What makes a normal ENT exam normal? Is the absence of tonsils worth noting? A bifid uvula? It depends. What does the template include in its definition of normal? More importantly, does the physician remember or did he ever know what his computer considers normal? With a single mouse click, he can create a crisp, laser-printable document that because of its legibility and level of detail appears to be the gospel truth.
But of course, sometimes and certainly too often, it’s not the truth. I recently received an e-mail from a pediatrician who said that he files the EHR records from specialists, emergency departments, and urgent care centers in the "fiction section." He cited an example of a report from a neurologist about a 10-month-old that included a "normal sense of smell" and a warning against driving while taking the medicine prescribed. I can’t top that; maybe you can. But I certainly have received numerous reports that clearly bore little relationship to what had transpired in the clinic or specialist’s office – complete neurologic exams that would have taken 30 minutes to perform, normal tympanic membranes in children with PE (pressure equalization) tubes or cavernous perforations.
Although I frequently complain about the sad state of the physical examination, a bigger problem may be the reliance on the EHR to document the result of the exam. I fear there is little incentive to correct the problem because of the malpractice lawyers’ mantra, "if you didn’t document it, it wasn’t done." Unfortunately, that has come to mean that if it’s legible and detailed, it must be the truth. I would enjoy hearing from you some examples in which you know this clearly wasn’t the case.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including "How to Say No to Your Toddler." E-mail him at [email protected].
Almonds
A tree species belonging to the Rosaceae family and native to the Middle East and South Asia, Prunus dulcis (also called Prunus amygdalus), popularly known as almond, is cultivated widely in warm, arid locations and used primarily for its edible seeds (J. Agric. Food Chem. 2007;55:8498-507; J. Agric. Food Chem. 2006;54:312-8). Almonds and almond skins are rich in polyphenols and are an important source of these phytonutrients, particularly flavan-3-ols and flavonols (J. Proteome Res. 2010;9:5859-67). Almonds also are known to contain an abundance of fiber (Anaerobe 2014;26:1-6). Almond extracts are used in cosmetic formulations because of their high concentration of polyphenols, particularly flavonoids and phenolic acids (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Key components
In 2006, Milbury et al. determined that the main flavonoids and phenolic acids in Prunus dulcis skins and kernels are isorhamnetin-3-O-rutinoside and isorhamnetin-3-O-glucoside (in combination), catechin, kaempferol-3-O-rutinoside, epicatechin, quercetin-3-O-galactoside, and isorhamnetin-3-O-galactoside (J. Agric. Food Chem. 2006;54:5027-33).
In a separate study that year, Wijeratne et al. identified quercetin, isorhamnetin, quercitrin, kaempferol 3-O-rutinoside, isorhamnetin 3-O-glucoside, and morin as the primary flavonoids in various whole-seed, brown, skin, and green-shell-cover almond extracts (J. Agric. Food Chem. 2006;54:312-8). Almond seed skin also has been shown to contain highly polymerized polyphenols that exhibit potent alpha-amylase inhibitory activity, thus slowing the absorption of carbohydrate (J. Agric. Food Chem. 2013;61:4570-6).
In 2010, Bartolomé et al. identified A- and B-type procyanidin, propelargonidin, and prodelphinidin polymers in almond skins. In human plasma and urine samples taken after consumption of almond skin polyphenols, the investigators detected O-methyl glucuronide sulfate and O-methyl sulfate derivatives of (epi)catechin; the glucuronide conjugates of naringenin and isorhamnetin; and sulfate conjugates of isorhamnetin, together with conjugates of hydroxyphenylvalerolactones. They also identified various microbial-derived metabolites, including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxyhippuric acids (Arch. Biochem. Biophys. 2010;501:124-33).
A functional food: Antioxidant constituents and activity
In a study of two human subjects conducted in 2009, Urpi-Sarda et al. profiled microbial-derived phenolic metabolites in plasma and urine samples before and after the consumption of almond skins. They detected glucuronide, O-methyl glucuronide sulfate, and O-methyl sulfate derivatives of epicatechin, the glucuronide conjugates of naringenin and glucuronide, and sulfate conjugates of isorhamnetin. The researchers also detected, in their glucuronide and sulfate forms, microbial-derived metabolites of flavanols, including 5-(dihydroxyphenyl)-gamma-valerolactone and 5-(hydroxymethoxyphenyl)-gamma-valerolactone (J. Agric. Food Chem. 2009;57:10134-42).
A 2010 study with 24 volunteers conducted by Llorach et al. investigated urinary metabolome changes during the 24-hour period following ingestion of a single dose of almond skin extract. The participants, who were following a polyphenol-free diet for 48 hours, were divided into two groups: the almond skin group or a placebo group. Thirty-four metabolites were linked to the consumption of the almond extract (J. Proteome Res. 2010;9:5859-67).
Monagas et al. previously led a comprehensive investigation of the phenolic composition of almond skins to elucidate its potential as a functional food. They identified 33 compounds, including flavanols, flavonols, dihydroflavonols, and flavanones, as well as nonflavonoid substances. The most abundant phenols were flavanols (38%-57%) and flavonol glycosides (14%-35%). Further, the researchers measured the oxygen radical absorbance capacity of almond skins at 0.398-0.500 mmol Trolox/g, a range that suggests its antioxidant potency (J. Agric. Food Chem. 2007;55:8498-507).
In 2008, Garrido et al. investigated the phenolic composition and antioxidant activity of almond skins (Prunus dulcis) obtained from three almond varieties and through various industrial processes, including blanching, blanching and drying, as well as roasting. Identified were 31 phenolic compounds, including flavan-3-ols, flavonol glycosides, hydroxybenzoic acids and aldehydes, flavonol aglycones, flavanone glycosides, flavanone aglycones, hydroxycinnamic acids, and dihydroflavonol aglycones. Phenolic content as well as antioxidant activity were significantly higher in the roasted samples (J. Food Sci. 2008;73:C106-15).
In 2014, Liu et al. conducted a study in healthy humans of the potential prebiotic effects of consuming almonds and almond skins. For 6 weeks, 48 adult volunteers ingested a daily dose of roasted almonds, almond skins, or a positive control (commercial fructo-oligosaccharides). The investigators collected fecal samples and analyzed them for microbiota composition. They observed significant increases in populations of Bifidobacterium spp. and Lactobacillus spp. in fecal samples after almond or almond skin supplementation; substantial inhibition of the growth of the pathogen Clostridium perfringens; and favorable changes in bacterial enzyme activities. They concluded that almonds and almond skins appear to exhibit potential prebiotic qualities (Anaerobe 2014;26:1-6).
Topical antiaging potential
In 2011, Sachdeva and Katyal assessed the antioxidant and antiwrinkle effects of almond skin extracts in UV-induced photoaging in mice. Twenty-five mice were used as an unirradiated control, receiving neither UV exposure nor almond skin treatment. A second group of 24 mice received only UV exposure of 5 minutes twice a day, and served as an irradiated control. Further groups of 24 mice received both UV radiation and treatment with prepared formulation. The treatment groups received various topical almond skin extract doses 2 hours prior to the same level of UV exposure. Significant decreases in malondialdehyde and increases in glutathione levels, respectively, suggested to the investigators that the almond skin extracts effectively scavenged free radicals while also enhancing moisturization. They concluded that almond skin extracts display potential as antiaging ingredients in topical cosmetic formulations (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Conclusion
Almonds are believed to be a healthy addition to the human diet, with their regular consumption thought to confer cardiovascular benefits. The healthful effects of dietary intake of almonds are often attributed to the presence of several polyphenolic constituents. While it is speculated that such ingredients also play a role in imparting cutaneous benefits, the body of evidence supporting such claims remains sparse to date. Nevertheless, P. dulcis is incorporated in various cosmetic formulations. More research is necessary to ascertain whether such inclusion is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
A tree species belonging to the Rosaceae family and native to the Middle East and South Asia, Prunus dulcis (also called Prunus amygdalus), popularly known as almond, is cultivated widely in warm, arid locations and used primarily for its edible seeds (J. Agric. Food Chem. 2007;55:8498-507; J. Agric. Food Chem. 2006;54:312-8). Almonds and almond skins are rich in polyphenols and are an important source of these phytonutrients, particularly flavan-3-ols and flavonols (J. Proteome Res. 2010;9:5859-67). Almonds also are known to contain an abundance of fiber (Anaerobe 2014;26:1-6). Almond extracts are used in cosmetic formulations because of their high concentration of polyphenols, particularly flavonoids and phenolic acids (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Key components
In 2006, Milbury et al. determined that the main flavonoids and phenolic acids in Prunus dulcis skins and kernels are isorhamnetin-3-O-rutinoside and isorhamnetin-3-O-glucoside (in combination), catechin, kaempferol-3-O-rutinoside, epicatechin, quercetin-3-O-galactoside, and isorhamnetin-3-O-galactoside (J. Agric. Food Chem. 2006;54:5027-33).
In a separate study that year, Wijeratne et al. identified quercetin, isorhamnetin, quercitrin, kaempferol 3-O-rutinoside, isorhamnetin 3-O-glucoside, and morin as the primary flavonoids in various whole-seed, brown, skin, and green-shell-cover almond extracts (J. Agric. Food Chem. 2006;54:312-8). Almond seed skin also has been shown to contain highly polymerized polyphenols that exhibit potent alpha-amylase inhibitory activity, thus slowing the absorption of carbohydrate (J. Agric. Food Chem. 2013;61:4570-6).
In 2010, Bartolomé et al. identified A- and B-type procyanidin, propelargonidin, and prodelphinidin polymers in almond skins. In human plasma and urine samples taken after consumption of almond skin polyphenols, the investigators detected O-methyl glucuronide sulfate and O-methyl sulfate derivatives of (epi)catechin; the glucuronide conjugates of naringenin and isorhamnetin; and sulfate conjugates of isorhamnetin, together with conjugates of hydroxyphenylvalerolactones. They also identified various microbial-derived metabolites, including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxyhippuric acids (Arch. Biochem. Biophys. 2010;501:124-33).
A functional food: Antioxidant constituents and activity
In a study of two human subjects conducted in 2009, Urpi-Sarda et al. profiled microbial-derived phenolic metabolites in plasma and urine samples before and after the consumption of almond skins. They detected glucuronide, O-methyl glucuronide sulfate, and O-methyl sulfate derivatives of epicatechin, the glucuronide conjugates of naringenin and glucuronide, and sulfate conjugates of isorhamnetin. The researchers also detected, in their glucuronide and sulfate forms, microbial-derived metabolites of flavanols, including 5-(dihydroxyphenyl)-gamma-valerolactone and 5-(hydroxymethoxyphenyl)-gamma-valerolactone (J. Agric. Food Chem. 2009;57:10134-42).
A 2010 study with 24 volunteers conducted by Llorach et al. investigated urinary metabolome changes during the 24-hour period following ingestion of a single dose of almond skin extract. The participants, who were following a polyphenol-free diet for 48 hours, were divided into two groups: the almond skin group or a placebo group. Thirty-four metabolites were linked to the consumption of the almond extract (J. Proteome Res. 2010;9:5859-67).
Monagas et al. previously led a comprehensive investigation of the phenolic composition of almond skins to elucidate its potential as a functional food. They identified 33 compounds, including flavanols, flavonols, dihydroflavonols, and flavanones, as well as nonflavonoid substances. The most abundant phenols were flavanols (38%-57%) and flavonol glycosides (14%-35%). Further, the researchers measured the oxygen radical absorbance capacity of almond skins at 0.398-0.500 mmol Trolox/g, a range that suggests its antioxidant potency (J. Agric. Food Chem. 2007;55:8498-507).
In 2008, Garrido et al. investigated the phenolic composition and antioxidant activity of almond skins (Prunus dulcis) obtained from three almond varieties and through various industrial processes, including blanching, blanching and drying, as well as roasting. Identified were 31 phenolic compounds, including flavan-3-ols, flavonol glycosides, hydroxybenzoic acids and aldehydes, flavonol aglycones, flavanone glycosides, flavanone aglycones, hydroxycinnamic acids, and dihydroflavonol aglycones. Phenolic content as well as antioxidant activity were significantly higher in the roasted samples (J. Food Sci. 2008;73:C106-15).
In 2014, Liu et al. conducted a study in healthy humans of the potential prebiotic effects of consuming almonds and almond skins. For 6 weeks, 48 adult volunteers ingested a daily dose of roasted almonds, almond skins, or a positive control (commercial fructo-oligosaccharides). The investigators collected fecal samples and analyzed them for microbiota composition. They observed significant increases in populations of Bifidobacterium spp. and Lactobacillus spp. in fecal samples after almond or almond skin supplementation; substantial inhibition of the growth of the pathogen Clostridium perfringens; and favorable changes in bacterial enzyme activities. They concluded that almonds and almond skins appear to exhibit potential prebiotic qualities (Anaerobe 2014;26:1-6).
Topical antiaging potential
In 2011, Sachdeva and Katyal assessed the antioxidant and antiwrinkle effects of almond skin extracts in UV-induced photoaging in mice. Twenty-five mice were used as an unirradiated control, receiving neither UV exposure nor almond skin treatment. A second group of 24 mice received only UV exposure of 5 minutes twice a day, and served as an irradiated control. Further groups of 24 mice received both UV radiation and treatment with prepared formulation. The treatment groups received various topical almond skin extract doses 2 hours prior to the same level of UV exposure. Significant decreases in malondialdehyde and increases in glutathione levels, respectively, suggested to the investigators that the almond skin extracts effectively scavenged free radicals while also enhancing moisturization. They concluded that almond skin extracts display potential as antiaging ingredients in topical cosmetic formulations (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Conclusion
Almonds are believed to be a healthy addition to the human diet, with their regular consumption thought to confer cardiovascular benefits. The healthful effects of dietary intake of almonds are often attributed to the presence of several polyphenolic constituents. While it is speculated that such ingredients also play a role in imparting cutaneous benefits, the body of evidence supporting such claims remains sparse to date. Nevertheless, P. dulcis is incorporated in various cosmetic formulations. More research is necessary to ascertain whether such inclusion is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
A tree species belonging to the Rosaceae family and native to the Middle East and South Asia, Prunus dulcis (also called Prunus amygdalus), popularly known as almond, is cultivated widely in warm, arid locations and used primarily for its edible seeds (J. Agric. Food Chem. 2007;55:8498-507; J. Agric. Food Chem. 2006;54:312-8). Almonds and almond skins are rich in polyphenols and are an important source of these phytonutrients, particularly flavan-3-ols and flavonols (J. Proteome Res. 2010;9:5859-67). Almonds also are known to contain an abundance of fiber (Anaerobe 2014;26:1-6). Almond extracts are used in cosmetic formulations because of their high concentration of polyphenols, particularly flavonoids and phenolic acids (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Key components
In 2006, Milbury et al. determined that the main flavonoids and phenolic acids in Prunus dulcis skins and kernels are isorhamnetin-3-O-rutinoside and isorhamnetin-3-O-glucoside (in combination), catechin, kaempferol-3-O-rutinoside, epicatechin, quercetin-3-O-galactoside, and isorhamnetin-3-O-galactoside (J. Agric. Food Chem. 2006;54:5027-33).
In a separate study that year, Wijeratne et al. identified quercetin, isorhamnetin, quercitrin, kaempferol 3-O-rutinoside, isorhamnetin 3-O-glucoside, and morin as the primary flavonoids in various whole-seed, brown, skin, and green-shell-cover almond extracts (J. Agric. Food Chem. 2006;54:312-8). Almond seed skin also has been shown to contain highly polymerized polyphenols that exhibit potent alpha-amylase inhibitory activity, thus slowing the absorption of carbohydrate (J. Agric. Food Chem. 2013;61:4570-6).
In 2010, Bartolomé et al. identified A- and B-type procyanidin, propelargonidin, and prodelphinidin polymers in almond skins. In human plasma and urine samples taken after consumption of almond skin polyphenols, the investigators detected O-methyl glucuronide sulfate and O-methyl sulfate derivatives of (epi)catechin; the glucuronide conjugates of naringenin and isorhamnetin; and sulfate conjugates of isorhamnetin, together with conjugates of hydroxyphenylvalerolactones. They also identified various microbial-derived metabolites, including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxyhippuric acids (Arch. Biochem. Biophys. 2010;501:124-33).
