Commentary

The pathogenesis of respiratory infections such as acute otitis media (AOM), sinusitis, and pneumonia involves complex interactions among bacteria, respiratory viruses, and host immune responses.

My clinical and laboratory group and others have described respiratory infections as resulting from the growth of a single otopathogen, such as Streptococcus pneumoniae (Spn), nontypeable Haemophilus influenzae (NTHi), or Moraxella catarrhalis (Mcat) in the nasopharynx (NP) followed by ascension to the middle ear, sinuses, or descent to the lungs. Recent research from my group and others has resulted in a shift from a single pathogen focus toward consideration of respiratory infections as a polymicrobial disease. Bacterial and viral interactions are critical in respiratory infection pathogenesis. Commensal bacteria can alter virulence of bacterial pathogens and interfere with antibiotic treatment.

The traditional view of the immune system is that it is an assembly of human tissues, cells, and molecules that work to eliminate pathogens. Recent discoveries indicate that commensals play a central role in regulating human immune responses. Thus, the key questions in the field are:

1) How do members of the NP microbiome and innate immune responses maintain health in young children over time?

2) Do specific deleterious members of the NP microbiome alter host innate immune responses in a manner that predisposes to respiratory infections?

3) How does the microbiome and innate response in the NP differ when recovery, relapse of infection, or persistent infection occurs?

Virtually all young children are colonized by Spn, NTHi, or Mcat during the first 3 years of life. My group and others have shown that competitive interactions among bacteria influence whether these potential pathogens successfully colonize and cause respiratory infections. Recent studies have demonstrated that hundreds of different bacterial species colonize the upper respiratory tract. Diverse communities have been shown to be more stable and resistant to invasion by foreign species. Data from cross-sectional studies demonstrate that specific commensals, including Dolosigranulum, Corynebacterium, and Lactococcus, are associated with decreased risk of respiratory infections. Prior studies have been limited by the use of culture-based methods or have been cross sectional in design. Therefore, the optimal levels of diversity and NP commensals critical for maintaining health in the upper respiratory tract of children are currently unknown and under study by my group and others. Studies that utilize high-throughput culture-independent molecular detection methods are now used to identify optimal levels of diversity and commensal members of the microbiome critical for maintaining health homeostasis.

The innate immune system constitutes the first line of defense against respiratory pathogen colonization and respiratory virus infection. It relies on pattern recognition receptors on innate immune cells to detect evolutionarily conserved pathogen-associated molecular patterns expressed on pathogen surfaces. Toll-like receptors (TLRs) are crucial in the innate immune response; TLR 3, 7, and 8 recognize respiratory infection-associated viral pathogens. TLR2, 4, and 5 recognize respiratory infection-associated bacterial pathogens, and TLR9 and TLR13 recognize both viral and bacterial pathogens. The activation of TLRs triggers signaling cascades and regulates the expression of a wide range of cytokines leading to antimicrobial and inflammatory responses. Cytokines (there are dozens) associated with the pathogenesis, development, severity, and clinical outcomes of respiratory infections identify hypotheses that our group is exploring to expand our understanding of how innate responses might be manipulated to favor the child host. Importantly, it has already been shown that cytokine profiles differ in the NP depending on the number and type of bacteria and viruses involved.

My group recently has shown that serum IL-10 levels are significantly higher in AOM from Spn than are the levels associated with NTHi and Mcat, suggesting use of detection of this cytokine as a serum biomarker. Others have shown that the levels of IL-1-beta, TNF-alpha, IL-6, IL-8, IL-10, and IL-17a in middle ear fluids from children with recurrent AOM correlate significantly with higher bacterial load (and worse disease). Previous studies on cytokine responses associated with AOM have focused on limited numbers of cytokines and have not examined any relationship with commensals of the NP microbiome. Moreover, the subset of children who experience excessively frequent respiratory infections likely have disturbances in their microbiome (made worse with antibiotics) and innate immune response. Because of our growing knowledge about the microbiome and innate immune response, I see a compelling need to assess interactions of the NP microbiome and innate immune responses in children that are associated with sustained health and control of respiratory infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said the work was supported by a National Institutes of Health grant, and he had no relevant conflicts of interest. E-mail him at [email protected].

The pathogenesis of respiratory infections such as acute otitis media (AOM), sinusitis, and pneumonia involves complex interactions among bacteria, respiratory viruses, and host immune responses.

My clinical and laboratory group and others have described respiratory infections as resulting from the growth of a single otopathogen, such as Streptococcus pneumoniae (Spn), nontypeable Haemophilus influenzae (NTHi), or Moraxella catarrhalis (Mcat) in the nasopharynx (NP) followed by ascension to the middle ear, sinuses, or descent to the lungs. Recent research from my group and others has resulted in a shift from a single pathogen focus toward consideration of respiratory infections as a polymicrobial disease. Bacterial and viral interactions are critical in respiratory infection pathogenesis. Commensal bacteria can alter virulence of bacterial pathogens and interfere with antibiotic treatment.

The traditional view of the immune system is that it is an assembly of human tissues, cells, and molecules that work to eliminate pathogens. Recent discoveries indicate that commensals play a central role in regulating human immune responses. Thus, the key questions in the field are:

1) How do members of the NP microbiome and innate immune responses maintain health in young children over time?

2) Do specific deleterious members of the NP microbiome alter host innate immune responses in a manner that predisposes to respiratory infections?

3) How does the microbiome and innate response in the NP differ when recovery, relapse of infection, or persistent infection occurs?

Virtually all young children are colonized by Spn, NTHi, or Mcat during the first 3 years of life. My group and others have shown that competitive interactions among bacteria influence whether these potential pathogens successfully colonize and cause respiratory infections. Recent studies have demonstrated that hundreds of different bacterial species colonize the upper respiratory tract. Diverse communities have been shown to be more stable and resistant to invasion by foreign species. Data from cross-sectional studies demonstrate that specific commensals, including Dolosigranulum, Corynebacterium, and Lactococcus, are associated with decreased risk of respiratory infections. Prior studies have been limited by the use of culture-based methods or have been cross sectional in design. Therefore, the optimal levels of diversity and NP commensals critical for maintaining health in the upper respiratory tract of children are currently unknown and under study by my group and others. Studies that utilize high-throughput culture-independent molecular detection methods are now used to identify optimal levels of diversity and commensal members of the microbiome critical for maintaining health homeostasis.

The innate immune system constitutes the first line of defense against respiratory pathogen colonization and respiratory virus infection. It relies on pattern recognition receptors on innate immune cells to detect evolutionarily conserved pathogen-associated molecular patterns expressed on pathogen surfaces. Toll-like receptors (TLRs) are crucial in the innate immune response; TLR 3, 7, and 8 recognize respiratory infection-associated viral pathogens. TLR2, 4, and 5 recognize respiratory infection-associated bacterial pathogens, and TLR9 and TLR13 recognize both viral and bacterial pathogens. The activation of TLRs triggers signaling cascades and regulates the expression of a wide range of cytokines leading to antimicrobial and inflammatory responses. Cytokines (there are dozens) associated with the pathogenesis, development, severity, and clinical outcomes of respiratory infections identify hypotheses that our group is exploring to expand our understanding of how innate responses might be manipulated to favor the child host. Importantly, it has already been shown that cytokine profiles differ in the NP depending on the number and type of bacteria and viruses involved.

My group recently has shown that serum IL-10 levels are significantly higher in AOM from Spn than are the levels associated with NTHi and Mcat, suggesting use of detection of this cytokine as a serum biomarker. Others have shown that the levels of IL-1-beta, TNF-alpha, IL-6, IL-8, IL-10, and IL-17a in middle ear fluids from children with recurrent AOM correlate significantly with higher bacterial load (and worse disease). Previous studies on cytokine responses associated with AOM have focused on limited numbers of cytokines and have not examined any relationship with commensals of the NP microbiome. Moreover, the subset of children who experience excessively frequent respiratory infections likely have disturbances in their microbiome (made worse with antibiotics) and innate immune response. Because of our growing knowledge about the microbiome and innate immune response, I see a compelling need to assess interactions of the NP microbiome and innate immune responses in children that are associated with sustained health and control of respiratory infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said the work was supported by a National Institutes of Health grant, and he had no relevant conflicts of interest. E-mail him at [email protected].

The pathogenesis of respiratory infections such as acute otitis media (AOM), sinusitis, and pneumonia involves complex interactions among bacteria, respiratory viruses, and host immune responses.

My clinical and laboratory group and others have described respiratory infections as resulting from the growth of a single otopathogen, such as Streptococcus pneumoniae (Spn), nontypeable Haemophilus influenzae (NTHi), or Moraxella catarrhalis (Mcat) in the nasopharynx (NP) followed by ascension to the middle ear, sinuses, or descent to the lungs. Recent research from my group and others has resulted in a shift from a single pathogen focus toward consideration of respiratory infections as a polymicrobial disease. Bacterial and viral interactions are critical in respiratory infection pathogenesis. Commensal bacteria can alter virulence of bacterial pathogens and interfere with antibiotic treatment.