A functional food: Antioxidant constituents and activity
In a study of two human subjects conducted in 2009, Urpi-Sarda et al. profiled microbial-derived phenolic metabolites in plasma and urine samples before and after the consumption of almond skins. They detected glucuronide, O-methyl glucuronide sulfate, and O-methyl sulfate derivatives of epicatechin, the glucuronide conjugates of naringenin and glucuronide, and sulfate conjugates of isorhamnetin. The researchers also detected, in their glucuronide and sulfate forms, microbial-derived metabolites of flavanols, including 5-(dihydroxyphenyl)-gamma-valerolactone and 5-(hydroxymethoxyphenyl)-gamma-valerolactone (J. Agric. Food Chem. 2009;57:10134-42).
A 2010 study with 24 volunteers conducted by Llorach et al. investigated urinary metabolome changes during the 24-hour period following ingestion of a single dose of almond skin extract. The participants, who were following a polyphenol-free diet for 48 hours, were divided into two groups: the almond skin group or a placebo group. Thirty-four metabolites were linked to the consumption of the almond extract (J. Proteome Res. 2010;9:5859-67).
Monagas et al. previously led a comprehensive investigation of the phenolic composition of almond skins to elucidate its potential as a functional food. They identified 33 compounds, including flavanols, flavonols, dihydroflavonols, and flavanones, as well as nonflavonoid substances. The most abundant phenols were flavanols (38%-57%) and flavonol glycosides (14%-35%). Further, the researchers measured the oxygen radical absorbance capacity of almond skins at 0.398-0.500 mmol Trolox/g, a range that suggests its antioxidant potency (J. Agric. Food Chem. 2007;55:8498-507).
In 2008, Garrido et al. investigated the phenolic composition and antioxidant activity of almond skins (Prunus dulcis) obtained from three almond varieties and through various industrial processes, including blanching, blanching and drying, as well as roasting. Identified were 31 phenolic compounds, including flavan-3-ols, flavonol glycosides, hydroxybenzoic acids and aldehydes, flavonol aglycones, flavanone glycosides, flavanone aglycones, hydroxycinnamic acids, and dihydroflavonol aglycones. Phenolic content as well as antioxidant activity were significantly higher in the roasted samples (J. Food Sci. 2008;73:C106-15).
In 2014, Liu et al. conducted a study in healthy humans of the potential prebiotic effects of consuming almonds and almond skins. For 6 weeks, 48 adult volunteers ingested a daily dose of roasted almonds, almond skins, or a positive control (commercial fructo-oligosaccharides). The investigators collected fecal samples and analyzed them for microbiota composition. They observed significant increases in populations of Bifidobacterium spp. and Lactobacillus spp. in fecal samples after almond or almond skin supplementation; substantial inhibition of the growth of the pathogen Clostridium perfringens; and favorable changes in bacterial enzyme activities. They concluded that almonds and almond skins appear to exhibit potential prebiotic qualities (Anaerobe 2014;26:1-6).
Topical antiaging potential
In 2011, Sachdeva and Katyal assessed the antioxidant and antiwrinkle effects of almond skin extracts in UV-induced photoaging in mice. Twenty-five mice were used as an unirradiated control, receiving neither UV exposure nor almond skin treatment. A second group of 24 mice received only UV exposure of 5 minutes twice a day, and served as an irradiated control. Further groups of 24 mice received both UV radiation and treatment with prepared formulation. The treatment groups received various topical almond skin extract doses 2 hours prior to the same level of UV exposure. Significant decreases in malondialdehyde and increases in glutathione levels, respectively, suggested to the investigators that the almond skin extracts effectively scavenged free radicals while also enhancing moisturization. They concluded that almond skin extracts display potential as antiaging ingredients in topical cosmetic formulations (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Conclusion
Almonds are believed to be a healthy addition to the human diet, with their regular consumption thought to confer cardiovascular benefits. The healthful effects of dietary intake of almonds are often attributed to the presence of several polyphenolic constituents. While it is speculated that such ingredients also play a role in imparting cutaneous benefits, the body of evidence supporting such claims remains sparse to date. Nevertheless, P. dulcis is incorporated in various cosmetic formulations. More research is necessary to ascertain whether such inclusion is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Why EHRs are not the face of digital health technology
Medical imaging was the first taste of digital health technology for physicians and most health care providers. The technology provides prompt high-quality information which improves efficiency and is mobile. Then came electronic health records (EHRs). EHRs were mandated as part of the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009. The goals of EHRs are to improve patient safety, decrease costs, and allow for the seamless exchange of information among providers and providing entities. As a proponent of digital health technologies, I submit that they are patient advocacy tools. The debate over the "effectiveness"of EHRs continues. It is too early to evaluate the true impact of EHRs on patient care at this juncture. Stage 1 of Meaningful Use (MU) of EHRs pertains solely to data capture. It is with Stages 2 and 3 that patient engagement and clinical decision support tools are incorporated in processes around the EHR. These stages have not been fully implemented and won’t be for a few years to come. Therefore those attributes of MU potentially having the most impact on patients are not in use today. What we do know is that: A) Physicians are spending more time looking at computer screens than into the faces of the people they are treating. B) That much of the data entered is to satisfy regulations of the HITECH Act and not directly related to patient care. C) That EHRs were designed for billing and regulatory purposes and do not in any way reflect clinical work flow. D) EHRs do not integrate well with medical devices or disparate digital health technology systems. However some excellent progress has been made in developing true interoperability among systems.
The EHR does not represent the face of digital technology in health care. Mobile health technologies, wearable sensor technologies, aging at home technologies, and ingestible medication sensor technology populate today’s digital health landscape. These are developments which will contribute directly to more efficient and improved patient care. They will address gaps in care. Having a mother who is ill and requiring significant help at home has taken me on a journey riddled with frustration and pain that is also experienced by my patients and their caregivers daily. It has made me a better physician, who realizes that the most important aspect of care is empathy. Most people view technology as a something that creates a divide between provider and patient. Effective technology can actually bring them closer. It can deliver trending data (which must be accurate, filtered, and actionable in order to be useful), drastically altering care recommendations and preventing hospitalizations and medical emergencies. While there remains much to be proven with regards to digital technologies, I expect them to become a backbone of the health care landscape.
Another digital health technology sector making its way into advanced health care enterprises is analytics. These tools take health care "big data" and make it relevant to treating individual patients as well as populations. Use cases for health care analytics demonstrate that EHRs, while being innately clumsy can be transformed into powerful sources of useful information.
Patients as consumers are demanding mobile tools long utilized in the retail and finance sectors . Examples can be seen in patient-physician video conferencing, mobile appointment schedulers, and even a smartphone ECG rhythm monitor. Digital health also involves social media. Patients are now finding themselves in online patient support groups. There are significant advantages of online versus real life support groups. On the provider side, digital tools such as Doximity and Epocratesare widely used.
In summary, the digital health landscape is much broader and friendlier than the EHR of today. I look forward to EHRs becoming more user friendly and clinically rewarding.
Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.
Medical imaging was the first taste of digital health technology for physicians and most health care providers. The technology provides prompt high-quality information which improves efficiency and is mobile. Then came electronic health records (EHRs). EHRs were mandated as part of the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009. The goals of EHRs are to improve patient safety, decrease costs, and allow for the seamless exchange of information among providers and providing entities. As a proponent of digital health technologies, I submit that they are patient advocacy tools. The debate over the "effectiveness"of EHRs continues. It is too early to evaluate the true impact of EHRs on patient care at this juncture. Stage 1 of Meaningful Use (MU) of EHRs pertains solely to data capture. It is with Stages 2 and 3 that patient engagement and clinical decision support tools are incorporated in processes around the EHR. These stages have not been fully implemented and won’t be for a few years to come. Therefore those attributes of MU potentially having the most impact on patients are not in use today. What we do know is that: A) Physicians are spending more time looking at computer screens than into the faces of the people they are treating. B) That much of the data entered is to satisfy regulations of the HITECH Act and not directly related to patient care. C) That EHRs were designed for billing and regulatory purposes and do not in any way reflect clinical work flow. D) EHRs do not integrate well with medical devices or disparate digital health technology systems. However some excellent progress has been made in developing true interoperability among systems.
The EHR does not represent the face of digital technology in health care. Mobile health technologies, wearable sensor technologies, aging at home technologies, and ingestible medication sensor technology populate today’s digital health landscape. These are developments which will contribute directly to more efficient and improved patient care. They will address gaps in care. Having a mother who is ill and requiring significant help at home has taken me on a journey riddled with frustration and pain that is also experienced by my patients and their caregivers daily. It has made me a better physician, who realizes that the most important aspect of care is empathy. Most people view technology as a something that creates a divide between provider and patient. Effective technology can actually bring them closer. It can deliver trending data (which must be accurate, filtered, and actionable in order to be useful), drastically altering care recommendations and preventing hospitalizations and medical emergencies. While there remains much to be proven with regards to digital technologies, I expect them to become a backbone of the health care landscape.
Another digital health technology sector making its way into advanced health care enterprises is analytics. These tools take health care "big data" and make it relevant to treating individual patients as well as populations. Use cases for health care analytics demonstrate that EHRs, while being innately clumsy can be transformed into powerful sources of useful information.
Patients as consumers are demanding mobile tools long utilized in the retail and finance sectors . Examples can be seen in patient-physician video conferencing, mobile appointment schedulers, and even a smartphone ECG rhythm monitor. Digital health also involves social media. Patients are now finding themselves in online patient support groups. There are significant advantages of online versus real life support groups. On the provider side, digital tools such as Doximity and Epocratesare widely used.
In summary, the digital health landscape is much broader and friendlier than the EHR of today. I look forward to EHRs becoming more user friendly and clinically rewarding.
Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.
Medical imaging was the first taste of digital health technology for physicians and most health care providers. The technology provides prompt high-quality information which improves efficiency and is mobile. Then came electronic health records (EHRs). EHRs were mandated as part of the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009. The goals of EHRs are to improve patient safety, decrease costs, and allow for the seamless exchange of information among providers and providing entities. As a proponent of digital health technologies, I submit that they are patient advocacy tools. The debate over the "effectiveness"of EHRs continues. It is too early to evaluate the true impact of EHRs on patient care at this juncture. Stage 1 of Meaningful Use (MU) of EHRs pertains solely to data capture. It is with Stages 2 and 3 that patient engagement and clinical decision support tools are incorporated in processes around the EHR. These stages have not been fully implemented and won’t be for a few years to come. Therefore those attributes of MU potentially having the most impact on patients are not in use today. What we do know is that: A) Physicians are spending more time looking at computer screens than into the faces of the people they are treating. B) That much of the data entered is to satisfy regulations of the HITECH Act and not directly related to patient care. C) That EHRs were designed for billing and regulatory purposes and do not in any way reflect clinical work flow. D) EHRs do not integrate well with medical devices or disparate digital health technology systems. However some excellent progress has been made in developing true interoperability among systems.
The EHR does not represent the face of digital technology in health care. Mobile health technologies, wearable sensor technologies, aging at home technologies, and ingestible medication sensor technology populate today’s digital health landscape. These are developments which will contribute directly to more efficient and improved patient care. They will address gaps in care. Having a mother who is ill and requiring significant help at home has taken me on a journey riddled with frustration and pain that is also experienced by my patients and their caregivers daily. It has made me a better physician, who realizes that the most important aspect of care is empathy. Most people view technology as a something that creates a divide between provider and patient. Effective technology can actually bring them closer. It can deliver trending data (which must be accurate, filtered, and actionable in order to be useful), drastically altering care recommendations and preventing hospitalizations and medical emergencies. While there remains much to be proven with regards to digital technologies, I expect them to become a backbone of the health care landscape.
Another digital health technology sector making its way into advanced health care enterprises is analytics. These tools take health care "big data" and make it relevant to treating individual patients as well as populations. Use cases for health care analytics demonstrate that EHRs, while being innately clumsy can be transformed into powerful sources of useful information.
Patients as consumers are demanding mobile tools long utilized in the retail and finance sectors . Examples can be seen in patient-physician video conferencing, mobile appointment schedulers, and even a smartphone ECG rhythm monitor. Digital health also involves social media. Patients are now finding themselves in online patient support groups. There are significant advantages of online versus real life support groups. On the provider side, digital tools such as Doximity and Epocratesare widely used.
In summary, the digital health landscape is much broader and friendlier than the EHR of today. I look forward to EHRs becoming more user friendly and clinically rewarding.
Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.
Robin Williams’s suspected suicide could encourage others to get help
The news last night was tragic: Robin Williams has died of an apparent suicide at the early age of 63. I saw the news and felt overwhelmingly sad. Really? He was a tremendous actor, a creative genius by any account, a man who I imagined had everything – talent, wealth, fame, the wonderful ability to make people laugh and to brighten lives. Such people also get draped with love and admiration, though certainly at a price. For what it’s worth, Robin Williams has been open about the fact that he’s struggled with both depression and addiction, but the complete story is never the one that gets told by the media.
Twitter started with 140-character links to suicide hotlines and suicide awareness, to statements about how depression is a treatable illness – Is it always? – and I hit retweet on a comment stating:" We’re never going to get anywhere till we take seriously that depression is an illness, not a weakness" and several people retweeted my retweet. I’m not sure why I did this; I don’t think that most people still think of mood disorders as a "weakness," or that those who do might change their minds because of a tweet. And I don’t think that suicide does anything to reduce stigma.
One psychiatrist friend tweeted a comment about how one should never ask someone why they are depressed, I guess because the "why?" implies something other than because biology dictated it, but if you’ve ever spoken to a person suffering from depression, you know that it comes in all shades of severity and that people often write a story to explain it. Sometimes that story is right: I’m depressed because of a breakup, or because I don’t have a job now, or because of ongoing work stress – and indeed, the person suffering often feels better after talking about the situation, after getting a new boyfriend or a new job, or after their boss moves to Zimbabwe.
I’m convinced that treatment works best when psychotherapy is combined with medication (if indicated), and while medicines are a miracle for some, they aren’t for others. As psychiatrists, we certainly see a good deal of treatment-resistant depression. And yes, the antipsychiatry faction may postulate that it is the treatment – the medications, specifically – that cause people to kill themselves and others, but I will leave you with the idea that the science just doesn’t support that. Certainly, they aren’t for everyone, but clinically, I have seen medications do more good than harm in clinical practice overall.
I know nothing about Robin Williams beyond what I’ve read in the media, and I know that the media reports are often incomplete and distorted. I do imagine that Mr. Williams had the resources to get good care and that he may well have had treatment for depression since he was open about his struggle. His story will be used to say: "Get help," and if you’re feeling suicidal and aren’t getting help, please do so. If you’re feeling suicidal and "help" isn’t making you feel better, please consider getting a second opinion or a different kind of help.
The tragic thing about suicide is that it’s a permanent answer to what is often a temporary problem.
Sometimes, I imagine that there are people who have tried and tried to get help and that their pain remains so unbearable for so long that suicide offers them the only possible relief – if such a thing is even to be had given that we don’t what comes next and some religions will say that suicide leads to nowhere good. Even if it provides relief to the person involved, it comes with the cost of leaving those who remain in horrible pain. Sadly, depressed people sometimes imagine that the world will be better off without them, and often that idea is just not true.
I hope that Robin Williams is in a better place, for his sake. I hope that before he ended his life, he tried every possible treatment option, and that this wasn’t an impulsive decision, or one based on an episodic relapse of either depression or substance abuse – a relapse that may have resolved and let him live for decades more. I hope his wife and children and all the people who knew and loved him will eventually find some peace. His death, however, is not simply a personal one because he touched us all with his talent and his charisma. What a tragic loss.
Dr. Miller also posted a version http://bit.ly/1kyO1a7 of this piece on the Shrink Rap News website. She is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: the Johns Hopkins University Press, 2011).
The news last night was tragic: Robin Williams has died of an apparent suicide at the early age of 63. I saw the news and felt overwhelmingly sad. Really? He was a tremendous actor, a creative genius by any account, a man who I imagined had everything – talent, wealth, fame, the wonderful ability to make people laugh and to brighten lives. Such people also get draped with love and admiration, though certainly at a price. For what it’s worth, Robin Williams has been open about the fact that he’s struggled with both depression and addiction, but the complete story is never the one that gets told by the media.
Twitter started with 140-character links to suicide hotlines and suicide awareness, to statements about how depression is a treatable illness – Is it always? – and I hit retweet on a comment stating:" We’re never going to get anywhere till we take seriously that depression is an illness, not a weakness" and several people retweeted my retweet. I’m not sure why I did this; I don’t think that most people still think of mood disorders as a "weakness," or that those who do might change their minds because of a tweet. And I don’t think that suicide does anything to reduce stigma.