The traditional view of the immune system is that it is an assembly of human tissues, cells, and molecules that work to eliminate pathogens. Recent discoveries indicate that commensals play a central role in regulating human immune responses. Thus, the key questions in the field are:

1) How do members of the NP microbiome and innate immune responses maintain health in young children over time?

2) Do specific deleterious members of the NP microbiome alter host innate immune responses in a manner that predisposes to respiratory infections?

3) How does the microbiome and innate response in the NP differ when recovery, relapse of infection, or persistent infection occurs?

Virtually all young children are colonized by Spn, NTHi, or Mcat during the first 3 years of life. My group and others have shown that competitive interactions among bacteria influence whether these potential pathogens successfully colonize and cause respiratory infections. Recent studies have demonstrated that hundreds of different bacterial species colonize the upper respiratory tract. Diverse communities have been shown to be more stable and resistant to invasion by foreign species. Data from cross-sectional studies demonstrate that specific commensals, including Dolosigranulum, Corynebacterium, and Lactococcus, are associated with decreased risk of respiratory infections. Prior studies have been limited by the use of culture-based methods or have been cross sectional in design. Therefore, the optimal levels of diversity and NP commensals critical for maintaining health in the upper respiratory tract of children are currently unknown and under study by my group and others. Studies that utilize high-throughput culture-independent molecular detection methods are now used to identify optimal levels of diversity and commensal members of the microbiome critical for maintaining health homeostasis.

The innate immune system constitutes the first line of defense against respiratory pathogen colonization and respiratory virus infection. It relies on pattern recognition receptors on innate immune cells to detect evolutionarily conserved pathogen-associated molecular patterns expressed on pathogen surfaces. Toll-like receptors (TLRs) are crucial in the innate immune response; TLR 3, 7, and 8 recognize respiratory infection-associated viral pathogens. TLR2, 4, and 5 recognize respiratory infection-associated bacterial pathogens, and TLR9 and TLR13 recognize both viral and bacterial pathogens. The activation of TLRs triggers signaling cascades and regulates the expression of a wide range of cytokines leading to antimicrobial and inflammatory responses. Cytokines (there are dozens) associated with the pathogenesis, development, severity, and clinical outcomes of respiratory infections identify hypotheses that our group is exploring to expand our understanding of how innate responses might be manipulated to favor the child host. Importantly, it has already been shown that cytokine profiles differ in the NP depending on the number and type of bacteria and viruses involved.

My group recently has shown that serum IL-10 levels are significantly higher in AOM from Spn than are the levels associated with NTHi and Mcat, suggesting use of detection of this cytokine as a serum biomarker. Others have shown that the levels of IL-1-beta, TNF-alpha, IL-6, IL-8, IL-10, and IL-17a in middle ear fluids from children with recurrent AOM correlate significantly with higher bacterial load (and worse disease). Previous studies on cytokine responses associated with AOM have focused on limited numbers of cytokines and have not examined any relationship with commensals of the NP microbiome. Moreover, the subset of children who experience excessively frequent respiratory infections likely have disturbances in their microbiome (made worse with antibiotics) and innate immune response. Because of our growing knowledge about the microbiome and innate immune response, I see a compelling need to assess interactions of the NP microbiome and innate immune responses in children that are associated with sustained health and control of respiratory infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said the work was supported by a National Institutes of Health grant, and he had no relevant conflicts of interest. E-mail him at [email protected].

Perhaps one of the biggest ways in which I’ve evolved as a doctor over the 4.5 years I’ve been in private practice is that I am not so shy about ordering tests anymore.

My point is illustrated by the case of a lovely lady I met when I was starting out in practice who complained of being in pain all the time. She was referred to me for a very low titer antinuclear antibody and a barely positive rheumatoid factor. She’d had a very long history of severe depression and anxiety. She clearly connected her symptoms to having stopped her antidepressants. She attributed her dry mouth to her benzodiazepine. I told her that I thought she had fibromyalgia and that, as she herself pointed out, it was probably related to her emotional health. We talked about the lack of any real pharmacologic treatment for the illness. We addressed self-care: that she needed to sleep better, exercise more, and treat her depression.

Three years later she came back to me with hand swelling, hypergammaglobulinemia, renal tubular acidosis, this time with significantly higher ANA and RF titers, and hypocomplementemia. You guessed it; she has Sjögren’s syndrome.

Seeing patients 40 hours a week has been incredibly challenging but also incredibly rewarding. While the large number of cases that I’ve seen has sharpened my clinical eye, it has also broadened my differential diagnoses and improved my knowledge of when it will be helpful to order more tests.

It used to be that I was extremely conservative about ordering tests. This comes from having gone to med school in the Philippines, where each test was paid for by the patient out of pocket and GDP per capita is $2,765 (compared with $53,041 for the United States) and minimum wage is less than 2 dollars a day. Every CBC has to count. If a professor asked you why you were ordering a test, “to establish a baseline” was an unacceptable reason. When I started residency here, I was incredulous that the admitted patients got a CBC and chem-7 daily. This seemed like a huge and unjustifiable waste to me.

Today, I am not so uptight. Of course, I am still extremely thoughtful about ordering tests. I do not order tests without knowing what I am looking for, or how the result will affect management. But I also recognize that there is a non-zero probability that what I suspect is fibromyalgia is something else, something with a different prognosis, better or worse, something that needs to be managed and monitored differently.

After all, “clinical judgment” does not mean relying on the history and physical exam alone. Good clinical judgment requires medical knowledge, informed by experience, supplemented by test results, and complemented by an open, inquisitive mind.

Dr. Chan practices rheumatology in Pawtucket, R.I.

Perhaps one of the biggest ways in which I’ve evolved as a doctor over the 4.5 years I’ve been in private practice is that I am not so shy about ordering tests anymore.

My point is illustrated by the case of a lovely lady I met when I was starting out in practice who complained of being in pain all the time. She was referred to me for a very low titer antinuclear antibody and a barely positive rheumatoid factor. She’d had a very long history of severe depression and anxiety. She clearly connected her symptoms to having stopped her antidepressants. She attributed her dry mouth to her benzodiazepine. I told her that I thought she had fibromyalgia and that, as she herself pointed out, it was probably related to her emotional health. We talked about the lack of any real pharmacologic treatment for the illness. We addressed self-care: that she needed to sleep better, exercise more, and treat her depression.

Three years later she came back to me with hand swelling, hypergammaglobulinemia, renal tubular acidosis, this time with significantly higher ANA and RF titers, and hypocomplementemia. You guessed it; she has Sjögren’s syndrome.

Seeing patients 40 hours a week has been incredibly challenging but also incredibly rewarding. While the large number of cases that I’ve seen has sharpened my clinical eye, it has also broadened my differential diagnoses and improved my knowledge of when it will be helpful to order more tests.

It used to be that I was extremely conservative about ordering tests. This comes from having gone to med school in the Philippines, where each test was paid for by the patient out of pocket and GDP per capita is $2,765 (compared with $53,041 for the United States) and minimum wage is less than 2 dollars a day. Every CBC has to count. If a professor asked you why you were ordering a test, “to establish a baseline” was an unacceptable reason. When I started residency here, I was incredulous that the admitted patients got a CBC and chem-7 daily. This seemed like a huge and unjustifiable waste to me.

Today, I am not so uptight. Of course, I am still extremely thoughtful about ordering tests. I do not order tests without knowing what I am looking for, or how the result will affect management. But I also recognize that there is a non-zero probability that what I suspect is fibromyalgia is something else, something with a different prognosis, better or worse, something that needs to be managed and monitored differently.

After all, “clinical judgment” does not mean relying on the history and physical exam alone. Good clinical judgment requires medical knowledge, informed by experience, supplemented by test results, and complemented by an open, inquisitive mind.

Dr. Chan practices rheumatology in Pawtucket, R.I.

Perhaps one of the biggest ways in which I’ve evolved as a doctor over the 4.5 years I’ve been in private practice is that I am not so shy about ordering tests anymore.

My point is illustrated by the case of a lovely lady I met when I was starting out in practice who complained of being in pain all the time. She was referred to me for a very low titer antinuclear antibody and a barely positive rheumatoid factor. She’d had a very long history of severe depression and anxiety. She clearly connected her symptoms to having stopped her antidepressants. She attributed her dry mouth to her benzodiazepine. I told her that I thought she had fibromyalgia and that, as she herself pointed out, it was probably related to her emotional health. We talked about the lack of any real pharmacologic treatment for the illness. We addressed self-care: that she needed to sleep better, exercise more, and treat her depression.

Three years later she came back to me with hand swelling, hypergammaglobulinemia, renal tubular acidosis, this time with significantly higher ANA and RF titers, and hypocomplementemia. You guessed it; she has Sjögren’s syndrome.