One psychiatrist friend tweeted a comment about how one should never ask someone why they are depressed, I guess because the "why?" implies something other than because biology dictated it, but if you’ve ever spoken to a person suffering from depression, you know that it comes in all shades of severity and that people often write a story to explain it. Sometimes that story is right: I’m depressed because of a breakup, or because I don’t have a job now, or because of ongoing work stress – and indeed, the person suffering often feels better after talking about the situation, after getting a new boyfriend or a new job, or after their boss moves to Zimbabwe.
I’m convinced that treatment works best when psychotherapy is combined with medication (if indicated), and while medicines are a miracle for some, they aren’t for others. As psychiatrists, we certainly see a good deal of treatment-resistant depression. And yes, the antipsychiatry faction may postulate that it is the treatment – the medications, specifically – that cause people to kill themselves and others, but I will leave you with the idea that the science just doesn’t support that. Certainly, they aren’t for everyone, but clinically, I have seen medications do more good than harm in clinical practice overall.
I know nothing about Robin Williams beyond what I’ve read in the media, and I know that the media reports are often incomplete and distorted. I do imagine that Mr. Williams had the resources to get good care and that he may well have had treatment for depression since he was open about his struggle. His story will be used to say: "Get help," and if you’re feeling suicidal and aren’t getting help, please do so. If you’re feeling suicidal and "help" isn’t making you feel better, please consider getting a second opinion or a different kind of help.
The tragic thing about suicide is that it’s a permanent answer to what is often a temporary problem.
Sometimes, I imagine that there are people who have tried and tried to get help and that their pain remains so unbearable for so long that suicide offers them the only possible relief – if such a thing is even to be had given that we don’t what comes next and some religions will say that suicide leads to nowhere good. Even if it provides relief to the person involved, it comes with the cost of leaving those who remain in horrible pain. Sadly, depressed people sometimes imagine that the world will be better off without them, and often that idea is just not true.
I hope that Robin Williams is in a better place, for his sake. I hope that before he ended his life, he tried every possible treatment option, and that this wasn’t an impulsive decision, or one based on an episodic relapse of either depression or substance abuse – a relapse that may have resolved and let him live for decades more. I hope his wife and children and all the people who knew and loved him will eventually find some peace. His death, however, is not simply a personal one because he touched us all with his talent and his charisma. What a tragic loss.
Dr. Miller also posted a version http://bit.ly/1kyO1a7 of this piece on the Shrink Rap News website. She is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: the Johns Hopkins University Press, 2011).
The news last night was tragic: Robin Williams has died of an apparent suicide at the early age of 63. I saw the news and felt overwhelmingly sad. Really? He was a tremendous actor, a creative genius by any account, a man who I imagined had everything – talent, wealth, fame, the wonderful ability to make people laugh and to brighten lives. Such people also get draped with love and admiration, though certainly at a price. For what it’s worth, Robin Williams has been open about the fact that he’s struggled with both depression and addiction, but the complete story is never the one that gets told by the media.
Twitter started with 140-character links to suicide hotlines and suicide awareness, to statements about how depression is a treatable illness – Is it always? – and I hit retweet on a comment stating:" We’re never going to get anywhere till we take seriously that depression is an illness, not a weakness" and several people retweeted my retweet. I’m not sure why I did this; I don’t think that most people still think of mood disorders as a "weakness," or that those who do might change their minds because of a tweet. And I don’t think that suicide does anything to reduce stigma.
One psychiatrist friend tweeted a comment about how one should never ask someone why they are depressed, I guess because the "why?" implies something other than because biology dictated it, but if you’ve ever spoken to a person suffering from depression, you know that it comes in all shades of severity and that people often write a story to explain it. Sometimes that story is right: I’m depressed because of a breakup, or because I don’t have a job now, or because of ongoing work stress – and indeed, the person suffering often feels better after talking about the situation, after getting a new boyfriend or a new job, or after their boss moves to Zimbabwe.
I’m convinced that treatment works best when psychotherapy is combined with medication (if indicated), and while medicines are a miracle for some, they aren’t for others. As psychiatrists, we certainly see a good deal of treatment-resistant depression. And yes, the antipsychiatry faction may postulate that it is the treatment – the medications, specifically – that cause people to kill themselves and others, but I will leave you with the idea that the science just doesn’t support that. Certainly, they aren’t for everyone, but clinically, I have seen medications do more good than harm in clinical practice overall.
I know nothing about Robin Williams beyond what I’ve read in the media, and I know that the media reports are often incomplete and distorted. I do imagine that Mr. Williams had the resources to get good care and that he may well have had treatment for depression since he was open about his struggle. His story will be used to say: "Get help," and if you’re feeling suicidal and aren’t getting help, please do so. If you’re feeling suicidal and "help" isn’t making you feel better, please consider getting a second opinion or a different kind of help.
The tragic thing about suicide is that it’s a permanent answer to what is often a temporary problem.
Sometimes, I imagine that there are people who have tried and tried to get help and that their pain remains so unbearable for so long that suicide offers them the only possible relief – if such a thing is even to be had given that we don’t what comes next and some religions will say that suicide leads to nowhere good. Even if it provides relief to the person involved, it comes with the cost of leaving those who remain in horrible pain. Sadly, depressed people sometimes imagine that the world will be better off without them, and often that idea is just not true.
I hope that Robin Williams is in a better place, for his sake. I hope that before he ended his life, he tried every possible treatment option, and that this wasn’t an impulsive decision, or one based on an episodic relapse of either depression or substance abuse – a relapse that may have resolved and let him live for decades more. I hope his wife and children and all the people who knew and loved him will eventually find some peace. His death, however, is not simply a personal one because he touched us all with his talent and his charisma. What a tragic loss.
Dr. Miller also posted a version http://bit.ly/1kyO1a7 of this piece on the Shrink Rap News website. She is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: the Johns Hopkins University Press, 2011).
Many eyes are better
Peer review is the filter that determines what is published in the scientific literature and what is not allowed to see the light of day. It has been considered "the gatekeeper of science." In modern times, peer review has consisted of a journal editor sending a submitted article to a limited number of experts in the field who then judge its worth for publication. Many specialists see reviewing manuscripts as a service to their profession, put considerable effort into their analysis, and provide extensive comments on revisions needed to strengthen papers.
However, the value of this venerable process as it is presently constituted has been questioned by numerous critics. Because manuscripts are reviewed by a limited number of often rival scientists in a highly specialized field, the practice is prone to bias. Innovation may be stifled when reviewers reject outlier concepts that may be correct but that do not fit into the mainstream of thought. Critiques are often superficial as they are performed by otherwise busy individuals who receive no compensation for their efforts. Finally, journal editors are given undue power in the process. Not only do they make the final decision to publish or reject a manuscript, they are also responsible for selecting reviewers and are then free to ignore or accept their recommendations.
These criticisms of this time-honored system have led to a strong impetus for change. Coincident with the motivation for modifying this essential component of the publication process have been technological advancements that are facilitating new approaches. The Internet has provided a mechanism for making peer review a more open, inclusive process with any member of the scientific community who so desires having the opportunity to contribute to the evaluation of published work. A recent incident highlights how uninvited, but valuable, input from the wider scientific community can rapidly and effectively improve the accuracy of the literature.
On July 2, 2014, National Public Radio’s Morning Edition broadcast "Easy method for making stem cells was too good to be true" and a New York Times headline proclaimed "Stem cell research papers are retracted." In January 2014, Haruko Obokata of the RIKEN Centre for Developmental Biology in Japan published an innovative and considerably simpler method of producing stem cells than extracting them from embryos or making them from skin cells in a complicated and prolonged process (Nature 2014;505: 641-7). At the time of publication, the work was viewed by many to be potentially Nobel Prize-worthy research—that is, until the stem cell research community chimed in with its extensive and detailed post-publication peer review.
A number of research groups questioned Obokata’s conclusions. Some even attempted to replicate the experiments, but with no success. Soon the critics’ findings and opinions appeared on a variety of websites and blogs, including the Nature website. The RIKEN Centre took notice and appointed a committee to investigate the research. The committee found that Obokata had manipulated her data on at least two occasions and concluded that she had participated in research misconduct. Pressure mounted, which led to the recent voluntary retraction of the article by its authors.
This case represents an extreme outcome resulting from a failure of pre-publication vetting followed by a successful post-hoc peer review. But it demonstrates how the emerging and more comprehensive means of evaluating published research is rapidly working its way into the fabric of how science and the reporting of it operate. It would be ideal if this extensive vetting of potentially important research could be done prior to rather than after its release to the general public. Physics academicians have accomplished this by posting their research papers as pre-prints on-line for their colleagues to evaluate. Only after a successful conclusion of this process is a work deemed acceptable for entry into the physics literature. Submission of biomedical research to a similar process has a significant downside in that new, possibly harmful therapies, not yet peer-reviewed, could be adopted by practitioners and/or patients before their time. However, some modification of it will likely evolve and lead to a more accurate assessment of submitted work than the present process allows.
How publications are valued is also being modified thanks to the omnibus means of rapid communication allowed by an ever-expanding Internet. Bibliometrics, most notably the number of times an article is subsequently cited in print, has been the mainstay in determining the value of individual articles. The journal impact factor, which has historically been the main measure of a journal\'s standing compared to that of others in its field, is derived from the aggregate of citations for all articles over a period of time. With the advent of the Internet, a new set of alternative metrics (altmetrics) is now contributing to the evaluation of published work. While print citations take years to accumulate, article downloads, mentions on Facebook, number of tweets on Twitter, and numerous other altmetrics have the considerable advantage of immediacy and can be logged by any reader, not only those authors who decide to subsequently cite certain publications. Although these new metrics are unlikely to replace traditional citations in assigning value to individual articles, along with them, they will be helpful in determining what must be read to maintain currency in one’s specialty.
So, readers of the surgical literature feel your newly found power and exert it. You along with your colleagues around the globe can, and in fact have an obligation to, play a role in determining what is worth reading from an ever-expanding volume of new information. Many eyes will almost certainly be better than relying solely on the opinions of a chosen few.
Dr. Rikkers is Editor in Chief of ACS Surgery News.
Peer review is the filter that determines what is published in the scientific literature and what is not allowed to see the light of day. It has been considered "the gatekeeper of science." In modern times, peer review has consisted of a journal editor sending a submitted article to a limited number of experts in the field who then judge its worth for publication. Many specialists see reviewing manuscripts as a service to their profession, put considerable effort into their analysis, and provide extensive comments on revisions needed to strengthen papers.
However, the value of this venerable process as it is presently constituted has been questioned by numerous critics. Because manuscripts are reviewed by a limited number of often rival scientists in a highly specialized field, the practice is prone to bias. Innovation may be stifled when reviewers reject outlier concepts that may be correct but that do not fit into the mainstream of thought. Critiques are often superficial as they are performed by otherwise busy individuals who receive no compensation for their efforts. Finally, journal editors are given undue power in the process. Not only do they make the final decision to publish or reject a manuscript, they are also responsible for selecting reviewers and are then free to ignore or accept their recommendations.
These criticisms of this time-honored system have led to a strong impetus for change. Coincident with the motivation for modifying this essential component of the publication process have been technological advancements that are facilitating new approaches. The Internet has provided a mechanism for making peer review a more open, inclusive process with any member of the scientific community who so desires having the opportunity to contribute to the evaluation of published work. A recent incident highlights how uninvited, but valuable, input from the wider scientific community can rapidly and effectively improve the accuracy of the literature.
On July 2, 2014, National Public Radio’s Morning Edition broadcast "Easy method for making stem cells was too good to be true" and a New York Times headline proclaimed "Stem cell research papers are retracted." In January 2014, Haruko Obokata of the RIKEN Centre for Developmental Biology in Japan published an innovative and considerably simpler method of producing stem cells than extracting them from embryos or making them from skin cells in a complicated and prolonged process (Nature 2014;505: 641-7). At the time of publication, the work was viewed by many to be potentially Nobel Prize-worthy research—that is, until the stem cell research community chimed in with its extensive and detailed post-publication peer review.
A number of research groups questioned Obokata’s conclusions. Some even attempted to replicate the experiments, but with no success. Soon the critics’ findings and opinions appeared on a variety of websites and blogs, including the Nature website. The RIKEN Centre took notice and appointed a committee to investigate the research. The committee found that Obokata had manipulated her data on at least two occasions and concluded that she had participated in research misconduct. Pressure mounted, which led to the recent voluntary retraction of the article by its authors.
This case represents an extreme outcome resulting from a failure of pre-publication vetting followed by a successful post-hoc peer review. But it demonstrates how the emerging and more comprehensive means of evaluating published research is rapidly working its way into the fabric of how science and the reporting of it operate. It would be ideal if this extensive vetting of potentially important research could be done prior to rather than after its release to the general public. Physics academicians have accomplished this by posting their research papers as pre-prints on-line for their colleagues to evaluate. Only after a successful conclusion of this process is a work deemed acceptable for entry into the physics literature. Submission of biomedical research to a similar process has a significant downside in that new, possibly harmful therapies, not yet peer-reviewed, could be adopted by practitioners and/or patients before their time. However, some modification of it will likely evolve and lead to a more accurate assessment of submitted work than the present process allows.
How publications are valued is also being modified thanks to the omnibus means of rapid communication allowed by an ever-expanding Internet. Bibliometrics, most notably the number of times an article is subsequently cited in print, has been the mainstay in determining the value of individual articles. The journal impact factor, which has historically been the main measure of a journal\'s standing compared to that of others in its field, is derived from the aggregate of citations for all articles over a period of time. With the advent of the Internet, a new set of alternative metrics (altmetrics) is now contributing to the evaluation of published work. While print citations take years to accumulate, article downloads, mentions on Facebook, number of tweets on Twitter, and numerous other altmetrics have the considerable advantage of immediacy and can be logged by any reader, not only those authors who decide to subsequently cite certain publications. Although these new metrics are unlikely to replace traditional citations in assigning value to individual articles, along with them, they will be helpful in determining what must be read to maintain currency in one’s specialty.
So, readers of the surgical literature feel your newly found power and exert it. You along with your colleagues around the globe can, and in fact have an obligation to, play a role in determining what is worth reading from an ever-expanding volume of new information. Many eyes will almost certainly be better than relying solely on the opinions of a chosen few.
Dr. Rikkers is Editor in Chief of ACS Surgery News.
Peer review is the filter that determines what is published in the scientific literature and what is not allowed to see the light of day. It has been considered "the gatekeeper of science." In modern times, peer review has consisted of a journal editor sending a submitted article to a limited number of experts in the field who then judge its worth for publication. Many specialists see reviewing manuscripts as a service to their profession, put considerable effort into their analysis, and provide extensive comments on revisions needed to strengthen papers.
However, the value of this venerable process as it is presently constituted has been questioned by numerous critics. Because manuscripts are reviewed by a limited number of often rival scientists in a highly specialized field, the practice is prone to bias. Innovation may be stifled when reviewers reject outlier concepts that may be correct but that do not fit into the mainstream of thought. Critiques are often superficial as they are performed by otherwise busy individuals who receive no compensation for their efforts. Finally, journal editors are given undue power in the process. Not only do they make the final decision to publish or reject a manuscript, they are also responsible for selecting reviewers and are then free to ignore or accept their recommendations.
These criticisms of this time-honored system have led to a strong impetus for change. Coincident with the motivation for modifying this essential component of the publication process have been technological advancements that are facilitating new approaches. The Internet has provided a mechanism for making peer review a more open, inclusive process with any member of the scientific community who so desires having the opportunity to contribute to the evaluation of published work. A recent incident highlights how uninvited, but valuable, input from the wider scientific community can rapidly and effectively improve the accuracy of the literature.
On July 2, 2014, National Public Radio’s Morning Edition broadcast "Easy method for making stem cells was too good to be true" and a New York Times headline proclaimed "Stem cell research papers are retracted." In January 2014, Haruko Obokata of the RIKEN Centre for Developmental Biology in Japan published an innovative and considerably simpler method of producing stem cells than extracting them from embryos or making them from skin cells in a complicated and prolonged process (Nature 2014;505: 641-7). At the time of publication, the work was viewed by many to be potentially Nobel Prize-worthy research—that is, until the stem cell research community chimed in with its extensive and detailed post-publication peer review.
A number of research groups questioned Obokata’s conclusions. Some even attempted to replicate the experiments, but with no success. Soon the critics’ findings and opinions appeared on a variety of websites and blogs, including the Nature website. The RIKEN Centre took notice and appointed a committee to investigate the research. The committee found that Obokata had manipulated her data on at least two occasions and concluded that she had participated in research misconduct. Pressure mounted, which led to the recent voluntary retraction of the article by its authors.
This case represents an extreme outcome resulting from a failure of pre-publication vetting followed by a successful post-hoc peer review. But it demonstrates how the emerging and more comprehensive means of evaluating published research is rapidly working its way into the fabric of how science and the reporting of it operate. It would be ideal if this extensive vetting of potentially important research could be done prior to rather than after its release to the general public. Physics academicians have accomplished this by posting their research papers as pre-prints on-line for their colleagues to evaluate. Only after a successful conclusion of this process is a work deemed acceptable for entry into the physics literature. Submission of biomedical research to a similar process has a significant downside in that new, possibly harmful therapies, not yet peer-reviewed, could be adopted by practitioners and/or patients before their time. However, some modification of it will likely evolve and lead to a more accurate assessment of submitted work than the present process allows.
How publications are valued is also being modified thanks to the omnibus means of rapid communication allowed by an ever-expanding Internet. Bibliometrics, most notably the number of times an article is subsequently cited in print, has been the mainstay in determining the value of individual articles. The journal impact factor, which has historically been the main measure of a journal\'s standing compared to that of others in its field, is derived from the aggregate of citations for all articles over a period of time. With the advent of the Internet, a new set of alternative metrics (altmetrics) is now contributing to the evaluation of published work. While print citations take years to accumulate, article downloads, mentions on Facebook, number of tweets on Twitter, and numerous other altmetrics have the considerable advantage of immediacy and can be logged by any reader, not only those authors who decide to subsequently cite certain publications. Although these new metrics are unlikely to replace traditional citations in assigning value to individual articles, along with them, they will be helpful in determining what must be read to maintain currency in one’s specialty.
So, readers of the surgical literature feel your newly found power and exert it. You along with your colleagues around the globe can, and in fact have an obligation to, play a role in determining what is worth reading from an ever-expanding volume of new information. Many eyes will almost certainly be better than relying solely on the opinions of a chosen few.
Dr. Rikkers is Editor in Chief of ACS Surgery News.
The Right Choice? Surgeons, patients, and ethical analysis
In July 2011, I first had the opportunity to write a column on ethics for ACS Surgery News. That article, "Responding to Family/Patient Requests," explored possible responses to the family members’ requests to "do everything" for a critically ill patient. The article was published under the tag line, "The Right Choice."
Since that first article, I have had the opportunity to write 12 additional columns on different ethical issues in the care of surgical patients. The issues have ranged from considerations of informed consent and disclosure of information to the challenges of innovative techniques and scarce resources. Each of these columns has continued to be under the heading "The Right Choice." As I considered what to write about this month, I reviewed my previous articles and I was struck by a worrisome possibility. In the challenging surgical cases presented, is the suggestion that I know "the right choice" actually wrong?
Medical ethics has increasingly become an important topic in medical schools and the clinical care of patients since the late 1970s. Although the medical and surgical care of patients has always had an ethical dimension, it has only been in the last several decades that the ethical issues have been separately identified and analyzed. As the acceptance of surgeons making decisions about what is "best" for their patients has shifted to increasing respect for the patient as an autonomous decision maker, we have seen the importance of understanding patient preferences increase.
At the same time, as medical and surgical care has improved, we now have more options to prolong patients’ lives even when the quality of those lives may be dramatically diminished. These factors have led to the increased consideration of ethical dimensions of decisions that we must help our patients make.
Although many authors have suggested ways to proceed with the ethical analysis of cases, few methods have been as widely adopted as that suggested by Albert Jonsen, Mark Siegler, and William Winslade in their influential book, "Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine," 7th edition (New York: Lange Clinical Science/McGraw Hill, 2010). These authors suggest that the analysis of a case should include attention to four sets of issues: medical indications, patient preferences, quality of life, and contextual features. By analyzing these issues for a difficult case, we are often able to see where the underlying principles of beneficence, nonmaleficence, respect for patient autonomy, and justice may be at odds.
For example, in the case that I discussed in the July 2011 issue, about the 80-year-old woman with extensive gangrenous bowel, a central concern was whether the surgical decision making should be altered by the family member’s request to "do everything you can." In this case, I suggested that requests from surrogate decision makers must be tempered by the realities of the case and the importance of not harming a patient by providing burdensome care that has minimal chance of success.
As I reread that prior article, I am struck by the fact that I suggest a way of thinking about the case and a series of considerations that are important. However, I am not comfortable saying that I have identified the single correct course of action. I believe that although ethical analysis of cases has tremendous value for doctors and patients, there is rarely one right answer. There may be several wrong answers, and there may be several acceptable answers, but there is rarely a single right choice. My goal in these columns that I wrote in the past and hope to write in the future is to raise awareness of the ethical dimensions of the case, to suggest important considerations, and perhaps even to identify some of the ethical principles that may be relevant. But I do not believe that I can identify "the right choice
In the very first edition of "Clinical Ethics" published in 1982, Jonsen, Siegler, and Winslade wrote in the preface, "We do not merely discuss or analyze the ethical problems; we offer counsel about decisions. Lest this be thought presumptuous, we do not consider our counsel the single and final answer. We offer it in the tradition of medical consultation: The consultant may bring to the practitioner’s view of the case not only broader information but another perspective."
I have tried to provide this type of information and perspective in the ACS Surgery News ethics columns and in view of the difficulty of determining the single right answer to many challenging cases, future columns will be found under the new heading, "The Right Choice?" By adding the critical question mark, I hope that readers will be reminded of the need for ongoing discussion of the challenging ethical questions that arise in the care of surgical patients.
Dr. Angelos is the Linda Kohler Anderson Professor of Surgery and Surgical Ethics; chief, endocrine surgery; and associate director, MacLean Center for Clinical Medical Ethics, at the University of Chicago.
In July 2011, I first had the opportunity to write a column on ethics for ACS Surgery News. That article, "Responding to Family/Patient Requests," explored possible responses to the family members’ requests to "do everything" for a critically ill patient. The article was published under the tag line, "The Right Choice."
Since that first article, I have had the opportunity to write 12 additional columns on different ethical issues in the care of surgical patients. The issues have ranged from considerations of informed consent and disclosure of information to the challenges of innovative techniques and scarce resources. Each of these columns has continued to be under the heading "The Right Choice." As I considered what to write about this month, I reviewed my previous articles and I was struck by a worrisome possibility. In the challenging surgical cases presented, is the suggestion that I know "the right choice" actually wrong?
Medical ethics has increasingly become an important topic in medical schools and the clinical care of patients since the late 1970s. Although the medical and surgical care of patients has always had an ethical dimension, it has only been in the last several decades that the ethical issues have been separately identified and analyzed. As the acceptance of surgeons making decisions about what is "best" for their patients has shifted to increasing respect for the patient as an autonomous decision maker, we have seen the importance of understanding patient preferences increase.
At the same time, as medical and surgical care has improved, we now have more options to prolong patients’ lives even when the quality of those lives may be dramatically diminished. These factors have led to the increased consideration of ethical dimensions of decisions that we must help our patients make.
Although many authors have suggested ways to proceed with the ethical analysis of cases, few methods have been as widely adopted as that suggested by Albert Jonsen, Mark Siegler, and William Winslade in their influential book, "Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine," 7th edition (New York: Lange Clinical Science/McGraw Hill, 2010). These authors suggest that the analysis of a case should include attention to four sets of issues: medical indications, patient preferences, quality of life, and contextual features. By analyzing these issues for a difficult case, we are often able to see where the underlying principles of beneficence, nonmaleficence, respect for patient autonomy, and justice may be at odds.
For example, in the case that I discussed in the July 2011 issue, about the 80-year-old woman with extensive gangrenous bowel, a central concern was whether the surgical decision making should be altered by the family member’s request to "do everything you can." In this case, I suggested that requests from surrogate decision makers must be tempered by the realities of the case and the importance of not harming a patient by providing burdensome care that has minimal chance of success.
As I reread that prior article, I am struck by the fact that I suggest a way of thinking about the case and a series of considerations that are important. However, I am not comfortable saying that I have identified the single correct course of action. I believe that although ethical analysis of cases has tremendous value for doctors and patients, there is rarely one right answer. There may be several wrong answers, and there may be several acceptable answers, but there is rarely a single right choice. My goal in these columns that I wrote in the past and hope to write in the future is to raise awareness of the ethical dimensions of the case, to suggest important considerations, and perhaps even to identify some of the ethical principles that may be relevant. But I do not believe that I can identify "the right choice
In the very first edition of "Clinical Ethics" published in 1982, Jonsen, Siegler, and Winslade wrote in the preface, "We do not merely discuss or analyze the ethical problems; we offer counsel about decisions. Lest this be thought presumptuous, we do not consider our counsel the single and final answer. We offer it in the tradition of medical consultation: The consultant may bring to the practitioner’s view of the case not only broader information but another perspective."
I have tried to provide this type of information and perspective in the ACS Surgery News ethics columns and in view of the difficulty of determining the single right answer to many challenging cases, future columns will be found under the new heading, "The Right Choice?" By adding the critical question mark, I hope that readers will be reminded of the need for ongoing discussion of the challenging ethical questions that arise in the care of surgical patients.
Dr. Angelos is the Linda Kohler Anderson Professor of Surgery and Surgical Ethics; chief, endocrine surgery; and associate director, MacLean Center for Clinical Medical Ethics, at the University of Chicago.
In July 2011, I first had the opportunity to write a column on ethics for ACS Surgery News. That article, "Responding to Family/Patient Requests," explored possible responses to the family members’ requests to "do everything" for a critically ill patient. The article was published under the tag line, "The Right Choice."
Since that first article, I have had the opportunity to write 12 additional columns on different ethical issues in the care of surgical patients. The issues have ranged from considerations of informed consent and disclosure of information to the challenges of innovative techniques and scarce resources. Each of these columns has continued to be under the heading "The Right Choice." As I considered what to write about this month, I reviewed my previous articles and I was struck by a worrisome possibility. In the challenging surgical cases presented, is the suggestion that I know "the right choice" actually wrong?
Medical ethics has increasingly become an important topic in medical schools and the clinical care of patients since the late 1970s. Although the medical and surgical care of patients has always had an ethical dimension, it has only been in the last several decades that the ethical issues have been separately identified and analyzed. As the acceptance of surgeons making decisions about what is "best" for their patients has shifted to increasing respect for the patient as an autonomous decision maker, we have seen the importance of understanding patient preferences increase.
At the same time, as medical and surgical care has improved, we now have more options to prolong patients’ lives even when the quality of those lives may be dramatically diminished. These factors have led to the increased consideration of ethical dimensions of decisions that we must help our patients make.
Although many authors have suggested ways to proceed with the ethical analysis of cases, few methods have been as widely adopted as that suggested by Albert Jonsen, Mark Siegler, and William Winslade in their influential book, "Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine," 7th edition (New York: Lange Clinical Science/McGraw Hill, 2010). These authors suggest that the analysis of a case should include attention to four sets of issues: medical indications, patient preferences, quality of life, and contextual features. By analyzing these issues for a difficult case, we are often able to see where the underlying principles of beneficence, nonmaleficence, respect for patient autonomy, and justice may be at odds.
For example, in the case that I discussed in the July 2011 issue, about the 80-year-old woman with extensive gangrenous bowel, a central concern was whether the surgical decision making should be altered by the family member’s request to "do everything you can." In this case, I suggested that requests from surrogate decision makers must be tempered by the realities of the case and the importance of not harming a patient by providing burdensome care that has minimal chance of success.
As I reread that prior article, I am struck by the fact that I suggest a way of thinking about the case and a series of considerations that are important. However, I am not comfortable saying that I have identified the single correct course of action. I believe that although ethical analysis of cases has tremendous value for doctors and patients, there is rarely one right answer. There may be several wrong answers, and there may be several acceptable answers, but there is rarely a single right choice. My goal in these columns that I wrote in the past and hope to write in the future is to raise awareness of the ethical dimensions of the case, to suggest important considerations, and perhaps even to identify some of the ethical principles that may be relevant. But I do not believe that I can identify "the right choice
In the very first edition of "Clinical Ethics" published in 1982, Jonsen, Siegler, and Winslade wrote in the preface, "We do not merely discuss or analyze the ethical problems; we offer counsel about decisions. Lest this be thought presumptuous, we do not consider our counsel the single and final answer. We offer it in the tradition of medical consultation: The consultant may bring to the practitioner’s view of the case not only broader information but another perspective."
I have tried to provide this type of information and perspective in the ACS Surgery News ethics columns and in view of the difficulty of determining the single right answer to many challenging cases, future columns will be found under the new heading, "The Right Choice?" By adding the critical question mark, I hope that readers will be reminded of the need for ongoing discussion of the challenging ethical questions that arise in the care of surgical patients.
Dr. Angelos is the Linda Kohler Anderson Professor of Surgery and Surgical Ethics; chief, endocrine surgery; and associate director, MacLean Center for Clinical Medical Ethics, at the University of Chicago.
Unsustainable
During a recent interview on public radio, the CEO of one of Maine’s small hospitals (we have only one hospital that might qualify as not small) observed that the implementation of the Affordable Care Act had already resulted in a decrease in the length of hospital stay and shifted some of the health care utilization away from his hospital. These changes have been reflected in decreased revenue for his institution. This in turn was making it difficult for it to subsidize the outpatient practices it had purchased. He added that over the last several years, outpatient medicine was not sustainable without subsidies.
We hear a lot these days about sustainability, but I had never considered outpatient pediatrics in terms of sustainability. But as I thought more about it, I realized that on several levels that primary care pediatrics had frequently had to adjust when its resources had been unable to keep up with demand.
Fifty years ago, outpatient pediatrics was comfortably sustainable, at least from the profit and loss perspective. Most practices were solo, owner-operated enterprises. Real estate was cheap, and many physicians practiced out of their homes. Overhead costs were low. There were no expensive immunizations to stockpile and then, as now, most pediatricians didn’t require much in the way of high tech equipment to make diagnoses. And certainly there were no costly computer systems to purchase and invest valuable time in learning to operate.
If there was something unsustainable about solo practice, it was the issue of coverage. A surprising number of physicians were able to find a balance between being available to their patients and having enough time and energy for personal restoration and a family. However, over time, an increasing number of physicians found solo practice unsustainable. They simply ran out of emotional capital. The solution was to join together in groups. This provided an answer to the on-call issue and offered the promise of an improved financial balance sheet. Business consultants preached the economy of scale. A group could buy things like toilet paper at a discount, and group members could share support staff, saving on payroll.
But it turns out that seeing patients in an outpatient setting doesn’t follow the rules of economy of scale that apply to a factory cranking out widgets. Physicians practice with different levels of efficiency. They are often independent-minded individuals for whom sharing overhead is a difficult concept to grasp. Sometimes, the result is an unsustainable dynamic in which the overhead of the less-efficient members dictates the overhead for the group. As groups grow bigger, even the physicians who understood how to run an office efficiently surrender control to business managers who may not understand medicine. The overhead continues to rise.
The result can be a tense and unsustainable atmosphere with the business manager saying, "You need to bring in more money by doing more studies and/or seeing more patients." The physicians respond, "But doing more procedures doesn’t translate into good medicine. And neither does seeing too many patients."
Even groups that had been able to craft a sustainable model began to face threat from third-party payers whose preferred provider lists that could change year to year might exclude them. This threat of instability created an unsustainable situation in which a practice could no longer count on having a panel of patients large enough to be profitable. The result was often selling out to an even larger entity.
On top of these scenarios consider the rising cost of college and medical school, and the reality that even the best electronic medical record systems adds at least 5 minutes to the physician’s time investment in each office visit. It is surprising that young people still choose primary care.
Is there hope for this bleak picture of unsustainability? I’m not sure, but there is clearly enough fat and waste in our health care system that a redistribution of resources toward primary care could make it sustainable and improve the quality.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including "How to Say No to Your Toddler." E-mail him at [email protected].
During a recent interview on public radio, the CEO of one of Maine’s small hospitals (we have only one hospital that might qualify as not small) observed that the implementation of the Affordable Care Act had already resulted in a decrease in the length of hospital stay and shifted some of the health care utilization away from his hospital. These changes have been reflected in decreased revenue for his institution. This in turn was making it difficult for it to subsidize the outpatient practices it had purchased. He added that over the last several years, outpatient medicine was not sustainable without subsidies.