Seeing patients 40 hours a week has been incredibly challenging but also incredibly rewarding. While the large number of cases that I’ve seen has sharpened my clinical eye, it has also broadened my differential diagnoses and improved my knowledge of when it will be helpful to order more tests.

It used to be that I was extremely conservative about ordering tests. This comes from having gone to med school in the Philippines, where each test was paid for by the patient out of pocket and GDP per capita is $2,765 (compared with $53,041 for the United States) and minimum wage is less than 2 dollars a day. Every CBC has to count. If a professor asked you why you were ordering a test, “to establish a baseline” was an unacceptable reason. When I started residency here, I was incredulous that the admitted patients got a CBC and chem-7 daily. This seemed like a huge and unjustifiable waste to me.

Today, I am not so uptight. Of course, I am still extremely thoughtful about ordering tests. I do not order tests without knowing what I am looking for, or how the result will affect management. But I also recognize that there is a non-zero probability that what I suspect is fibromyalgia is something else, something with a different prognosis, better or worse, something that needs to be managed and monitored differently.

After all, “clinical judgment” does not mean relying on the history and physical exam alone. Good clinical judgment requires medical knowledge, informed by experience, supplemented by test results, and complemented by an open, inquisitive mind.

Dr. Chan practices rheumatology in Pawtucket, R.I.

Editors note: The following are a selection of responses from the SVS membership sent to Dr. Peter Lawrence based upon his article in a recent issue of Vascular Specialist on the topic of the abuse of peripheral artery disease stenting in Medicare patients.

Despite the unfortunate press, we as a more global medical vascular community are unable to police our own. I have been involved in two specific instances in which inappropriate and overuse of endovascular therapy has been addressed. Unfortunately, these practitioners continue to perform unindicated procedures while hospitals and state medical boards refuse to act.

What is Medicare to do when our own medical regulatory bodies fail to act on behalf of patients and the payor? The two routes of targeting practitioners through Medicare high outliers and legal recourse for poor outcome in unindicated procedures will remain until our societies (this includes SVIR and ACC) decide to collaborate and ensure appropriate practice. Simply stating that SVS has guidelines in place will not solve the problem.

Jason M. Johanning, M.D., Omaha, Neb.

My office of five vascular surgeons actually has an in-office procedure suite. We have converted about 30%-40% of our minimally invasive patient care to this setting. In review of what we have done, we have actually decreased the cost of patient care as there is no facility or hospital add-on charge. Our cost per patient is actually about one-third of what is typically charged by the hospital, and our quality based on our independent QA is the same in our office setting as it is in the hospital. These types of settings can significantly reduce health care costs if done in the proper fashion.

Dennis Fry, M.D., West Des Moines, Iowa

The comments in the article that hospitals confer a greater degree of oversight seems to come right from the AHA. The problem is not office-based procedures but the ethics of fraudulent practices, something that occurs in and among hospitals as well. Hospitals can be as much driven by case volume, even at academic centers, as are the practices of private outpatient procedures.

Paul Gagne, M.D., Darien, Conn.

I cannot help but wonder how our specialty’s lack of identity – and thus lack of appreciation of its responsibility and role in public awareness – has contributed to this scenario. Our inclusion under the umbrella of the American Heart Association, again without any designation of our separate identity, leads only to more confusion about our specialty in the eyes of the public.

The SVS must address its lack of a public identity in a more forceful manner. Unfortunately, it’s biggest hurdle in this may well be the hospital-employed vascular surgeons who cannot fight the administrators marketing theme of “Heart and Vascular,” implying to the public that we are all one, “like the cardiologists do” as many patients state. This is not to fault anyone, but it is to awaken our leadership to the need to establish a separate, independent “awareness” vehicle to better craft our identity as a separate specialty to the entire nation.

It will take time but will be a project which, when done properly, we will never regret. It calls for a board heavily weighted toward the independent vascular surgeons, who try daily, with limited resources, to accomplish this.

Carlo Dall’Olmo, M.D., Flint, Mich.

What the article misrepresents is that this happens only in outpatient labs. The same thing occurs, albeit to a lesser degree, in our hospitals. I am glad to see no vascular surgeons were named. I am also glad they are starting to shine a light on the massive ongoing fraud in EVLT and RF ablation procedures. This is particularly bad in Florida. I wonder if SVS can come up with some response to suggest ways to police this behavior. None of us want more government oversight, but it seems like something needs to be done at the state board level to better regulate these procedures.

Geoffrey L. Risley, M.D., Jacksonville, Fla.

I think most members of SVS have intimate knowledge of a handful of physicians in their communities whose practices would be considered abusive, if not overtly fraudulent. We have struggled locally with the belief that we, as ethical and well-reasoned providers, should have some obligation to report these providers to someone. However, there are no acceptable mechanisms with which to do so, and there is a sense that this would not be accepted well by our colleagues.

We also do not want to be written off as disgruntled competitors. Physicians have never done a good job of policing themselves. Maybe articles like this can be a springboard to discuss ways to reign in the outlier providers in our communities.

Steven Merrell, M.D., Murray, Utah

I agree with Dr. Lawrence 100%. We need the SVS to be a major speaker in this debate. We have to give patients the confidence that they are being cared for by physicians who are not only capable to diagnose the problem but are also able to care for it in the most appropriate fashion. We need to silence the naysayers and the media hogs by developing a method so that surgeons who care for vascular patients in an office-based vascular suite are certified by the Society in the form a Center of Excellence designation. Initial certification would be followed by ongoing proactive reviews on a serial basis. I would ask that the leaders of our society take a step toward developing the concept of this certification body as soon as possible. We need to police ourselves and this may be the way to do it.

Thank you in advance for your attention and ongoing vigilance for the vascular surgical community.

Khash Salartash, M.D., Galloway, N.J.

Editors note: The following are a selection of responses from the SVS membership sent to Dr. Peter Lawrence based upon his article in a recent issue of Vascular Specialist on the topic of the abuse of peripheral artery disease stenting in Medicare patients.

Despite the unfortunate press, we as a more global medical vascular community are unable to police our own. I have been involved in two specific instances in which inappropriate and overuse of endovascular therapy has been addressed. Unfortunately, these practitioners continue to perform unindicated procedures while hospitals and state medical boards refuse to act.

What is Medicare to do when our own medical regulatory bodies fail to act on behalf of patients and the payor? The two routes of targeting practitioners through Medicare high outliers and legal recourse for poor outcome in unindicated procedures will remain until our societies (this includes SVIR and ACC) decide to collaborate and ensure appropriate practice. Simply stating that SVS has guidelines in place will not solve the problem.

Jason M. Johanning, M.D., Omaha, Neb.

My office of five vascular surgeons actually has an in-office procedure suite. We have converted about 30%-40% of our minimally invasive patient care to this setting. In review of what we have done, we have actually decreased the cost of patient care as there is no facility or hospital add-on charge. Our cost per patient is actually about one-third of what is typically charged by the hospital, and our quality based on our independent QA is the same in our office setting as it is in the hospital. These types of settings can significantly reduce health care costs if done in the proper fashion.

Dennis Fry, M.D., West Des Moines, Iowa

The comments in the article that hospitals confer a greater degree of oversight seems to come right from the AHA. The problem is not office-based procedures but the ethics of fraudulent practices, something that occurs in and among hospitals as well. Hospitals can be as much driven by case volume, even at academic centers, as are the practices of private outpatient procedures.

Paul Gagne, M.D., Darien, Conn.

I cannot help but wonder how our specialty’s lack of identity – and thus lack of appreciation of its responsibility and role in public awareness – has contributed to this scenario. Our inclusion under the umbrella of the American Heart Association, again without any designation of our separate identity, leads only to more confusion about our specialty in the eyes of the public.

The SVS must address its lack of a public identity in a more forceful manner. Unfortunately, it’s biggest hurdle in this may well be the hospital-employed vascular surgeons who cannot fight the administrators marketing theme of “Heart and Vascular,” implying to the public that we are all one, “like the cardiologists do” as many patients state. This is not to fault anyone, but it is to awaken our leadership to the need to establish a separate, independent “awareness” vehicle to better craft our identity as a separate specialty to the entire nation.

It will take time but will be a project which, when done properly, we will never regret. It calls for a board heavily weighted toward the independent vascular surgeons, who try daily, with limited resources, to accomplish this.

Carlo Dall’Olmo, M.D., Flint, Mich.

What the article misrepresents is that this happens only in outpatient labs. The same thing occurs, albeit to a lesser degree, in our hospitals. I am glad to see no vascular surgeons were named. I am also glad they are starting to shine a light on the massive ongoing fraud in EVLT and RF ablation procedures. This is particularly bad in Florida. I wonder if SVS can come up with some response to suggest ways to police this behavior. None of us want more government oversight, but it seems like something needs to be done at the state board level to better regulate these procedures.

Geoffrey L. Risley, M.D., Jacksonville, Fla.