We hear a lot these days about sustainability, but I had never considered outpatient pediatrics in terms of sustainability. But as I thought more about it, I realized that on several levels that primary care pediatrics had frequently had to adjust when its resources had been unable to keep up with demand.
Fifty years ago, outpatient pediatrics was comfortably sustainable, at least from the profit and loss perspective. Most practices were solo, owner-operated enterprises. Real estate was cheap, and many physicians practiced out of their homes. Overhead costs were low. There were no expensive immunizations to stockpile and then, as now, most pediatricians didn’t require much in the way of high tech equipment to make diagnoses. And certainly there were no costly computer systems to purchase and invest valuable time in learning to operate.
If there was something unsustainable about solo practice, it was the issue of coverage. A surprising number of physicians were able to find a balance between being available to their patients and having enough time and energy for personal restoration and a family. However, over time, an increasing number of physicians found solo practice unsustainable. They simply ran out of emotional capital. The solution was to join together in groups. This provided an answer to the on-call issue and offered the promise of an improved financial balance sheet. Business consultants preached the economy of scale. A group could buy things like toilet paper at a discount, and group members could share support staff, saving on payroll.
But it turns out that seeing patients in an outpatient setting doesn’t follow the rules of economy of scale that apply to a factory cranking out widgets. Physicians practice with different levels of efficiency. They are often independent-minded individuals for whom sharing overhead is a difficult concept to grasp. Sometimes, the result is an unsustainable dynamic in which the overhead of the less-efficient members dictates the overhead for the group. As groups grow bigger, even the physicians who understood how to run an office efficiently surrender control to business managers who may not understand medicine. The overhead continues to rise.
The result can be a tense and unsustainable atmosphere with the business manager saying, "You need to bring in more money by doing more studies and/or seeing more patients." The physicians respond, "But doing more procedures doesn’t translate into good medicine. And neither does seeing too many patients."
Even groups that had been able to craft a sustainable model began to face threat from third-party payers whose preferred provider lists that could change year to year might exclude them. This threat of instability created an unsustainable situation in which a practice could no longer count on having a panel of patients large enough to be profitable. The result was often selling out to an even larger entity.
On top of these scenarios consider the rising cost of college and medical school, and the reality that even the best electronic medical record systems adds at least 5 minutes to the physician’s time investment in each office visit. It is surprising that young people still choose primary care.
Is there hope for this bleak picture of unsustainability? I’m not sure, but there is clearly enough fat and waste in our health care system that a redistribution of resources toward primary care could make it sustainable and improve the quality.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including "How to Say No to Your Toddler." E-mail him at [email protected].
During a recent interview on public radio, the CEO of one of Maine’s small hospitals (we have only one hospital that might qualify as not small) observed that the implementation of the Affordable Care Act had already resulted in a decrease in the length of hospital stay and shifted some of the health care utilization away from his hospital. These changes have been reflected in decreased revenue for his institution. This in turn was making it difficult for it to subsidize the outpatient practices it had purchased. He added that over the last several years, outpatient medicine was not sustainable without subsidies.
We hear a lot these days about sustainability, but I had never considered outpatient pediatrics in terms of sustainability. But as I thought more about it, I realized that on several levels that primary care pediatrics had frequently had to adjust when its resources had been unable to keep up with demand.
Fifty years ago, outpatient pediatrics was comfortably sustainable, at least from the profit and loss perspective. Most practices were solo, owner-operated enterprises. Real estate was cheap, and many physicians practiced out of their homes. Overhead costs were low. There were no expensive immunizations to stockpile and then, as now, most pediatricians didn’t require much in the way of high tech equipment to make diagnoses. And certainly there were no costly computer systems to purchase and invest valuable time in learning to operate.
If there was something unsustainable about solo practice, it was the issue of coverage. A surprising number of physicians were able to find a balance between being available to their patients and having enough time and energy for personal restoration and a family. However, over time, an increasing number of physicians found solo practice unsustainable. They simply ran out of emotional capital. The solution was to join together in groups. This provided an answer to the on-call issue and offered the promise of an improved financial balance sheet. Business consultants preached the economy of scale. A group could buy things like toilet paper at a discount, and group members could share support staff, saving on payroll.
But it turns out that seeing patients in an outpatient setting doesn’t follow the rules of economy of scale that apply to a factory cranking out widgets. Physicians practice with different levels of efficiency. They are often independent-minded individuals for whom sharing overhead is a difficult concept to grasp. Sometimes, the result is an unsustainable dynamic in which the overhead of the less-efficient members dictates the overhead for the group. As groups grow bigger, even the physicians who understood how to run an office efficiently surrender control to business managers who may not understand medicine. The overhead continues to rise.
The result can be a tense and unsustainable atmosphere with the business manager saying, "You need to bring in more money by doing more studies and/or seeing more patients." The physicians respond, "But doing more procedures doesn’t translate into good medicine. And neither does seeing too many patients."
Even groups that had been able to craft a sustainable model began to face threat from third-party payers whose preferred provider lists that could change year to year might exclude them. This threat of instability created an unsustainable situation in which a practice could no longer count on having a panel of patients large enough to be profitable. The result was often selling out to an even larger entity.
On top of these scenarios consider the rising cost of college and medical school, and the reality that even the best electronic medical record systems adds at least 5 minutes to the physician’s time investment in each office visit. It is surprising that young people still choose primary care.
Is there hope for this bleak picture of unsustainability? I’m not sure, but there is clearly enough fat and waste in our health care system that a redistribution of resources toward primary care could make it sustainable and improve the quality.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including "How to Say No to Your Toddler." E-mail him at [email protected].
The Medical Roundtable: The HDL Quandary
DR. WONG: It’s certainly well-established from studies dating back to the Framingham study1 that a low HDL level is associated with higher cardiovascular risk. We also have data from studies on patients with stable coronary artery disease (CAD), such as the Treating to New Targets (TNT) trial,2 showing that even in people with well-controlled low-density lipoprotein (LDL) levels (eg, approximately 70 mg/dL), there is a residual risk for subsequent coronary heart disease events in those with a low HDL cholesterol level. Therefore, I think most people agree that it’s a good biomarker of cardiovascular disease risk. Whether it is really a risk factor and whether we can really modify it and reduce the risk have been seriously contemplated on in recent studies, in particular, in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial,3 although that trial was conducted in patients with known CAD, and they were successfully treated to achieve an LDL level of approximately 70 mg/dL.
I think there’s a general consensus that healthy levels of HDL are good for one’s cardiovascular health and that we should strive to attain such levels (at least nonpharmacologically). In addition to controlling the LDL cholesterol level, which remains the main target for lipid treatment, the question remains about whether an increase in HDL cholesterol is going to provide added benefit. Therefore, we need to wait for further data from upcoming trials like Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-Thrive)4 and some of the cholesteryl ester transfer protein (CETP) inhibitor trials7 to better understand the facts.
DR. GOTTO: I wish to iterate the same point as Dr. Wong: evidence about HDL having protective effects dates back to before the Framingham study,1 to Gofman’s analytical ultracentrifuge8 studies in the 1950s that showed an association between cardioprotection and higher levels of HDL fractions. A paper from 1951 in the American Journal of Medicine showed higher levels of HDL in women.9 In addition, there were a number of early studies dating back to the Lipid Research Clinics trial,10,11 in which the calculations appeared to show a benefit of high HDL. In this trial, there was a relative risk reduction of approximately 19%, which could be explained mainly by the LDL level reduction, and a small increase in HDL levels was found to be independently associated with a reduced cardiovascular risk in the treatment group. Similarly, in the Helsinki Heart Study,12 a reduced cardiovascular risk was noted primarily in individuals with the lipid triad, but again, this was explained by the combined reduction in LDL cholesterol levels and the increase in HDL levels. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT),13 the benefit was more closely related to the small increase in HDL than to the changes in triglyceride concentration, and the LDL levels did not change at all. So, while it hasn’t been conclusively proven that increasing the HDL level will reduce the risk and increasing the HDL level may depend on the mechanism involved in increasing the level and type of HDL that results from this process, our data over the years certainly support the concept that increasing HDL levels may be beneficial and protective.
DR. RADER: I certainly agree with that. I think HDL is actually an excellent biomarker of cardiovascular risk. Epidemiologically, there’s a very strong inverse association between HDL and CAD. There are certainly environmental factors such as a low-fat diet that lower the HDL level but don’t increase the risk, and very high levels of alcohol intake increase the HDL level but don’t necessarily reduce the risk. From a genetic standpoint, there are genes that cause a reduction in HDL levels that don’t seem to increase the cardiovascular risk, and there are other genes that cause an increase in HDL levels that don’t seem to reduce the cardiovascular risk. So, I think that for an individual patient, the HDL level is not necessarily a perfect predictor of risk, and HDL responds particularly to pharmacologic intervention but has not been proven to be a marker of the success of that pharmacologic intervention. Much more work is needed in that regard.
DR. LAROSA: Would you believe that HDL is a better predictor in populations in which the LDL levels are in the atherogenic range compared with populations in which the LDL levels are quite low?
DR. GOTTO: Yes. In Turkey, for example, there is a genetically determined low level of HDL. My impression from observing Turkish patients over many years is that outside the cities where the diet is different and the LDL and cholesterol levels are not as high, a low HDL level is not associated with such an increase in the cardiovascular risk. When people move into the cities and their diet changes, the LDL level increases and the low HDL level becomes a more significant predictor.
DR. RADER: Yes, I think Dr. Gotto made a good point, although LDL and HDL levels are clearly statistically independent predictors of risk when viewed separately in large populations. However, I think that as one particularly achieves lower levels of LDL, as Dr. Gotto suggested, the risk associated with a low HDL level seems to be attenuated.
DR. LAROSA: And that’s certainly in keeping with both the TNT trial2 and the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),14 isn’t it?
DR. WONG: Yes, and I think this is primarily why we’ve seen benefits in earlier trials, such as the Coronary Drug Project,15 the Familial Atherosclerosis Treatment Study (FATS),16 and the HDL Atherosclerosis Treatment Study (HATS),17 involving many more people who did not have well-controlled atherogenic lipoprotein levels. In the more recent studies, such as TNT2 and, of course, AIM-HIGH, you’ve had people who were very well treated, and so, the effect of a low HDL level and the impact of managing it were attenuated.
DR. LAROSA: I think we all agree that HDL is a good biomarker. In fact, it is probably one of the better ones, but it’s not perfect. A corollary question is “Should we be measuring the HDL cholesterol levels?” Is there some other fraction or component of HDL that would perform better as a biomarker?
DR. WONG: The recent Multi-Ethnic Study of Atherosclerosis (MESA) paper18 was quite interesting because it showed that looking at HDL particles was perhaps more predictive of future coronary event risk than HDL cholesterol concentration; so, these particles might be a more appropriate measure than HDL concentration. In that study, the authors found that HDL and HDL particle concentrations were associated with carotid intima-media thickness, and future coronary heart disease event risk was not affected when they adjusted for atherogenic lipoproteins as well as HDL and HDL particle size. However, the relation of HDL cholesterol concentration with coronary heart disease risk was attenuated if they adjusted for the other measures, which suggests that its relationship to risk might be best explained by HDL particles.
DR. RADER: I do think the HDL particle data are interesting, but I’m not sure if that particular study using surrogate measures of atherosclerosis is necessarily the definitive work. I think we need concrete data on HDL cholesterol versus HDL particles for hard cardiovascular endpoints. I’ll just add that apoA-I, the major HDL protein, has been of great interest as a potential—and perhaps improved—alternative to HDL cholesterol. Some available data suggest that apoA-I may be slightly better, but actually, it’s not much better when you look at the abundance of existing data. Further, there is the concept that some measure of HDL function, such as efflux capacity, might ultimately be a better predictor of risk. However, we have very little data on that particular topic at this point.
DR. LAROSA: Let’s segue into the issue of clinical trials that have been either completed or stopped and what they might reveal about increasing HDL levels as a beneficial therapeutic move. We could discuss the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial,19 the dalcetrapib study,20 and AIM-HIGH,3 all of which failed to answer the question of whether increasing the HDL level would be effective.
DR. GOTTO: In the ILLUMINATE trial, if you look at the changes in lipoproteins, you would think that there would have been some cardiovascular benefit with the level of HDL increase and LDL decrease, so it’s hard to blame one or the other lipoprotein fraction. I think it remains to be determined whether the phenomenon is completely explained on the basis of the blood pressure change and the increased aldosterone secretion. There may be some other toxicity related to the vessel wall if there was some off-target drug action. We don’t have a complete report of the dalcetrapib study yet,20 but we know that HDL levels increased and the LDL levels did not change, but there was an increase in the cardiovascular end points. Based on what we know at this point, I don’t think we can determine whether the mechanism is wrong or the drug wasn’t strong enough.
There’s a great deal of speculation about the AIM-HIGH study.3 The investigators still claim that they should have seen some benefit from the changes and the predictions, although there was only a 4 mg/dL difference in the HDL level between the 2 comparison groups. They also introduced a lower dose of nicotinic acid in the comparison group and used ezetimibe to equalize the LDL levels. So, the larger Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE study)4 should clarify the benefit of niacin therapy.
DR. WONG: An important point about AIM-HIGH3 is that this was a secondary prevention trial, and many subjects were on several other recommended therapies for coronary diseases. Additionally, the subjects were very well treated to achieve an LDL level of <70 mg/dL. So, I think the failure of AIM-HIGH3 suggests that, perhaps, niacin therapy may not work in such a well-controlled population, ie, those who are well treated on the basis of LDL level. We’ll have to see whether a larger study like HPS2-THRIVE4 is going to show a different result, but I think this does not disprove the speculation that an increase in the HDL level might work in other populations—perhaps, populations with metabolic syndrome or primary prevention—that do not necessarily have well-controlled LDL levels. There are still many open questions resulting from the AIM-HIGH trial.3
DR. GOTTO: There is another aspect about HDL trials worth mentioning. In the statin trials, individuals who have benefited the most from statin intervention—whether it’s on the basis of quantitative coronary angiography or clinical endpoints—are those who start off with the lowest HDL levels. So, there could be a difference based on what HDL level you begin with.
DR. RADER: The outcome of the HPS2-THRIVE trial,4 which has not yet been reported at the time of this recording, will shed some light on the niacin issue. With regard to HDL as a marker of therapeutic benefit, I think the biggest challenge to that hypothesis is the dal-OUTCOMES trial with dalcetrapib.20 Here, we have a drug that increased the HDL level up to approximately 30% and its administration was stopped for futility because there was no reduction in cardiovascular events. Thus, unless there was some sort of off-target adverse effect of the drug that counterbalanced the benefits of increased HDL levels, it’s very hard to continue to support the simplistic hypothesis that increasing the HDL cholesterol levels reduces the cardiovascular risk. This trial clearly suggests that the situation is more complicated than that.
DR. RADER: It’s very possible that an increase in the HDL level by CETP inhibition may not necessarily be very protective by nature because the mechanism by which it is being increased is not desirable; however, there could be other mechanisms that increased HDL cholesterol levels through different approaches that might still be beneficial. I’m not suggesting that an increase in HDL levels is never going to be beneficial under any circumstances, but it certainly poses a challenge to the generic hypothesis.
DR. WONG: Yes, I think we really need to see how CETP inhibitors affect the structure and function of various HDL sub-fractions, and not much data are available on that. There’s still hope for some of the other CETP inhibitors, namely, evacetrapib and anacetrapib, which increase the HDL levels above 120%—a much larger increase than you get with dalcetrapib. However, I think we’ll need to await the endpoint trials to determine whether this really has an advantage over statin therapy and therapy involving lowering of the LDL cholesterol levels, specifically to understand how HDL structure and function is affected by these drugs.
DR. GOTTO: I’d be interested in Dr. Rader’s comments on this because he studied HDL particles that resulted from CETP inhibition with torcetrapib and found that they were fully active in promoting cholesterol efflux in cells.
DR. RADER: Yes, it’s a complicated area because torcetrapib may have had off-target effects that counterbalance the beneficial effects of efflux. However, it’s also possible that there are different ways of measuring efflux, and certain pathways may be beneficial, while others may not. We just don’t have the data yet to know how to fully interpret the different types of efflux assays for different types of HDL particles. We also don’t know whether those pathways are themselves atheroprotective.
DR. LAROSA: That’s a good segue into the next topic: mechanistically, how does having a high HDL level benefit us? The mechanism that we have focused on the most is the ability of HDL to promote reverse cholesterol transport, but HDL has other properties that might be beneficial, including its antiinflammatory and antioxidative properties. In fact, some investigators believe that these properties rather than reverse cholesterol transport are responsible for HDL’s alleged benefits.