I think most members of SVS have intimate knowledge of a handful of physicians in their communities whose practices would be considered abusive, if not overtly fraudulent. We have struggled locally with the belief that we, as ethical and well-reasoned providers, should have some obligation to report these providers to someone. However, there are no acceptable mechanisms with which to do so, and there is a sense that this would not be accepted well by our colleagues.

We also do not want to be written off as disgruntled competitors. Physicians have never done a good job of policing themselves. Maybe articles like this can be a springboard to discuss ways to reign in the outlier providers in our communities.

Steven Merrell, M.D., Murray, Utah

I agree with Dr. Lawrence 100%. We need the SVS to be a major speaker in this debate. We have to give patients the confidence that they are being cared for by physicians who are not only capable to diagnose the problem but are also able to care for it in the most appropriate fashion. We need to silence the naysayers and the media hogs by developing a method so that surgeons who care for vascular patients in an office-based vascular suite are certified by the Society in the form a Center of Excellence designation. Initial certification would be followed by ongoing proactive reviews on a serial basis. I would ask that the leaders of our society take a step toward developing the concept of this certification body as soon as possible. We need to police ourselves and this may be the way to do it.

Thank you in advance for your attention and ongoing vigilance for the vascular surgical community.

Khash Salartash, M.D., Galloway, N.J.

Editors note: The following are a selection of responses from the SVS membership sent to Dr. Peter Lawrence based upon his article in a recent issue of Vascular Specialist on the topic of the abuse of peripheral artery disease stenting in Medicare patients.

Despite the unfortunate press, we as a more global medical vascular community are unable to police our own. I have been involved in two specific instances in which inappropriate and overuse of endovascular therapy has been addressed. Unfortunately, these practitioners continue to perform unindicated procedures while hospitals and state medical boards refuse to act.

What is Medicare to do when our own medical regulatory bodies fail to act on behalf of patients and the payor? The two routes of targeting practitioners through Medicare high outliers and legal recourse for poor outcome in unindicated procedures will remain until our societies (this includes SVIR and ACC) decide to collaborate and ensure appropriate practice. Simply stating that SVS has guidelines in place will not solve the problem.

Jason M. Johanning, M.D., Omaha, Neb.

My office of five vascular surgeons actually has an in-office procedure suite. We have converted about 30%-40% of our minimally invasive patient care to this setting. In review of what we have done, we have actually decreased the cost of patient care as there is no facility or hospital add-on charge. Our cost per patient is actually about one-third of what is typically charged by the hospital, and our quality based on our independent QA is the same in our office setting as it is in the hospital. These types of settings can significantly reduce health care costs if done in the proper fashion.

Dennis Fry, M.D., West Des Moines, Iowa

The comments in the article that hospitals confer a greater degree of oversight seems to come right from the AHA. The problem is not office-based procedures but the ethics of fraudulent practices, something that occurs in and among hospitals as well. Hospitals can be as much driven by case volume, even at academic centers, as are the practices of private outpatient procedures.

Paul Gagne, M.D., Darien, Conn.

I cannot help but wonder how our specialty’s lack of identity – and thus lack of appreciation of its responsibility and role in public awareness – has contributed to this scenario. Our inclusion under the umbrella of the American Heart Association, again without any designation of our separate identity, leads only to more confusion about our specialty in the eyes of the public.

The SVS must address its lack of a public identity in a more forceful manner. Unfortunately, it’s biggest hurdle in this may well be the hospital-employed vascular surgeons who cannot fight the administrators marketing theme of “Heart and Vascular,” implying to the public that we are all one, “like the cardiologists do” as many patients state. This is not to fault anyone, but it is to awaken our leadership to the need to establish a separate, independent “awareness” vehicle to better craft our identity as a separate specialty to the entire nation.

It will take time but will be a project which, when done properly, we will never regret. It calls for a board heavily weighted toward the independent vascular surgeons, who try daily, with limited resources, to accomplish this.

Carlo Dall’Olmo, M.D., Flint, Mich.

What the article misrepresents is that this happens only in outpatient labs. The same thing occurs, albeit to a lesser degree, in our hospitals. I am glad to see no vascular surgeons were named. I am also glad they are starting to shine a light on the massive ongoing fraud in EVLT and RF ablation procedures. This is particularly bad in Florida. I wonder if SVS can come up with some response to suggest ways to police this behavior. None of us want more government oversight, but it seems like something needs to be done at the state board level to better regulate these procedures.

Geoffrey L. Risley, M.D., Jacksonville, Fla.

I think most members of SVS have intimate knowledge of a handful of physicians in their communities whose practices would be considered abusive, if not overtly fraudulent. We have struggled locally with the belief that we, as ethical and well-reasoned providers, should have some obligation to report these providers to someone. However, there are no acceptable mechanisms with which to do so, and there is a sense that this would not be accepted well by our colleagues.

We also do not want to be written off as disgruntled competitors. Physicians have never done a good job of policing themselves. Maybe articles like this can be a springboard to discuss ways to reign in the outlier providers in our communities.

Steven Merrell, M.D., Murray, Utah

I agree with Dr. Lawrence 100%. We need the SVS to be a major speaker in this debate. We have to give patients the confidence that they are being cared for by physicians who are not only capable to diagnose the problem but are also able to care for it in the most appropriate fashion. We need to silence the naysayers and the media hogs by developing a method so that surgeons who care for vascular patients in an office-based vascular suite are certified by the Society in the form a Center of Excellence designation. Initial certification would be followed by ongoing proactive reviews on a serial basis. I would ask that the leaders of our society take a step toward developing the concept of this certification body as soon as possible. We need to police ourselves and this may be the way to do it.

Thank you in advance for your attention and ongoing vigilance for the vascular surgical community.

Khash Salartash, M.D., Galloway, N.J.

Neurology, like any other field, has its share of tragic and incurable diseases. We do our best to shepherd patients and their families through a disorder by offering advice, symptomatic treatment, Family and Medical Leave Act signatures, and a shoulder.

But, inevitably, we come down to one of the most difficult discussions: the end game.

Hospice is never an easy subject to raise. I try to initiate the discussion in advance, so that the decisions and paperwork are in place.

One of the hardest parts is the misconception that hospice means you’re giving up: giving up on caring, giving up on hoping, giving up on treating. I work to try and overcome this.

Hospice may be a change in the treatment plan, but it’s still part of treatment. Finding a way to relieve suffering and provide comfortable surroundings in the final days, while often overlooked, is very important. Peace at a difficult time is sorely needed, more so than another round of tests or invasive procedures.

Yet, it’s not seen that way. Maybe this is cultural. Here, medicine is seen as a cutting-edge field, where there’s always something else that can be done: more scans, another hi-tech bioengineered drug, or some sort of amazing interventional procedure. Although we usually think of all the things we can do, it’s equally important to focus on what we should do. They aren’t always the same – a point that’s often lost.

Sometimes the best thing to do is … everything you can to just make someone comfortable. That’s not giving up. It’s recognizing when it becomes the right decision for the patient and not their family, friends, or anyone else. The patient is the one who really matters.

In an age when newer and flashier facilities and treatments are promoted, keeping the patient’s best interests in mind is critical. Sometimes we get blindsided by the amazing breakthroughs we didn’t have 20, 10, even 5 years ago. So we need to recognize when the best treatment is … to stop.

Quality of life extends all the way up to the moment of death. Part of our job is to keep the Grim Reaper away, but we inevitably lose. It is equally important, though, and sometimes forgotten, to keep the patient as comfortable as possible on the journey. And that isn’t giving up.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Neurology, like any other field, has its share of tragic and incurable diseases. We do our best to shepherd patients and their families through a disorder by offering advice, symptomatic treatment, Family and Medical Leave Act signatures, and a shoulder.

But, inevitably, we come down to one of the most difficult discussions: the end game.

Hospice is never an easy subject to raise. I try to initiate the discussion in advance, so that the decisions and paperwork are in place.

One of the hardest parts is the misconception that hospice means you’re giving up: giving up on caring, giving up on hoping, giving up on treating. I work to try and overcome this.

Hospice may be a change in the treatment plan, but it’s still part of treatment. Finding a way to relieve suffering and provide comfortable surroundings in the final days, while often overlooked, is very important. Peace at a difficult time is sorely needed, more so than another round of tests or invasive procedures.

Yet, it’s not seen that way. Maybe this is cultural. Here, medicine is seen as a cutting-edge field, where there’s always something else that can be done: more scans, another hi-tech bioengineered drug, or some sort of amazing interventional procedure. Although we usually think of all the things we can do, it’s equally important to focus on what we should do. They aren’t always the same – a point that’s often lost.

Sometimes the best thing to do is … everything you can to just make someone comfortable. That’s not giving up. It’s recognizing when it becomes the right decision for the patient and not their family, friends, or anyone else. The patient is the one who really matters.

In an age when newer and flashier facilities and treatments are promoted, keeping the patient’s best interests in mind is critical. Sometimes we get blindsided by the amazing breakthroughs we didn’t have 20, 10, even 5 years ago. So we need to recognize when the best treatment is … to stop.