DR. GOTTO: Regarding the antiinflammatory effects, HDL is associated with paraoxonases, which have strong antioxidant properties, and it inhibits the induction and formation of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and E-selectin. This may be due to the inhibition of sphingosine kinase, which is required for the action of tumor necrosis factor-alpha on ICAM and VCAM. HDL also inhibits LDL oxidation and monocyte chemotactic protein-1. In fact, these are just a few of the numerous actions of HDL; it also binds endotoxin/lipopolysaccharides. Therefore, HDL has a number of antiinflammatory and antioxidative effects that can be demonstrated by in vitro experiments.
DR. RADER: There are several interesting properties of HDL that are potentially antiatherogenic. It certainly can be argued that they would be. What we don’t know yet is which of these, if any, are operative in humans, and what is the difference among different HDL particles and different individuals in these different assays. One of the problems is that these are difficult assays that are not standardized by any means and haven’t been examined in large epidemiologic studies with regard to their relationship to cardiovascular risk. This is clearly the direction for future research, but it’s a big challenge for the field to amass that degree of high-quality data in order to actually make sense of these different properties and their roles in HDL atheroprotection.
DR. LAROSA: Is there currently an assay available for reverse cholesterol transport or cholesterol efflux that might be clinically useful?
DR. RADER: If you mean one that can be ordered by a clinician in the office, then the answer is no. I think these are still research tools that aren’t amenable for use in the clinic at this point. Having said that, I believe that it is feasible to try to develop an assay for efflux capacity, or even one or more of these other functions, possibly with a cell-based assay. For example, Dr. Gotto mentioned that sphingosine-1-phosphateon HDL was a very interesting marker, which over time, if validated, could potentially be used in clinical practice. However, this validation is going to take a while, several years maybe.
DR. LAROSA: Are any of these assays being incorporated into ongoing trials now?
DR. RADER: I am aware of interest in measuring efflux capacity as a component of a clinical trial. I suspect that some of these other effects (eg, antiinflammatory effects) are possibly of interest as well.
DR. GOTTO: I think that some of these effects were measured in the dalcetrapib trial,20 but they were ancillary studies. I haven’t come across any reports about other trials.
DR. WONG: Do you know whether HPS2-THRIVE4 or any of the other CETP trials are measuring them?
DR. GOTTO: No, I don’t.
DR. RADER: Yes, but I don’t know what’s in the public domain at this point.
DR. WONG: We do have some emerging epidemiologic data indicating that the protective function of HDL may be attenuated in the presence of an inflammatory state such as that indicated by high C-reactive protein levels and potentially by other inflammatory factors as well.
DR. LAROSA: So, what we can say at this point is that we don’t know to what extent it could be protective. We have evidence of various properties of HDL that might be theoretically useful for describing its potential benefit, but we don’t have either a clinical trial or other prospective evidence indicating that any of these properties are explanatory. Is that a fair statement?
DR. WONG: Yes, I agree.
DR. LAROSA: Okay, let’s talk a little bit about new studies that are currently in the field or new drugs that are currently on the horizon that might help us clarify some of these issues.
DR. RADER: We’ve already talked at length about the CETP inhibitors. I think this is a very interesting class, and I won’t add much more except that we are awaiting results from the ones that are still in clinical trials. I personally am moving more toward the concept of the HDL flux hypothesis (versus the HDL cholesterol hypothesis), ie, promoting flux might be a better mechanism for reducing risk compared with just increasing HDL cholesterol levels. In that regard, there are interesting interventions that are in the relatively early stages of development that would potentially promote flux, including infusing reconstituted apoA-I through a variety of different approaches, increasing apoA-I production with a small molecule, increasing macrophage transporters of efflux such as an LXR agonist, or an anti-microRNA-33 (miR-33) approach. These approaches need to be tested, of course, but good pre-clinical data are available that suggest they may be antiatherogenic.
DR. WONG: Some of the newer upcoming trials include HPS2-THRIVE4 as well as the CETP7 outcomes.
DR. LAROSA: I think it would be useful if we defined that study just briefly, because it’s been mentioned several times and some of our readers might not know what it is.
DR. WONG: HPS2-THRIVE4 is a large niacin trial examining more than 25 000 subjects. The trial has been essentially completed now, and they’re basically analyzing the data. Patients with known coronary disease were randomized between the newer niacin product developed by Merck and placebo on top of statin therapy. They actually did report interim data at the European Society of Cardiology Congress in 2012 that showed a 20% reduction in LDL levels and a 17% increase in HDL levels after 8 weeks, and 76% of the treated subjects remained compliant. So, this trial is going to have many more endpoints than the AIM-HIGH3 did.
Because AIM-HIGH3 had virtually no hazard ratio, the question is whether this larger sample size with HPS2-THRIVE4 is going to produce any different results. It’s going to be important to try to determine how to separate the effects of the increase in HDL levels from the additional reductions in LDL levels that you’re going to get from niacin or even from the other CETP inhibitors in those trials.
DR. LAROSA: The strategy of AIM-HIGH3 was to avoid those issues by essentially titrating LDL so that they wouldn’t interfere.
DR. GOTTO: One of the interesting aspects about this HPS2 study4 is that approximately a quarter of the participants are from China, and I think we have limited data about the effects of niacin in Chinese patients. Also, the preliminary data they released showed that during the screening leading up to the randomization, about one-third of the 25 000 participants dropped out mainly due to flushing. So, despite the antiflushing component of the drug, there’s still a problem with flushing.
DR. LAROSA: We shall see about that in the results soon, but I don’t think sample size is an issue here. I agree that the inclusion of a group who may be genetically different in their response to niacin is a potential issue.
DR. LAROSA: Nobody’s mentioned VA-HIT;13 is that for a good reason?
DR. GOTTO: I mentioned that the trial showed an association between increasing HDL levels and reduced cardiovascular risk. There was no association/correlation in this trial between triglyceride reduction and LDL concentration. LDL cholesterol levels remained the same, triglyceride levels decreased by 31%, and HDL levels increased by 6%, and according to the investigators, the 22% decrease in risk could be explained mainly in individuals who had metabolic syndrome or insulin resistance. So, that’s where there was most benefit. There was also a correlation between event reduction and HDL increase, and the individuals with clinical events in this trial had lower concentrations of the large HDL particles and higher concentrations of the small, pre-beta HDL particles.
DR. LAROSA: What do we think that doctors should be doing with HDL measurements at this point?
DR. RADER: We should still measure HDL levels in clinical practice, and such measurement should be part of a full lipid profile. It has some advantages and value in terms of predictive ability, as we’ve discussed, and it helps identify people who might be at high risk. I think the issue is about what we are supposed to do with a low HDL level when you identify it. My personal viewpoint is that we need to view that patient as presumably having a higher risk, and treat him/her slightly more aggressively than we might have otherwise, including a very aggressive reduction in the LDL level and, of course, active lifestyle management. I don’t think we’re currently in a position to actively recommend pharmacotherapy to increase HDL levels in patients with low HDL levels; however, the results of the HPS2-THRIVE4 trial may change that.
DR. WONG: I completely agree, and I think a low HDL level should certainly be an impetus to encourage the patient to note whatever lifestyle issues might be responsible for that. Cigarette smoking can reduce HDL levels by up to 20%, and appropriate weight control is not emphasized enough. So, this would be another reason to help emphasize weight loss, particularly in someone with visceral adiposity, which could certainly contribute to low HDL levels. Aerobic exercise, even brisk walking, can help. We need to encourage our patients to improve their lifestyle. This is, of course, an issue that is often not adequately dealt with, particularly in the primary care setting.
DR. LAROSA: Are there any other final comments?
DR. GOTTO: We know that patients with low HDL levels who are at high or average risk benefit remarkably from statin treatment. We carried out a study with lovastatin with individuals who had HDL levels below 50 mg/dL and who had no evidence of cardiovascular disease. At that time, they were considered to have average rather than elevated cholesterol and LDL levels, although we’d consider those levels too high now. They benefited remarkably from statin treatment within 5 years even though they had no signs or evidence of cardiovascular disease, and we put them on an intensive program of diet, exercise, and lifestyle modification.21
DR. LAROSA: I’d like to thank Dr. Wong, Dr. Gotto, and Dr. Rader for a very stimulating discussion, and I will now declare these proceedings closed.
*Since this interview was conducted, the full results of HPS2-Thrive were presented at the American College of Cardiology Scientific Sessions in March 2013. The trial was prematurely discontinued due to lack of efficacy as well as futility in reaching the primary endpoint of coronary death, nonfatal myocardial infarction, stroke, or coronary revascularization that occurred in 15.0% of patients in the control arm and 12.5% of patients in the niacin/laropiprant arm, and the difference between these 2 values was not significant. Moreover, there was an excess of adverse events noted in the niacin/laropiprant arm (approximately 30 adverse events per 1000 treated patients), including a 3.7% absolute excess risk of diabetic complications and 1.8% excess risk of new-onset diabetes.5 In addition, there was a greater risk of myopathy, particularly among the Chinese patients enrolled in the study.6 The investigators concluded that in light of these findings, the role of extended-release niacin for the prevention of cardiovascular disease needs to be reconsidered.
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DR. WONG: It’s certainly well-established from studies dating back to the Framingham study1 that a low HDL level is associated with higher cardiovascular risk. We also have data from studies on patients with stable coronary artery disease (CAD), such as the Treating to New Targets (TNT) trial,2 showing that even in people with well-controlled low-density lipoprotein (LDL) levels (eg, approximately 70 mg/dL), there is a residual risk for subsequent coronary heart disease events in those with a low HDL cholesterol level. Therefore, I think most people agree that it’s a good biomarker of cardiovascular disease risk. Whether it is really a risk factor and whether we can really modify it and reduce the risk have been seriously contemplated on in recent studies, in particular, in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial,3 although that trial was conducted in patients with known CAD, and they were successfully treated to achieve an LDL level of approximately 70 mg/dL.
I think there’s a general consensus that healthy levels of HDL are good for one’s cardiovascular health and that we should strive to attain such levels (at least nonpharmacologically). In addition to controlling the LDL cholesterol level, which remains the main target for lipid treatment, the question remains about whether an increase in HDL cholesterol is going to provide added benefit. Therefore, we need to wait for further data from upcoming trials like Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-Thrive)4 and some of the cholesteryl ester transfer protein (CETP) inhibitor trials7 to better understand the facts.
DR. GOTTO: I wish to iterate the same point as Dr. Wong: evidence about HDL having protective effects dates back to before the Framingham study,1 to Gofman’s analytical ultracentrifuge8 studies in the 1950s that showed an association between cardioprotection and higher levels of HDL fractions. A paper from 1951 in the American Journal of Medicine showed higher levels of HDL in women.9 In addition, there were a number of early studies dating back to the Lipid Research Clinics trial,10,11 in which the calculations appeared to show a benefit of high HDL. In this trial, there was a relative risk reduction of approximately 19%, which could be explained mainly by the LDL level reduction, and a small increase in HDL levels was found to be independently associated with a reduced cardiovascular risk in the treatment group. Similarly, in the Helsinki Heart Study,12 a reduced cardiovascular risk was noted primarily in individuals with the lipid triad, but again, this was explained by the combined reduction in LDL cholesterol levels and the increase in HDL levels. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT),13 the benefit was more closely related to the small increase in HDL than to the changes in triglyceride concentration, and the LDL levels did not change at all. So, while it hasn’t been conclusively proven that increasing the HDL level will reduce the risk and increasing the HDL level may depend on the mechanism involved in increasing the level and type of HDL that results from this process, our data over the years certainly support the concept that increasing HDL levels may be beneficial and protective.
DR. RADER: I certainly agree with that. I think HDL is actually an excellent biomarker of cardiovascular risk. Epidemiologically, there’s a very strong inverse association between HDL and CAD. There are certainly environmental factors such as a low-fat diet that lower the HDL level but don’t increase the risk, and very high levels of alcohol intake increase the HDL level but don’t necessarily reduce the risk. From a genetic standpoint, there are genes that cause a reduction in HDL levels that don’t seem to increase the cardiovascular risk, and there are other genes that cause an increase in HDL levels that don’t seem to reduce the cardiovascular risk. So, I think that for an individual patient, the HDL level is not necessarily a perfect predictor of risk, and HDL responds particularly to pharmacologic intervention but has not been proven to be a marker of the success of that pharmacologic intervention. Much more work is needed in that regard.
DR. LAROSA: Would you believe that HDL is a better predictor in populations in which the LDL levels are in the atherogenic range compared with populations in which the LDL levels are quite low?
DR. GOTTO: Yes. In Turkey, for example, there is a genetically determined low level of HDL. My impression from observing Turkish patients over many years is that outside the cities where the diet is different and the LDL and cholesterol levels are not as high, a low HDL level is not associated with such an increase in the cardiovascular risk. When people move into the cities and their diet changes, the LDL level increases and the low HDL level becomes a more significant predictor.
DR. RADER: Yes, I think Dr. Gotto made a good point, although LDL and HDL levels are clearly statistically independent predictors of risk when viewed separately in large populations. However, I think that as one particularly achieves lower levels of LDL, as Dr. Gotto suggested, the risk associated with a low HDL level seems to be attenuated.
DR. LAROSA: And that’s certainly in keeping with both the TNT trial2 and the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),14 isn’t it?
DR. WONG: Yes, and I think this is primarily why we’ve seen benefits in earlier trials, such as the Coronary Drug Project,15 the Familial Atherosclerosis Treatment Study (FATS),16 and the HDL Atherosclerosis Treatment Study (HATS),17 involving many more people who did not have well-controlled atherogenic lipoprotein levels. In the more recent studies, such as TNT2 and, of course, AIM-HIGH, you’ve had people who were very well treated, and so, the effect of a low HDL level and the impact of managing it were attenuated.
DR. LAROSA: I think we all agree that HDL is a good biomarker. In fact, it is probably one of the better ones, but it’s not perfect. A corollary question is “Should we be measuring the HDL cholesterol levels?” Is there some other fraction or component of HDL that would perform better as a biomarker?
DR. WONG: The recent Multi-Ethnic Study of Atherosclerosis (MESA) paper18 was quite interesting because it showed that looking at HDL particles was perhaps more predictive of future coronary event risk than HDL cholesterol concentration; so, these particles might be a more appropriate measure than HDL concentration. In that study, the authors found that HDL and HDL particle concentrations were associated with carotid intima-media thickness, and future coronary heart disease event risk was not affected when they adjusted for atherogenic lipoproteins as well as HDL and HDL particle size. However, the relation of HDL cholesterol concentration with coronary heart disease risk was attenuated if they adjusted for the other measures, which suggests that its relationship to risk might be best explained by HDL particles.
DR. RADER: I do think the HDL particle data are interesting, but I’m not sure if that particular study using surrogate measures of atherosclerosis is necessarily the definitive work. I think we need concrete data on HDL cholesterol versus HDL particles for hard cardiovascular endpoints. I’ll just add that apoA-I, the major HDL protein, has been of great interest as a potential—and perhaps improved—alternative to HDL cholesterol. Some available data suggest that apoA-I may be slightly better, but actually, it’s not much better when you look at the abundance of existing data. Further, there is the concept that some measure of HDL function, such as efflux capacity, might ultimately be a better predictor of risk. However, we have very little data on that particular topic at this point.
DR. LAROSA: Let’s segue into the issue of clinical trials that have been either completed or stopped and what they might reveal about increasing HDL levels as a beneficial therapeutic move. We could discuss the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial,19 the dalcetrapib study,20 and AIM-HIGH,3 all of which failed to answer the question of whether increasing the HDL level would be effective.
DR. GOTTO: In the ILLUMINATE trial, if you look at the changes in lipoproteins, you would think that there would have been some cardiovascular benefit with the level of HDL increase and LDL decrease, so it’s hard to blame one or the other lipoprotein fraction. I think it remains to be determined whether the phenomenon is completely explained on the basis of the blood pressure change and the increased aldosterone secretion. There may be some other toxicity related to the vessel wall if there was some off-target drug action. We don’t have a complete report of the dalcetrapib study yet,20 but we know that HDL levels increased and the LDL levels did not change, but there was an increase in the cardiovascular end points. Based on what we know at this point, I don’t think we can determine whether the mechanism is wrong or the drug wasn’t strong enough.