Quality of life extends all the way up to the moment of death. Part of our job is to keep the Grim Reaper away, but we inevitably lose. It is equally important, though, and sometimes forgotten, to keep the patient as comfortable as possible on the journey. And that isn’t giving up.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Neurology, like any other field, has its share of tragic and incurable diseases. We do our best to shepherd patients and their families through a disorder by offering advice, symptomatic treatment, Family and Medical Leave Act signatures, and a shoulder.

But, inevitably, we come down to one of the most difficult discussions: the end game.

Hospice is never an easy subject to raise. I try to initiate the discussion in advance, so that the decisions and paperwork are in place.

One of the hardest parts is the misconception that hospice means you’re giving up: giving up on caring, giving up on hoping, giving up on treating. I work to try and overcome this.

Hospice may be a change in the treatment plan, but it’s still part of treatment. Finding a way to relieve suffering and provide comfortable surroundings in the final days, while often overlooked, is very important. Peace at a difficult time is sorely needed, more so than another round of tests or invasive procedures.

Yet, it’s not seen that way. Maybe this is cultural. Here, medicine is seen as a cutting-edge field, where there’s always something else that can be done: more scans, another hi-tech bioengineered drug, or some sort of amazing interventional procedure. Although we usually think of all the things we can do, it’s equally important to focus on what we should do. They aren’t always the same – a point that’s often lost.

Sometimes the best thing to do is … everything you can to just make someone comfortable. That’s not giving up. It’s recognizing when it becomes the right decision for the patient and not their family, friends, or anyone else. The patient is the one who really matters.

In an age when newer and flashier facilities and treatments are promoted, keeping the patient’s best interests in mind is critical. Sometimes we get blindsided by the amazing breakthroughs we didn’t have 20, 10, even 5 years ago. So we need to recognize when the best treatment is … to stop.

Quality of life extends all the way up to the moment of death. Part of our job is to keep the Grim Reaper away, but we inevitably lose. It is equally important, though, and sometimes forgotten, to keep the patient as comfortable as possible on the journey. And that isn’t giving up.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Times are changing! To compete in to today’s times, doctors are faced with the challenge of seeing 30-plus patients per day, keeping the wait times down, adhering to the meaningful use guidelines – all while participating in the endless maintenance of certification activities. But like it or not, medicine has changed, and you have to keep up or you likely are going to be left behind.

Pediatricians and family physicians more than other specialties are inundated with phone calls and lengthy conversations on constipation and congestion. Most of us just take the call with a smile, and chalk it up to part of the job. But what if you could provide a service that allowed you to get paid for those lengthy conversations, offered the convenience of a consultation without the patient having to come in the office – without the risk of your giving faulty advice because you haven’t actually evaluated the patient. Well, that’s what telemedicine has to offer. For a nominal monthly fee, your patients can subscribe to your “virtual” office. Whether you schedule during your office hours or set aside time before or after clinic, you now can capture a whole new clientele.

For teens, access to their doctors through their electronic devices would provide the convenience they need. Even if the issue cannot be treated without a visit, it allows for early evaluation. Acne, skin rashes, emotional issues, menstrual issues, hair issues, weight issues – all of these can be addressed via telemedicine.

The American Academy of Pediatrics’ Section on Telehealth Care (SOTC) helps guide you on how to bill for telemedicine services. It provides newsletters, educational series, and liability information. Much of the concern with telemedicine is the inconsistency of reimbursement for the service, but things are changing, and more and more of these services are being recognized for their value in meeting the needs of the patient.

There are different products on the market to assist you in setting up your virtual office. Understanding the differences in services is important. Services such as Doctor on Demand have a team of doctors available for fee-for-consult, at approximately $40. Other services, such as myowndoctor.com, set up a virtual office for you, which allows more of a concierge type service for a nominal monthly fee – approximately the amount of a copay – to allow patients access to the telemedicine service with their own physicians. This a great option that can create a cash revenue for you and broader access to patients.

There are several services provided by insurance companies – MDLIVE (Cigna), LiveHealth Online (WellPoint), and Online Care Anywhere (BC/BS Minnesota) – where providers are reimbursed at $45-$49 per visit. What is important to know when choosing a company is to be sure that the software is HIPAA (Health Insurance Portability and Accountability Act) compliant. Currently there are more than 15 companies on the market, and many more to come.

Staying up with the times is going to be key in surviving the current changes in health care. Teens in particular are a difficult group to access, but telemedicine provides that access and the comfort in continuity of care with their own physicians.

Dr. Pearce is a pediatrician in Frankfort, Ill. She said she had no relevant financial disclosures. E-mail her at [email protected].

Times are changing! To compete in to today’s times, doctors are faced with the challenge of seeing 30-plus patients per day, keeping the wait times down, adhering to the meaningful use guidelines – all while participating in the endless maintenance of certification activities. But like it or not, medicine has changed, and you have to keep up or you likely are going to be left behind.

Pediatricians and family physicians more than other specialties are inundated with phone calls and lengthy conversations on constipation and congestion. Most of us just take the call with a smile, and chalk it up to part of the job. But what if you could provide a service that allowed you to get paid for those lengthy conversations, offered the convenience of a consultation without the patient having to come in the office – without the risk of your giving faulty advice because you haven’t actually evaluated the patient. Well, that’s what telemedicine has to offer. For a nominal monthly fee, your patients can subscribe to your “virtual” office. Whether you schedule during your office hours or set aside time before or after clinic, you now can capture a whole new clientele.

For teens, access to their doctors through their electronic devices would provide the convenience they need. Even if the issue cannot be treated without a visit, it allows for early evaluation. Acne, skin rashes, emotional issues, menstrual issues, hair issues, weight issues – all of these can be addressed via telemedicine.

The American Academy of Pediatrics’ Section on Telehealth Care (SOTC) helps guide you on how to bill for telemedicine services. It provides newsletters, educational series, and liability information. Much of the concern with telemedicine is the inconsistency of reimbursement for the service, but things are changing, and more and more of these services are being recognized for their value in meeting the needs of the patient.

There are different products on the market to assist you in setting up your virtual office. Understanding the differences in services is important. Services such as Doctor on Demand have a team of doctors available for fee-for-consult, at approximately $40. Other services, such as myowndoctor.com, set up a virtual office for you, which allows more of a concierge type service for a nominal monthly fee – approximately the amount of a copay – to allow patients access to the telemedicine service with their own physicians. This a great option that can create a cash revenue for you and broader access to patients.

There are several services provided by insurance companies – MDLIVE (Cigna), LiveHealth Online (WellPoint), and Online Care Anywhere (BC/BS Minnesota) – where providers are reimbursed at $45-$49 per visit. What is important to know when choosing a company is to be sure that the software is HIPAA (Health Insurance Portability and Accountability Act) compliant. Currently there are more than 15 companies on the market, and many more to come.

Staying up with the times is going to be key in surviving the current changes in health care. Teens in particular are a difficult group to access, but telemedicine provides that access and the comfort in continuity of care with their own physicians.

Dr. Pearce is a pediatrician in Frankfort, Ill. She said she had no relevant financial disclosures. E-mail her at [email protected].

Times are changing! To compete in to today’s times, doctors are faced with the challenge of seeing 30-plus patients per day, keeping the wait times down, adhering to the meaningful use guidelines – all while participating in the endless maintenance of certification activities. But like it or not, medicine has changed, and you have to keep up or you likely are going to be left behind.

Pediatricians and family physicians more than other specialties are inundated with phone calls and lengthy conversations on constipation and congestion. Most of us just take the call with a smile, and chalk it up to part of the job. But what if you could provide a service that allowed you to get paid for those lengthy conversations, offered the convenience of a consultation without the patient having to come in the office – without the risk of your giving faulty advice because you haven’t actually evaluated the patient. Well, that’s what telemedicine has to offer. For a nominal monthly fee, your patients can subscribe to your “virtual” office. Whether you schedule during your office hours or set aside time before or after clinic, you now can capture a whole new clientele.

For teens, access to their doctors through their electronic devices would provide the convenience they need. Even if the issue cannot be treated without a visit, it allows for early evaluation. Acne, skin rashes, emotional issues, menstrual issues, hair issues, weight issues – all of these can be addressed via telemedicine.

The American Academy of Pediatrics’ Section on Telehealth Care (SOTC) helps guide you on how to bill for telemedicine services. It provides newsletters, educational series, and liability information. Much of the concern with telemedicine is the inconsistency of reimbursement for the service, but things are changing, and more and more of these services are being recognized for their value in meeting the needs of the patient.

There are different products on the market to assist you in setting up your virtual office. Understanding the differences in services is important. Services such as Doctor on Demand have a team of doctors available for fee-for-consult, at approximately $40. Other services, such as myowndoctor.com, set up a virtual office for you, which allows more of a concierge type service for a nominal monthly fee – approximately the amount of a copay – to allow patients access to the telemedicine service with their own physicians. This a great option that can create a cash revenue for you and broader access to patients.

There are several services provided by insurance companies – MDLIVE (Cigna), LiveHealth Online (WellPoint), and Online Care Anywhere (BC/BS Minnesota) – where providers are reimbursed at $45-$49 per visit. What is important to know when choosing a company is to be sure that the software is HIPAA (Health Insurance Portability and Accountability Act) compliant. Currently there are more than 15 companies on the market, and many more to come.

Staying up with the times is going to be key in surviving the current changes in health care. Teens in particular are a difficult group to access, but telemedicine provides that access and the comfort in continuity of care with their own physicians.

Dr. Pearce is a pediatrician in Frankfort, Ill. She said she had no relevant financial disclosures. E-mail her at [email protected].

Stroke is one of the most feared medical conditions, with the specter of suddenly finding oneself unable to talk, eat, walk, or live independently, according to study results.

In mid-February, results from three trials reported at the International Stroke Conference in Nashville, Tenn., changed the face of ischemic stroke treatment by proving that emergency endovascular catheterization to remove the embolus blocking cerebral blood flow produced better long-term outcomes than standard treatment with intravenous thrombolysis.

Courtesy American Heart Association

It wasn’t just that patients did better with endovascular embolectomy; it was how much they did better. In the two trials run in the United States and abroad, SWIFT PRIME and ESCAPE, the percentage of patients rated as not disabled (a modified Rankin Scale score of 0-1) when assessed after 90 days was 36% and 42% for patients treated with endovascular therapy in the two studies, compared with 17% and 19% in the two control arms. Embolectomy boosted the fraction of patients having the best stroke outcomes more than twofold, a breathtaking leap in efficacy.

Dr. Jeffrey L. Saver from UCLA, lead investigator for SWIFT PRIME, called it a “once-in-a-field” result, meaning that never again will stroke clinicians see this degree of incremental improvement by adding a new intervention.

The frustrating irony is how challenging delivery of this disease-altering treatment will be on a national scale. One problem is that it didn’t result from a single change in treatment, but from a careful mix of new diagnostic techniques with sophisticated CT imaging, new systems for expediting diagnosis, triage, transport, and treatment, in combination with new technology in the form of emboli-retrieving stents.

Stroke management specialists see a daunting series of issues to tackle as they attempt to roll out emergency endovascular interventions on a routine scale throughout much of the United States. Many more centers must open, modeled on the ones that succeeded in the trials. The centers need to be rationally positioned so they are close to patients but also give each center enough case volume to foster high interventional-skill levels. Staffing must be found for fast-moving stroke response teams that can make the diagnostics and interventions available around the clock and interpret the images to select appropriate patients. Ambulance systems have to be set up that take likely stroke patients to the centers that will best meet their treatment needs.

The stroke and public health communities will need to invest a lot of time, money, and leadership to make this happen, but it’s a clear mandate, given the promise endovascular treatment now holds to blunt the impact of one of medicine’s most feared maladies.

[email protected]


On Twitter @mitchelzoler

Stroke is one of the most feared medical conditions, with the specter of suddenly finding oneself unable to talk, eat, walk, or live independently, according to study results.

In mid-February, results from three trials reported at the International Stroke Conference in Nashville, Tenn., changed the face of ischemic stroke treatment by proving that emergency endovascular catheterization to remove the embolus blocking cerebral blood flow produced better long-term outcomes than standard treatment with intravenous thrombolysis.

Courtesy American Heart Association

It wasn’t just that patients did better with endovascular embolectomy; it was how much they did better. In the two trials run in the United States and abroad, SWIFT PRIME and ESCAPE, the percentage of patients rated as not disabled (a modified Rankin Scale score of 0-1) when assessed after 90 days was 36% and 42% for patients treated with endovascular therapy in the two studies, compared with 17% and 19% in the two control arms. Embolectomy boosted the fraction of patients having the best stroke outcomes more than twofold, a breathtaking leap in efficacy.

Dr. Jeffrey L. Saver from UCLA, lead investigator for SWIFT PRIME, called it a “once-in-a-field” result, meaning that never again will stroke clinicians see this degree of incremental improvement by adding a new intervention.

The frustrating irony is how challenging delivery of this disease-altering treatment will be on a national scale. One problem is that it didn’t result from a single change in treatment, but from a careful mix of new diagnostic techniques with sophisticated CT imaging, new systems for expediting diagnosis, triage, transport, and treatment, in combination with new technology in the form of emboli-retrieving stents.

Stroke management specialists see a daunting series of issues to tackle as they attempt to roll out emergency endovascular interventions on a routine scale throughout much of the United States. Many more centers must open, modeled on the ones that succeeded in the trials. The centers need to be rationally positioned so they are close to patients but also give each center enough case volume to foster high interventional-skill levels. Staffing must be found for fast-moving stroke response teams that can make the diagnostics and interventions available around the clock and interpret the images to select appropriate patients. Ambulance systems have to be set up that take likely stroke patients to the centers that will best meet their treatment needs.

The stroke and public health communities will need to invest a lot of time, money, and leadership to make this happen, but it’s a clear mandate, given the promise endovascular treatment now holds to blunt the impact of one of medicine’s most feared maladies.

[email protected]


On Twitter @mitchelzoler

Stroke is one of the most feared medical conditions, with the specter of suddenly finding oneself unable to talk, eat, walk, or live independently, according to study results.

In mid-February, results from three trials reported at the International Stroke Conference in Nashville, Tenn., changed the face of ischemic stroke treatment by proving that emergency endovascular catheterization to remove the embolus blocking cerebral blood flow produced better long-term outcomes than standard treatment with intravenous thrombolysis.

Courtesy American Heart Association

It wasn’t just that patients did better with endovascular embolectomy; it was how much they did better. In the two trials run in the United States and abroad, SWIFT PRIME and ESCAPE, the percentage of patients rated as not disabled (a modified Rankin Scale score of 0-1) when assessed after 90 days was 36% and 42% for patients treated with endovascular therapy in the two studies, compared with 17% and 19% in the two control arms. Embolectomy boosted the fraction of patients having the best stroke outcomes more than twofold, a breathtaking leap in efficacy.

Dr. Jeffrey L. Saver from UCLA, lead investigator for SWIFT PRIME, called it a “once-in-a-field” result, meaning that never again will stroke clinicians see this degree of incremental improvement by adding a new intervention.

The frustrating irony is how challenging delivery of this disease-altering treatment will be on a national scale. One problem is that it didn’t result from a single change in treatment, but from a careful mix of new diagnostic techniques with sophisticated CT imaging, new systems for expediting diagnosis, triage, transport, and treatment, in combination with new technology in the form of emboli-retrieving stents.

Stroke management specialists see a daunting series of issues to tackle as they attempt to roll out emergency endovascular interventions on a routine scale throughout much of the United States. Many more centers must open, modeled on the ones that succeeded in the trials. The centers need to be rationally positioned so they are close to patients but also give each center enough case volume to foster high interventional-skill levels. Staffing must be found for fast-moving stroke response teams that can make the diagnostics and interventions available around the clock and interpret the images to select appropriate patients. Ambulance systems have to be set up that take likely stroke patients to the centers that will best meet their treatment needs.

The stroke and public health communities will need to invest a lot of time, money, and leadership to make this happen, but it’s a clear mandate, given the promise endovascular treatment now holds to blunt the impact of one of medicine’s most feared maladies.

[email protected]


On Twitter @mitchelzoler

Before we dispense advice about staying healthy, we should know the effect of whatever we are recommending—be it diet, supplements, chemoprevention, or screening—on all meaningful outcomes, including overall mortality, quality of life, harms, inconveniences, and cost. Even though looking at all these outcomes may seem self-evidently wise, many research studies do not do it, and health care providers do not do it enough.

How would looking at all the outcomes change our opinion of health practices?

COMPARING GRAPEFRUIT AND PEACHES

A 2013 study linked eating berries with lower rates of myocardial infarction in women,¹ another found that people who ate some fruits (blackberries and grapefruit) but not others (peaches and oranges) had a lower rate of incident diabetes,² and a third linked a healthy diet to a lower incidence of pancreatic cancer.³ However, none of these studies examined all-cause mortality rates. A fourth study found that drinking green tea was associated with a lower risk of death from pneumonia in Japanese women, but not men.⁴

For the sake of argument, let us put aside concern about whether observational studies can reliably inform recommendations for clinical practice⁵ and concede that they can. The point is that studies such as those above look at some but not all meaningful outcomes, undermining the utility of their findings. If healthy people conclude that they should eat grapefruit instead of peaches, they may miss out on benefits of peaches that the study did not examine. Eating a healthy diet remains prudent, but the study linking it to a lower rate of pancreatic cancer is no tipping point, as pancreatic cancer is just one way to die. And advocating green tea to Japanese women but not men, to avoid pneumonia, would be a questionable public health strategy. Pneumonia is the sixth leading cause of death and accounts for 3.9% of disability-adjusted life-years lost,⁶ but what about the first five causes, which account for 96.1%?