There’s a great deal of speculation about the AIM-HIGH study.3 The investigators still claim that they should have seen some benefit from the changes and the predictions, although there was only a 4 mg/dL difference in the HDL level between the 2 comparison groups. They also introduced a lower dose of nicotinic acid in the comparison group and used ezetimibe to equalize the LDL levels. So, the larger Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE study)4 should clarify the benefit of niacin therapy.
DR. WONG: An important point about AIM-HIGH3 is that this was a secondary prevention trial, and many subjects were on several other recommended therapies for coronary diseases. Additionally, the subjects were very well treated to achieve an LDL level of <70 mg/dL. So, I think the failure of AIM-HIGH3 suggests that, perhaps, niacin therapy may not work in such a well-controlled population, ie, those who are well treated on the basis of LDL level. We’ll have to see whether a larger study like HPS2-THRIVE4 is going to show a different result, but I think this does not disprove the speculation that an increase in the HDL level might work in other populations—perhaps, populations with metabolic syndrome or primary prevention—that do not necessarily have well-controlled LDL levels. There are still many open questions resulting from the AIM-HIGH trial.3
DR. GOTTO: There is another aspect about HDL trials worth mentioning. In the statin trials, individuals who have benefited the most from statin intervention—whether it’s on the basis of quantitative coronary angiography or clinical endpoints—are those who start off with the lowest HDL levels. So, there could be a difference based on what HDL level you begin with.
DR. RADER: The outcome of the HPS2-THRIVE trial,4 which has not yet been reported at the time of this recording, will shed some light on the niacin issue. With regard to HDL as a marker of therapeutic benefit, I think the biggest challenge to that hypothesis is the dal-OUTCOMES trial with dalcetrapib.20 Here, we have a drug that increased the HDL level up to approximately 30% and its administration was stopped for futility because there was no reduction in cardiovascular events. Thus, unless there was some sort of off-target adverse effect of the drug that counterbalanced the benefits of increased HDL levels, it’s very hard to continue to support the simplistic hypothesis that increasing the HDL cholesterol levels reduces the cardiovascular risk. This trial clearly suggests that the situation is more complicated than that.
DR. RADER: It’s very possible that an increase in the HDL level by CETP inhibition may not necessarily be very protective by nature because the mechanism by which it is being increased is not desirable; however, there could be other mechanisms that increased HDL cholesterol levels through different approaches that might still be beneficial. I’m not suggesting that an increase in HDL levels is never going to be beneficial under any circumstances, but it certainly poses a challenge to the generic hypothesis.
DR. WONG: Yes, I think we really need to see how CETP inhibitors affect the structure and function of various HDL sub-fractions, and not much data are available on that. There’s still hope for some of the other CETP inhibitors, namely, evacetrapib and anacetrapib, which increase the HDL levels above 120%—a much larger increase than you get with dalcetrapib. However, I think we’ll need to await the endpoint trials to determine whether this really has an advantage over statin therapy and therapy involving lowering of the LDL cholesterol levels, specifically to understand how HDL structure and function is affected by these drugs.
DR. GOTTO: I’d be interested in Dr. Rader’s comments on this because he studied HDL particles that resulted from CETP inhibition with torcetrapib and found that they were fully active in promoting cholesterol efflux in cells.
DR. RADER: Yes, it’s a complicated area because torcetrapib may have had off-target effects that counterbalance the beneficial effects of efflux. However, it’s also possible that there are different ways of measuring efflux, and certain pathways may be beneficial, while others may not. We just don’t have the data yet to know how to fully interpret the different types of efflux assays for different types of HDL particles. We also don’t know whether those pathways are themselves atheroprotective.
DR. LAROSA: That’s a good segue into the next topic: mechanistically, how does having a high HDL level benefit us? The mechanism that we have focused on the most is the ability of HDL to promote reverse cholesterol transport, but HDL has other properties that might be beneficial, including its antiinflammatory and antioxidative properties. In fact, some investigators believe that these properties rather than reverse cholesterol transport are responsible for HDL’s alleged benefits.
DR. GOTTO: Regarding the antiinflammatory effects, HDL is associated with paraoxonases, which have strong antioxidant properties, and it inhibits the induction and formation of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and E-selectin. This may be due to the inhibition of sphingosine kinase, which is required for the action of tumor necrosis factor-alpha on ICAM and VCAM. HDL also inhibits LDL oxidation and monocyte chemotactic protein-1. In fact, these are just a few of the numerous actions of HDL; it also binds endotoxin/lipopolysaccharides. Therefore, HDL has a number of antiinflammatory and antioxidative effects that can be demonstrated by in vitro experiments.
DR. RADER: There are several interesting properties of HDL that are potentially antiatherogenic. It certainly can be argued that they would be. What we don’t know yet is which of these, if any, are operative in humans, and what is the difference among different HDL particles and different individuals in these different assays. One of the problems is that these are difficult assays that are not standardized by any means and haven’t been examined in large epidemiologic studies with regard to their relationship to cardiovascular risk. This is clearly the direction for future research, but it’s a big challenge for the field to amass that degree of high-quality data in order to actually make sense of these different properties and their roles in HDL atheroprotection.
DR. LAROSA: Is there currently an assay available for reverse cholesterol transport or cholesterol efflux that might be clinically useful?
DR. RADER: If you mean one that can be ordered by a clinician in the office, then the answer is no. I think these are still research tools that aren’t amenable for use in the clinic at this point. Having said that, I believe that it is feasible to try to develop an assay for efflux capacity, or even one or more of these other functions, possibly with a cell-based assay. For example, Dr. Gotto mentioned that sphingosine-1-phosphateon HDL was a very interesting marker, which over time, if validated, could potentially be used in clinical practice. However, this validation is going to take a while, several years maybe.
DR. LAROSA: Are any of these assays being incorporated into ongoing trials now?
DR. RADER: I am aware of interest in measuring efflux capacity as a component of a clinical trial. I suspect that some of these other effects (eg, antiinflammatory effects) are possibly of interest as well.
DR. GOTTO: I think that some of these effects were measured in the dalcetrapib trial,20 but they were ancillary studies. I haven’t come across any reports about other trials.
DR. WONG: Do you know whether HPS2-THRIVE4 or any of the other CETP trials are measuring them?
DR. GOTTO: No, I don’t.
DR. RADER: Yes, but I don’t know what’s in the public domain at this point.
DR. WONG: We do have some emerging epidemiologic data indicating that the protective function of HDL may be attenuated in the presence of an inflammatory state such as that indicated by high C-reactive protein levels and potentially by other inflammatory factors as well.
DR. LAROSA: So, what we can say at this point is that we don’t know to what extent it could be protective. We have evidence of various properties of HDL that might be theoretically useful for describing its potential benefit, but we don’t have either a clinical trial or other prospective evidence indicating that any of these properties are explanatory. Is that a fair statement?
DR. WONG: Yes, I agree.
DR. LAROSA: Okay, let’s talk a little bit about new studies that are currently in the field or new drugs that are currently on the horizon that might help us clarify some of these issues.
DR. RADER: We’ve already talked at length about the CETP inhibitors. I think this is a very interesting class, and I won’t add much more except that we are awaiting results from the ones that are still in clinical trials. I personally am moving more toward the concept of the HDL flux hypothesis (versus the HDL cholesterol hypothesis), ie, promoting flux might be a better mechanism for reducing risk compared with just increasing HDL cholesterol levels. In that regard, there are interesting interventions that are in the relatively early stages of development that would potentially promote flux, including infusing reconstituted apoA-I through a variety of different approaches, increasing apoA-I production with a small molecule, increasing macrophage transporters of efflux such as an LXR agonist, or an anti-microRNA-33 (miR-33) approach. These approaches need to be tested, of course, but good pre-clinical data are available that suggest they may be antiatherogenic.
DR. WONG: Some of the newer upcoming trials include HPS2-THRIVE4 as well as the CETP7 outcomes.
DR. LAROSA: I think it would be useful if we defined that study just briefly, because it’s been mentioned several times and some of our readers might not know what it is.
DR. WONG: HPS2-THRIVE4 is a large niacin trial examining more than 25 000 subjects. The trial has been essentially completed now, and they’re basically analyzing the data. Patients with known coronary disease were randomized between the newer niacin product developed by Merck and placebo on top of statin therapy. They actually did report interim data at the European Society of Cardiology Congress in 2012 that showed a 20% reduction in LDL levels and a 17% increase in HDL levels after 8 weeks, and 76% of the treated subjects remained compliant. So, this trial is going to have many more endpoints than the AIM-HIGH3 did.
Because AIM-HIGH3 had virtually no hazard ratio, the question is whether this larger sample size with HPS2-THRIVE4 is going to produce any different results. It’s going to be important to try to determine how to separate the effects of the increase in HDL levels from the additional reductions in LDL levels that you’re going to get from niacin or even from the other CETP inhibitors in those trials.
DR. LAROSA: The strategy of AIM-HIGH3 was to avoid those issues by essentially titrating LDL so that they wouldn’t interfere.
DR. GOTTO: One of the interesting aspects about this HPS2 study4 is that approximately a quarter of the participants are from China, and I think we have limited data about the effects of niacin in Chinese patients. Also, the preliminary data they released showed that during the screening leading up to the randomization, about one-third of the 25 000 participants dropped out mainly due to flushing. So, despite the antiflushing component of the drug, there’s still a problem with flushing.
DR. LAROSA: We shall see about that in the results soon, but I don’t think sample size is an issue here. I agree that the inclusion of a group who may be genetically different in their response to niacin is a potential issue.
DR. LAROSA: Nobody’s mentioned VA-HIT;13 is that for a good reason?
DR. GOTTO: I mentioned that the trial showed an association between increasing HDL levels and reduced cardiovascular risk. There was no association/correlation in this trial between triglyceride reduction and LDL concentration. LDL cholesterol levels remained the same, triglyceride levels decreased by 31%, and HDL levels increased by 6%, and according to the investigators, the 22% decrease in risk could be explained mainly in individuals who had metabolic syndrome or insulin resistance. So, that’s where there was most benefit. There was also a correlation between event reduction and HDL increase, and the individuals with clinical events in this trial had lower concentrations of the large HDL particles and higher concentrations of the small, pre-beta HDL particles.
DR. LAROSA: What do we think that doctors should be doing with HDL measurements at this point?
DR. RADER: We should still measure HDL levels in clinical practice, and such measurement should be part of a full lipid profile. It has some advantages and value in terms of predictive ability, as we’ve discussed, and it helps identify people who might be at high risk. I think the issue is about what we are supposed to do with a low HDL level when you identify it. My personal viewpoint is that we need to view that patient as presumably having a higher risk, and treat him/her slightly more aggressively than we might have otherwise, including a very aggressive reduction in the LDL level and, of course, active lifestyle management. I don’t think we’re currently in a position to actively recommend pharmacotherapy to increase HDL levels in patients with low HDL levels; however, the results of the HPS2-THRIVE4 trial may change that.
DR. WONG: I completely agree, and I think a low HDL level should certainly be an impetus to encourage the patient to note whatever lifestyle issues might be responsible for that. Cigarette smoking can reduce HDL levels by up to 20%, and appropriate weight control is not emphasized enough. So, this would be another reason to help emphasize weight loss, particularly in someone with visceral adiposity, which could certainly contribute to low HDL levels. Aerobic exercise, even brisk walking, can help. We need to encourage our patients to improve their lifestyle. This is, of course, an issue that is often not adequately dealt with, particularly in the primary care setting.
DR. LAROSA: Are there any other final comments?
DR. GOTTO: We know that patients with low HDL levels who are at high or average risk benefit remarkably from statin treatment. We carried out a study with lovastatin with individuals who had HDL levels below 50 mg/dL and who had no evidence of cardiovascular disease. At that time, they were considered to have average rather than elevated cholesterol and LDL levels, although we’d consider those levels too high now. They benefited remarkably from statin treatment within 5 years even though they had no signs or evidence of cardiovascular disease, and we put them on an intensive program of diet, exercise, and lifestyle modification.21
DR. LAROSA: I’d like to thank Dr. Wong, Dr. Gotto, and Dr. Rader for a very stimulating discussion, and I will now declare these proceedings closed.
*Since this interview was conducted, the full results of HPS2-Thrive were presented at the American College of Cardiology Scientific Sessions in March 2013. The trial was prematurely discontinued due to lack of efficacy as well as futility in reaching the primary endpoint of coronary death, nonfatal myocardial infarction, stroke, or coronary revascularization that occurred in 15.0% of patients in the control arm and 12.5% of patients in the niacin/laropiprant arm, and the difference between these 2 values was not significant. Moreover, there was an excess of adverse events noted in the niacin/laropiprant arm (approximately 30 adverse events per 1000 treated patients), including a 3.7% absolute excess risk of diabetic complications and 1.8% excess risk of new-onset diabetes.5 In addition, there was a greater risk of myopathy, particularly among the Chinese patients enrolled in the study.6 The investigators concluded that in light of these findings, the role of extended-release niacin for the prevention of cardiovascular disease needs to be reconsidered.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
DR. WONG: It’s certainly well-established from studies dating back to the Framingham study1 that a low HDL level is associated with higher cardiovascular risk. We also have data from studies on patients with stable coronary artery disease (CAD), such as the Treating to New Targets (TNT) trial,2 showing that even in people with well-controlled low-density lipoprotein (LDL) levels (eg, approximately 70 mg/dL), there is a residual risk for subsequent coronary heart disease events in those with a low HDL cholesterol level. Therefore, I think most people agree that it’s a good biomarker of cardiovascular disease risk. Whether it is really a risk factor and whether we can really modify it and reduce the risk have been seriously contemplated on in recent studies, in particular, in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial,3 although that trial was conducted in patients with known CAD, and they were successfully treated to achieve an LDL level of approximately 70 mg/dL.
I think there’s a general consensus that healthy levels of HDL are good for one’s cardiovascular health and that we should strive to attain such levels (at least nonpharmacologically). In addition to controlling the LDL cholesterol level, which remains the main target for lipid treatment, the question remains about whether an increase in HDL cholesterol is going to provide added benefit. Therefore, we need to wait for further data from upcoming trials like Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-Thrive)4 and some of the cholesteryl ester transfer protein (CETP) inhibitor trials7 to better understand the facts.
DR. GOTTO: I wish to iterate the same point as Dr. Wong: evidence about HDL having protective effects dates back to before the Framingham study,1 to Gofman’s analytical ultracentrifuge8 studies in the 1950s that showed an association between cardioprotection and higher levels of HDL fractions. A paper from 1951 in the American Journal of Medicine showed higher levels of HDL in women.9 In addition, there were a number of early studies dating back to the Lipid Research Clinics trial,10,11 in which the calculations appeared to show a benefit of high HDL. In this trial, there was a relative risk reduction of approximately 19%, which could be explained mainly by the LDL level reduction, and a small increase in HDL levels was found to be independently associated with a reduced cardiovascular risk in the treatment group. Similarly, in the Helsinki Heart Study,12 a reduced cardiovascular risk was noted primarily in individuals with the lipid triad, but again, this was explained by the combined reduction in LDL cholesterol levels and the increase in HDL levels. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT),13 the benefit was more closely related to the small increase in HDL than to the changes in triglyceride concentration, and the LDL levels did not change at all. So, while it hasn’t been conclusively proven that increasing the HDL level will reduce the risk and increasing the HDL level may depend on the mechanism involved in increasing the level and type of HDL that results from this process, our data over the years certainly support the concept that increasing HDL levels may be beneficial and protective.
DR. RADER: I certainly agree with that. I think HDL is actually an excellent biomarker of cardiovascular risk. Epidemiologically, there’s a very strong inverse association between HDL and CAD. There are certainly environmental factors such as a low-fat diet that lower the HDL level but don’t increase the risk, and very high levels of alcohol intake increase the HDL level but don’t necessarily reduce the risk. From a genetic standpoint, there are genes that cause a reduction in HDL levels that don’t seem to increase the cardiovascular risk, and there are other genes that cause an increase in HDL levels that don’t seem to reduce the cardiovascular risk. So, I think that for an individual patient, the HDL level is not necessarily a perfect predictor of risk, and HDL responds particularly to pharmacologic intervention but has not been proven to be a marker of the success of that pharmacologic intervention. Much more work is needed in that regard.
DR. LAROSA: Would you believe that HDL is a better predictor in populations in which the LDL levels are in the atherogenic range compared with populations in which the LDL levels are quite low?
DR. GOTTO: Yes. In Turkey, for example, there is a genetically determined low level of HDL. My impression from observing Turkish patients over many years is that outside the cities where the diet is different and the LDL and cholesterol levels are not as high, a low HDL level is not associated with such an increase in the cardiovascular risk. When people move into the cities and their diet changes, the LDL level increases and the low HDL level becomes a more significant predictor.