We should know the effect of what we recommend on all meaningful outcomes

These and many other studies of dietary habits of people who are well fail to consider end points that healthy people care about. Suppose that drinking more coffee would prevent all deaths from pancreatic cancer but would modestly increase cardiovascular deaths—say, by 5%. On a population level, recommending more coffee would be wrong, because it would result in far more deaths. Suppose that drinking tea decreased deaths from pneumonia—we should still not advise patients to drink tea, as we do not know whether tea’s net effect is beneficial.

Some may argue that these epidemiologic studies are merely hypothesis-generating, but my colleagues and I analyzed all the nonrandomized studies published in several leading medical journals in 1 year and found that 59% made specific practice recommendations.⁵ Other studies may be misused in this fashion, even though the authors refrained from doing so.

CALCIUM PROTECTS BONES, BUT WHAT ABOUT THE HEART?

Narrow end points are not limited to dietary studies. Calcium supplementation with or without vitamin D has been vigorously promoted for decades⁷ to treat and prevent osteoporosis in pre- and postmenopausal women, and data confirm that these agents decrease the risk of fracture.⁸

But bone health is only one end point important to women, and long-term supplementation of a mineral or vitamin with the goal of strengthening bones may have unforeseen adverse effects.

In 2010, calcium supplementation without vitamin D was linked to higher rates of myocardial infarction (with some suggestion of increased rates of all-cause death) in pooled analyses of 15 trials.⁹ In 2011, a higher risk of cardiovascular events (stroke and myocardial infarction) was found in recipients of calcium with vitamin D in a reanalysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study,¹⁰ adjusting for the widespread use of these supplements at baseline, and this was corroborated by a meta-analysis of eight other studies.¹⁰ A more recent study confirmed that supplemental calcium increases cardiovascular risk in men.¹¹

Although the increase in cardiovascular risk seems to be modest, millions of people take calcium supplements; thus, many people may be harmed. Our exuberance for bone health suggests that, at times, a single outcome can distract.

DOES SCREENING IMPROVE SURVIVAL?

On the whole, the evidence for screening continues to focus only on certain outcomes. With the exception of the National Lung Cancer Screening Trial,¹² to date, no cancer screening trial has shown an improvement in the overall survival rate.

In fact, a 2013 Cochrane review¹³ found that mammographic screening failed to lower the rate of death from all cancers, including breast cancer, after 10 years (relative risk [RR] 1.02, 95% confidence interval [CI] 0.95–1.10) and the rate of death from all causes after 13 years (RR 0.99, 95% CI 0.95–1.03). Although screening lowered the breast cancer mortality rate, the authors argued that we should not look at only some outcomes and concluded that “breast cancer mortality was an unreliable outcome” that was biased in favor of screening, mainly because of “differential misclassification of cause of death.”¹³

Significance-chasing and selective reporting are common in observational studies

Black et al¹⁴ found that of 12 major cancer screening trials examining both disease-specific mortality and all-cause mortality, 5 had differences in mortality rates that went in opposite directions (eg, the rate of disease-specific mortality improved while overall survival was harmed, or vice-versa), suggesting paradoxical effects. In another 2 studies, differences in all-cause mortality exceeded gains in disease-specific mortality. Thus, in 7 (58%) of the 12 trials, inconsistencies existed between rates of disease-specific mortality and all-cause mortality, prompting doubt about the conclusions of the studies.¹⁴

For some cancers, data suggest that screening increases deaths from other causes, and these extra deaths are not included in the data on disease-specific mortality. For instance, men who are screened for prostate cancer have higher rates of death from cardiovascular disease and suicide,¹⁵ which might negate the tenuous benefits of screening in terms of deaths from prostate cancer.

Studies of screening for diseases other than cancer have also focused on only some outcomes. For example, the United States Preventive Services Task Force supports screening for abdominal aortic aneurysm once with ultrasonography in men ages 65 to 75 who have ever smoked,¹⁶ but the recommendation is based on improvements in the death rate from abdominal aortic aneurysm, not in all-cause mortality.¹⁷ This, along with a declining incidence of this disease and changes in how it is treated (with endovascular repair on the rise and open surgical repair declining), has led some to question if we should continue to screen for it.¹⁸

CHEMOPREVENTION: NO FREE LUNCH

Finasteride

In 2013, an analysis¹⁹ that looked at all of the outcomes laid to rest 10 years of debate over the Prostate Cancer Prevention Trial, which had randomized more than 18,000 healthy men over age 55 with no signs or symptoms of prostate cancer to receive finasteride or placebo, with the end point of prostate cancer incidence. The initial results, published in 2003,²⁰ had found that the drug decreased the rate of incident prostate cancer but paradoxically increased the rate of high-grade (Gleason score ≥ 7) tumors. Whether these results were real or an artifact of ascertainment was debated, as was whether the adverse effects—decreases in sexual potency, libido, and ejaculation—were worth the 25% reduction in prostate cancer incidence.

Much of the debate ended with the 2013 publication, which showed that regardless of finasteride’s effect on prostate cancer, overall mortality curves at 18-year follow-up were absolutely indistinguishable.¹⁹ Healthy patients hoping that finasteride will help them live longer or better can be safely told that it does neither.

Statins as primary prevention

As for statin therapy as primary prevention, the best meta-analysis to date (which meticulously excluded secondary-prevention patients after analyzing individual patient-level data) found no improvement in overall mortality despite more than 240,000 patient-years of follow-up.²¹ Because of this, and because the harms of statin therapy are being increasingly (but still poorly) documented, widespread use of statins has been questioned.²²

Proponents point to the ability of statins to reduce end points such as revascularization, stroke, and nonfatal myocardial infarction.²³ But the main question facing healthy users is whether improvement in these end points translates to longer life or better quality of life. These questions remain unresolved.

Aspirin as primary prevention

Another example of the importance of considering all the outcomes is the issue of aspirin as primary prevention.

Enthusiasm for aspirin as primary prevention has been recently reinvigorated, with data showing it can prevent colorectal cancers that overexpress cyclooxygenase-2.²⁴ But a meta-analysis of nine randomized trials of aspirin²⁵ with more than 1,000 participants found that, although aspirin decreases the rate of nonfatal myocardial infarction (odds ratio [OR] 0.80, 95% CI 0.67–0.96), it does not significantly reduce cancer mortality (OR 0.93, 95% CI 0.84–1.03), and it increases the risk of nontrivial bleeding (OR 1.31; 95% CI 1.14–1.50). Its effects on overall mortality were not statistically significant but were possibly favorable (OR 0.94, 95% CI 0.88–1.00), so this requires further study.

After broad consideration of the risks and benefits of aspirin, the US Food and Drug Administration has issued a statement that aspirin is not recommended as primary prevention.²⁶

WHY STUDIES LOOK ONLY AT SOME OUTCOMES

There are many reasons why researchers favor examining some outcomes over others, but there is no clear justification for ignoring overall mortality. Overall mortality should routinely be examined in large population studies of diet and supplements and in trials of medications²⁷ and cancer screening.

Healthy people do not care about some outcomes; they care about all outcomes

With regard to large observational studies, it is hard to understand why some would not include survival analyses, unless the results would fail to support the study’s hypothesis. In fact, some studies do report overall survival results,²⁸ but others do not. The omission of overall survival in large data-set research should raise concerns of multiple hypothesis testing and selective reporting. Eating peaches as opposed to grapefruit may not be associated with differences in rates of all-cause mortality, myocardial infarction, pneumonia, or lung cancer, but if you look at 20 different variables, chances are that one will have a P value less than .05, and an investigator might be tempted to report it as statistically significant and even meaningful.

Empirical studies support this claim. One group found that for 80% of ingredients randomly selected from a cookbook, there existed Medline-indexed articles assessing cancer risk, with 65% of studies finding nominally significant differences in the risk of some type of cancer.²⁹

An excess of significant findings such as this argues that significance-chasing and selective reporting are common in this field and has led to calls for methodologic improvements, including routine falsification testing³⁰ and up-front registration of observational studies.³¹

WHY ALL OUTCOMES MATTER

Healthy people do not care about some outcomes; they care about all outcomes. Some patients may truly have unique priorities (quality of life vs quantity of life), but others may overestimate their risk of death from some causes and underestimate their risk from others, and practitioners have the obligation to counsel them appropriately.

For instance, a patient who watches a brother pass away from pancreatic adenocarcinoma may wish to do everything possible to avoid that illness. But often, as in this case, fear may surpass risk. The patient’s risk of pancreatic cancer is no different than that in the general population: the best data show³² an odds ratio of 1.8, with a confidence interval spanning 1. As such, pancreatic cancer is still not among his five most likely causes of death.

Some patients may care about their bone mineral density or cholesterol level. But again, physicians have an obligation to direct patients’ attention to all of the outcomes that should be of interest to them.

OBJECTIONS TO INCLUDING ALL OUTCOMES

There are important objections to the argument I am presenting here.