DR. RADER: Yes, I think Dr. Gotto made a good point, although LDL and HDL levels are clearly statistically independent predictors of risk when viewed separately in large populations. However, I think that as one particularly achieves lower levels of LDL, as Dr. Gotto suggested, the risk associated with a low HDL level seems to be attenuated.
DR. LAROSA: And that’s certainly in keeping with both the TNT trial2 and the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),14 isn’t it?
DR. WONG: Yes, and I think this is primarily why we’ve seen benefits in earlier trials, such as the Coronary Drug Project,15 the Familial Atherosclerosis Treatment Study (FATS),16 and the HDL Atherosclerosis Treatment Study (HATS),17 involving many more people who did not have well-controlled atherogenic lipoprotein levels. In the more recent studies, such as TNT2 and, of course, AIM-HIGH, you’ve had people who were very well treated, and so, the effect of a low HDL level and the impact of managing it were attenuated.
DR. LAROSA: I think we all agree that HDL is a good biomarker. In fact, it is probably one of the better ones, but it’s not perfect. A corollary question is “Should we be measuring the HDL cholesterol levels?” Is there some other fraction or component of HDL that would perform better as a biomarker?
DR. WONG: The recent Multi-Ethnic Study of Atherosclerosis (MESA) paper18 was quite interesting because it showed that looking at HDL particles was perhaps more predictive of future coronary event risk than HDL cholesterol concentration; so, these particles might be a more appropriate measure than HDL concentration. In that study, the authors found that HDL and HDL particle concentrations were associated with carotid intima-media thickness, and future coronary heart disease event risk was not affected when they adjusted for atherogenic lipoproteins as well as HDL and HDL particle size. However, the relation of HDL cholesterol concentration with coronary heart disease risk was attenuated if they adjusted for the other measures, which suggests that its relationship to risk might be best explained by HDL particles.
DR. RADER: I do think the HDL particle data are interesting, but I’m not sure if that particular study using surrogate measures of atherosclerosis is necessarily the definitive work. I think we need concrete data on HDL cholesterol versus HDL particles for hard cardiovascular endpoints. I’ll just add that apoA-I, the major HDL protein, has been of great interest as a potential—and perhaps improved—alternative to HDL cholesterol. Some available data suggest that apoA-I may be slightly better, but actually, it’s not much better when you look at the abundance of existing data. Further, there is the concept that some measure of HDL function, such as efflux capacity, might ultimately be a better predictor of risk. However, we have very little data on that particular topic at this point.
DR. LAROSA: Let’s segue into the issue of clinical trials that have been either completed or stopped and what they might reveal about increasing HDL levels as a beneficial therapeutic move. We could discuss the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial,19 the dalcetrapib study,20 and AIM-HIGH,3 all of which failed to answer the question of whether increasing the HDL level would be effective.
DR. GOTTO: In the ILLUMINATE trial, if you look at the changes in lipoproteins, you would think that there would have been some cardiovascular benefit with the level of HDL increase and LDL decrease, so it’s hard to blame one or the other lipoprotein fraction. I think it remains to be determined whether the phenomenon is completely explained on the basis of the blood pressure change and the increased aldosterone secretion. There may be some other toxicity related to the vessel wall if there was some off-target drug action. We don’t have a complete report of the dalcetrapib study yet,20 but we know that HDL levels increased and the LDL levels did not change, but there was an increase in the cardiovascular end points. Based on what we know at this point, I don’t think we can determine whether the mechanism is wrong or the drug wasn’t strong enough.
There’s a great deal of speculation about the AIM-HIGH study.3 The investigators still claim that they should have seen some benefit from the changes and the predictions, although there was only a 4 mg/dL difference in the HDL level between the 2 comparison groups. They also introduced a lower dose of nicotinic acid in the comparison group and used ezetimibe to equalize the LDL levels. So, the larger Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE study)4 should clarify the benefit of niacin therapy.
DR. WONG: An important point about AIM-HIGH3 is that this was a secondary prevention trial, and many subjects were on several other recommended therapies for coronary diseases. Additionally, the subjects were very well treated to achieve an LDL level of <70 mg/dL. So, I think the failure of AIM-HIGH3 suggests that, perhaps, niacin therapy may not work in such a well-controlled population, ie, those who are well treated on the basis of LDL level. We’ll have to see whether a larger study like HPS2-THRIVE4 is going to show a different result, but I think this does not disprove the speculation that an increase in the HDL level might work in other populations—perhaps, populations with metabolic syndrome or primary prevention—that do not necessarily have well-controlled LDL levels. There are still many open questions resulting from the AIM-HIGH trial.3
DR. GOTTO: There is another aspect about HDL trials worth mentioning. In the statin trials, individuals who have benefited the most from statin intervention—whether it’s on the basis of quantitative coronary angiography or clinical endpoints—are those who start off with the lowest HDL levels. So, there could be a difference based on what HDL level you begin with.
DR. RADER: The outcome of the HPS2-THRIVE trial,4 which has not yet been reported at the time of this recording, will shed some light on the niacin issue. With regard to HDL as a marker of therapeutic benefit, I think the biggest challenge to that hypothesis is the dal-OUTCOMES trial with dalcetrapib.20 Here, we have a drug that increased the HDL level up to approximately 30% and its administration was stopped for futility because there was no reduction in cardiovascular events. Thus, unless there was some sort of off-target adverse effect of the drug that counterbalanced the benefits of increased HDL levels, it’s very hard to continue to support the simplistic hypothesis that increasing the HDL cholesterol levels reduces the cardiovascular risk. This trial clearly suggests that the situation is more complicated than that.
DR. RADER: It’s very possible that an increase in the HDL level by CETP inhibition may not necessarily be very protective by nature because the mechanism by which it is being increased is not desirable; however, there could be other mechanisms that increased HDL cholesterol levels through different approaches that might still be beneficial. I’m not suggesting that an increase in HDL levels is never going to be beneficial under any circumstances, but it certainly poses a challenge to the generic hypothesis.
DR. WONG: Yes, I think we really need to see how CETP inhibitors affect the structure and function of various HDL sub-fractions, and not much data are available on that. There’s still hope for some of the other CETP inhibitors, namely, evacetrapib and anacetrapib, which increase the HDL levels above 120%—a much larger increase than you get with dalcetrapib. However, I think we’ll need to await the endpoint trials to determine whether this really has an advantage over statin therapy and therapy involving lowering of the LDL cholesterol levels, specifically to understand how HDL structure and function is affected by these drugs.
DR. GOTTO: I’d be interested in Dr. Rader’s comments on this because he studied HDL particles that resulted from CETP inhibition with torcetrapib and found that they were fully active in promoting cholesterol efflux in cells.
DR. RADER: Yes, it’s a complicated area because torcetrapib may have had off-target effects that counterbalance the beneficial effects of efflux. However, it’s also possible that there are different ways of measuring efflux, and certain pathways may be beneficial, while others may not. We just don’t have the data yet to know how to fully interpret the different types of efflux assays for different types of HDL particles. We also don’t know whether those pathways are themselves atheroprotective.
DR. LAROSA: That’s a good segue into the next topic: mechanistically, how does having a high HDL level benefit us? The mechanism that we have focused on the most is the ability of HDL to promote reverse cholesterol transport, but HDL has other properties that might be beneficial, including its antiinflammatory and antioxidative properties. In fact, some investigators believe that these properties rather than reverse cholesterol transport are responsible for HDL’s alleged benefits.
DR. GOTTO: Regarding the antiinflammatory effects, HDL is associated with paraoxonases, which have strong antioxidant properties, and it inhibits the induction and formation of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and E-selectin. This may be due to the inhibition of sphingosine kinase, which is required for the action of tumor necrosis factor-alpha on ICAM and VCAM. HDL also inhibits LDL oxidation and monocyte chemotactic protein-1. In fact, these are just a few of the numerous actions of HDL; it also binds endotoxin/lipopolysaccharides. Therefore, HDL has a number of antiinflammatory and antioxidative effects that can be demonstrated by in vitro experiments.
DR. RADER: There are several interesting properties of HDL that are potentially antiatherogenic. It certainly can be argued that they would be. What we don’t know yet is which of these, if any, are operative in humans, and what is the difference among different HDL particles and different individuals in these different assays. One of the problems is that these are difficult assays that are not standardized by any means and haven’t been examined in large epidemiologic studies with regard to their relationship to cardiovascular risk. This is clearly the direction for future research, but it’s a big challenge for the field to amass that degree of high-quality data in order to actually make sense of these different properties and their roles in HDL atheroprotection.
DR. LAROSA: Is there currently an assay available for reverse cholesterol transport or cholesterol efflux that might be clinically useful?
DR. RADER: If you mean one that can be ordered by a clinician in the office, then the answer is no. I think these are still research tools that aren’t amenable for use in the clinic at this point. Having said that, I believe that it is feasible to try to develop an assay for efflux capacity, or even one or more of these other functions, possibly with a cell-based assay. For example, Dr. Gotto mentioned that sphingosine-1-phosphateon HDL was a very interesting marker, which over time, if validated, could potentially be used in clinical practice. However, this validation is going to take a while, several years maybe.
DR. LAROSA: Are any of these assays being incorporated into ongoing trials now?
DR. RADER: I am aware of interest in measuring efflux capacity as a component of a clinical trial. I suspect that some of these other effects (eg, antiinflammatory effects) are possibly of interest as well.
DR. GOTTO: I think that some of these effects were measured in the dalcetrapib trial,20 but they were ancillary studies. I haven’t come across any reports about other trials.
DR. WONG: Do you know whether HPS2-THRIVE4 or any of the other CETP trials are measuring them?
DR. GOTTO: No, I don’t.
DR. RADER: Yes, but I don’t know what’s in the public domain at this point.
DR. WONG: We do have some emerging epidemiologic data indicating that the protective function of HDL may be attenuated in the presence of an inflammatory state such as that indicated by high C-reactive protein levels and potentially by other inflammatory factors as well.
DR. LAROSA: So, what we can say at this point is that we don’t know to what extent it could be protective. We have evidence of various properties of HDL that might be theoretically useful for describing its potential benefit, but we don’t have either a clinical trial or other prospective evidence indicating that any of these properties are explanatory. Is that a fair statement?
DR. WONG: Yes, I agree.
DR. LAROSA: Okay, let’s talk a little bit about new studies that are currently in the field or new drugs that are currently on the horizon that might help us clarify some of these issues.
DR. RADER: We’ve already talked at length about the CETP inhibitors. I think this is a very interesting class, and I won’t add much more except that we are awaiting results from the ones that are still in clinical trials. I personally am moving more toward the concept of the HDL flux hypothesis (versus the HDL cholesterol hypothesis), ie, promoting flux might be a better mechanism for reducing risk compared with just increasing HDL cholesterol levels. In that regard, there are interesting interventions that are in the relatively early stages of development that would potentially promote flux, including infusing reconstituted apoA-I through a variety of different approaches, increasing apoA-I production with a small molecule, increasing macrophage transporters of efflux such as an LXR agonist, or an anti-microRNA-33 (miR-33) approach. These approaches need to be tested, of course, but good pre-clinical data are available that suggest they may be antiatherogenic.
DR. WONG: Some of the newer upcoming trials include HPS2-THRIVE4 as well as the CETP7 outcomes.
DR. LAROSA: I think it would be useful if we defined that study just briefly, because it’s been mentioned several times and some of our readers might not know what it is.
DR. WONG: HPS2-THRIVE4 is a large niacin trial examining more than 25 000 subjects. The trial has been essentially completed now, and they’re basically analyzing the data. Patients with known coronary disease were randomized between the newer niacin product developed by Merck and placebo on top of statin therapy. They actually did report interim data at the European Society of Cardiology Congress in 2012 that showed a 20% reduction in LDL levels and a 17% increase in HDL levels after 8 weeks, and 76% of the treated subjects remained compliant. So, this trial is going to have many more endpoints than the AIM-HIGH3 did.
Because AIM-HIGH3 had virtually no hazard ratio, the question is whether this larger sample size with HPS2-THRIVE4 is going to produce any different results. It’s going to be important to try to determine how to separate the effects of the increase in HDL levels from the additional reductions in LDL levels that you’re going to get from niacin or even from the other CETP inhibitors in those trials.
DR. LAROSA: The strategy of AIM-HIGH3 was to avoid those issues by essentially titrating LDL so that they wouldn’t interfere.
DR. GOTTO: One of the interesting aspects about this HPS2 study4 is that approximately a quarter of the participants are from China, and I think we have limited data about the effects of niacin in Chinese patients. Also, the preliminary data they released showed that during the screening leading up to the randomization, about one-third of the 25 000 participants dropped out mainly due to flushing. So, despite the antiflushing component of the drug, there’s still a problem with flushing.
DR. LAROSA: We shall see about that in the results soon, but I don’t think sample size is an issue here. I agree that the inclusion of a group who may be genetically different in their response to niacin is a potential issue.
DR. LAROSA: Nobody’s mentioned VA-HIT;13 is that for a good reason?
DR. GOTTO: I mentioned that the trial showed an association between increasing HDL levels and reduced cardiovascular risk. There was no association/correlation in this trial between triglyceride reduction and LDL concentration. LDL cholesterol levels remained the same, triglyceride levels decreased by 31%, and HDL levels increased by 6%, and according to the investigators, the 22% decrease in risk could be explained mainly in individuals who had metabolic syndrome or insulin resistance. So, that’s where there was most benefit. There was also a correlation between event reduction and HDL increase, and the individuals with clinical events in this trial had lower concentrations of the large HDL particles and higher concentrations of the small, pre-beta HDL particles.
DR. LAROSA: What do we think that doctors should be doing with HDL measurements at this point?
DR. RADER: We should still measure HDL levels in clinical practice, and such measurement should be part of a full lipid profile. It has some advantages and value in terms of predictive ability, as we’ve discussed, and it helps identify people who might be at high risk. I think the issue is about what we are supposed to do with a low HDL level when you identify it. My personal viewpoint is that we need to view that patient as presumably having a higher risk, and treat him/her slightly more aggressively than we might have otherwise, including a very aggressive reduction in the LDL level and, of course, active lifestyle management. I don’t think we’re currently in a position to actively recommend pharmacotherapy to increase HDL levels in patients with low HDL levels; however, the results of the HPS2-THRIVE4 trial may change that.
DR. WONG: I completely agree, and I think a low HDL level should certainly be an impetus to encourage the patient to note whatever lifestyle issues might be responsible for that. Cigarette smoking can reduce HDL levels by up to 20%, and appropriate weight control is not emphasized enough. So, this would be another reason to help emphasize weight loss, particularly in someone with visceral adiposity, which could certainly contribute to low HDL levels. Aerobic exercise, even brisk walking, can help. We need to encourage our patients to improve their lifestyle. This is, of course, an issue that is often not adequately dealt with, particularly in the primary care setting.
DR. LAROSA: Are there any other final comments?
DR. GOTTO: We know that patients with low HDL levels who are at high or average risk benefit remarkably from statin treatment. We carried out a study with lovastatin with individuals who had HDL levels below 50 mg/dL and who had no evidence of cardiovascular disease. At that time, they were considered to have average rather than elevated cholesterol and LDL levels, although we’d consider those levels too high now. They benefited remarkably from statin treatment within 5 years even though they had no signs or evidence of cardiovascular disease, and we put them on an intensive program of diet, exercise, and lifestyle modification.21
DR. LAROSA: I’d like to thank Dr. Wong, Dr. Gotto, and Dr. Rader for a very stimulating discussion, and I will now declare these proceedings closed.
*Since this interview was conducted, the full results of HPS2-Thrive were presented at the American College of Cardiology Scientific Sessions in March 2013. The trial was prematurely discontinued due to lack of efficacy as well as futility in reaching the primary endpoint of coronary death, nonfatal myocardial infarction, stroke, or coronary revascularization that occurred in 15.0% of patients in the control arm and 12.5% of patients in the niacin/laropiprant arm, and the difference between these 2 values was not significant. Moreover, there was an excess of adverse events noted in the niacin/laropiprant arm (approximately 30 adverse events per 1000 treated patients), including a 3.7% absolute excess risk of diabetic complications and 1.8% excess risk of new-onset diabetes.5 In addition, there was a greater risk of myopathy, particularly among the Chinese patients enrolled in the study.6 The investigators concluded that in light of these findings, the role of extended-release niacin for the prevention of cardiovascular disease needs to be reconsidered.
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