First, including all outcomes is expensive. For studies involving retrospective analysis of existing data, looking at overall mortality would not incur additional costs, only an additional analysis. But for prospective trials to have statistical power to detect a difference in overall mortality, larger sample sizes or longer follow-up might be needed—either of which would add to the cost.

In chemoprevention trials, the rate of incident cancer has been called the gold standard end point.³³ To design a thrifty chemoprevention study, investigators can either target a broad population and aim for incident malignancy, or target a restricted, high-risk population and aim for overall mortality. The latter is preferable because although it can inform the decisions of only some people, the former cannot inform any people, as was seen with difficulties in interpreting the Prostate Cancer Prevention Trial and trials showing reduced breast cancer incidence from tamoxifen, raloxifene, and exemestane.

In large cancer screening trials, the cost of powering the trial for overall mortality would be greater, and though a carefully selected, high-risk population can be enrolled, historically this has not been popular. In cancer screening, it is a mistake to contrast the costs of trials powered for overall mortality with those of lesser studies examining disease-specific death. Instead, we must consider the larger societal costs incurred by cancer screening that does not truly improve quantity or quality of life.³⁴

The recent reversal of recommendations for prostate-specific antigen testing by the United States Preventive Services Task Force³⁵ suggests that erroneous recommendations, practiced for decades, can cost society hundreds of billions of dollars but fail to improve meaningful outcomes.

The history of medicine is replete with examples of widely recommended practices and interventions that not only failed to improve the outcomes they claimed to improve, but at times increased the rate of all-cause mortality or carried harms that far outweighed benefits.^36,37 The costs of conducting research to fully understand all outcomes are only a fraction of the costs of a practice that is widely disseminated.³⁸

The history of medicine is replete with practices that harmed more than helped

A second objection to my analysis is that there is more to life than survival, and outcomes besides overall mortality are important. This is a self-evident truth. That an intervention improves the rate of overall mortality is neither necessary nor sufficient for its recommendation. Practices may improve survival but worsen quality of life to such a degree that they should not be recommended. Conversely, practices that improve quality of life should be endorsed even if they fail to prolong life.

Thus, overall mortality and quality of life must be considered together, but the end points that are favored currently (disease-specific death, incident cancer, diabetes mellitus, myocardial infarction) do not do a good job of capturing either. Disease-specific death is not meaningful to any patient if deaths from other causes are increased so that overall mortality is unchanged. Furthermore, preventing a diagnosis of cancer or diabetes may offer some psychological comfort, but well-crafted quality-of-life instruments are best suited to capture just how great that benefit is and whether it justifies the cost of such interventions, particularly if the rate of survival is unchanged.

Preventing stroke or myocardial infarction is important, but we should be cautious of interpreting data when decreasing the rate of these morbid events does not lead to commensurate improvements in survival. Alternatively, if morbid events are truly avoided but survival analyses are underpowered, quality-of-life measurements should demonstrate the benefit. But the end points currently used capture neither survival nor quality of life in a meaningful way.

WHEN ADVISING HEALTHY PEOPLE

Looking at all outcomes is important when caring for patients who are sick, but even more so for patients who are well. We need to know an intervention has a net benefit before we recommend it to a healthy person. Overall mortality should be reported routinely in this population, particularly in settings where the cost to do so is trivial (ie, in observational studies). Designers of thrifty trials should try to include people at high risk and power the trial for definite end points, rather than being broadly inclusive and reaching disputed conclusions. Research and decision-making should look at all outcomes. Healthy people deserve no less.

Before we dispense advice about staying healthy, we should know the effect of whatever we are recommending—be it diet, supplements, chemoprevention, or screening—on all meaningful outcomes, including overall mortality, quality of life, harms, inconveniences, and cost. Even though looking at all these outcomes may seem self-evidently wise, many research studies do not do it, and health care providers do not do it enough.

How would looking at all the outcomes change our opinion of health practices?

COMPARING GRAPEFRUIT AND PEACHES

A 2013 study linked eating berries with lower rates of myocardial infarction in women,¹ another found that people who ate some fruits (blackberries and grapefruit) but not others (peaches and oranges) had a lower rate of incident diabetes,² and a third linked a healthy diet to a lower incidence of pancreatic cancer.³ However, none of these studies examined all-cause mortality rates. A fourth study found that drinking green tea was associated with a lower risk of death from pneumonia in Japanese women, but not men.⁴

For the sake of argument, let us put aside concern about whether observational studies can reliably inform recommendations for clinical practice⁵ and concede that they can. The point is that studies such as those above look at some but not all meaningful outcomes, undermining the utility of their findings. If healthy people conclude that they should eat grapefruit instead of peaches, they may miss out on benefits of peaches that the study did not examine. Eating a healthy diet remains prudent, but the study linking it to a lower rate of pancreatic cancer is no tipping point, as pancreatic cancer is just one way to die. And advocating green tea to Japanese women but not men, to avoid pneumonia, would be a questionable public health strategy. Pneumonia is the sixth leading cause of death and accounts for 3.9% of disability-adjusted life-years lost,⁶ but what about the first five causes, which account for 96.1%?

We should know the effect of what we recommend on all meaningful outcomes

These and many other studies of dietary habits of people who are well fail to consider end points that healthy people care about. Suppose that drinking more coffee would prevent all deaths from pancreatic cancer but would modestly increase cardiovascular deaths—say, by 5%. On a population level, recommending more coffee would be wrong, because it would result in far more deaths. Suppose that drinking tea decreased deaths from pneumonia—we should still not advise patients to drink tea, as we do not know whether tea’s net effect is beneficial.

Some may argue that these epidemiologic studies are merely hypothesis-generating, but my colleagues and I analyzed all the nonrandomized studies published in several leading medical journals in 1 year and found that 59% made specific practice recommendations.⁵ Other studies may be misused in this fashion, even though the authors refrained from doing so.

CALCIUM PROTECTS BONES, BUT WHAT ABOUT THE HEART?

Narrow end points are not limited to dietary studies. Calcium supplementation with or without vitamin D has been vigorously promoted for decades⁷ to treat and prevent osteoporosis in pre- and postmenopausal women, and data confirm that these agents decrease the risk of fracture.⁸

But bone health is only one end point important to women, and long-term supplementation of a mineral or vitamin with the goal of strengthening bones may have unforeseen adverse effects.

In 2010, calcium supplementation without vitamin D was linked to higher rates of myocardial infarction (with some suggestion of increased rates of all-cause death) in pooled analyses of 15 trials.⁹ In 2011, a higher risk of cardiovascular events (stroke and myocardial infarction) was found in recipients of calcium with vitamin D in a reanalysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study,¹⁰ adjusting for the widespread use of these supplements at baseline, and this was corroborated by a meta-analysis of eight other studies.¹⁰ A more recent study confirmed that supplemental calcium increases cardiovascular risk in men.¹¹

Although the increase in cardiovascular risk seems to be modest, millions of people take calcium supplements; thus, many people may be harmed. Our exuberance for bone health suggests that, at times, a single outcome can distract.

DOES SCREENING IMPROVE SURVIVAL?

On the whole, the evidence for screening continues to focus only on certain outcomes. With the exception of the National Lung Cancer Screening Trial,¹² to date, no cancer screening trial has shown an improvement in the overall survival rate.

In fact, a 2013 Cochrane review¹³ found that mammographic screening failed to lower the rate of death from all cancers, including breast cancer, after 10 years (relative risk [RR] 1.02, 95% confidence interval [CI] 0.95–1.10) and the rate of death from all causes after 13 years (RR 0.99, 95% CI 0.95–1.03). Although screening lowered the breast cancer mortality rate, the authors argued that we should not look at only some outcomes and concluded that “breast cancer mortality was an unreliable outcome” that was biased in favor of screening, mainly because of “differential misclassification of cause of death.”¹³

Significance-chasing and selective reporting are common in observational studies

Black et al¹⁴ found that of 12 major cancer screening trials examining both disease-specific mortality and all-cause mortality, 5 had differences in mortality rates that went in opposite directions (eg, the rate of disease-specific mortality improved while overall survival was harmed, or vice-versa), suggesting paradoxical effects. In another 2 studies, differences in all-cause mortality exceeded gains in disease-specific mortality. Thus, in 7 (58%) of the 12 trials, inconsistencies existed between rates of disease-specific mortality and all-cause mortality, prompting doubt about the conclusions of the studies.¹⁴

For some cancers, data suggest that screening increases deaths from other causes, and these extra deaths are not included in the data on disease-specific mortality. For instance, men who are screened for prostate cancer have higher rates of death from cardiovascular disease and suicide,¹⁵ which might negate the tenuous benefits of screening in terms of deaths from prostate cancer.

Studies of screening for diseases other than cancer have also focused on only some outcomes. For example, the United States Preventive Services Task Force supports screening for abdominal aortic aneurysm once with ultrasonography in men ages 65 to 75 who have ever smoked,¹⁶ but the recommendation is based on improvements in the death rate from abdominal aortic aneurysm, not in all-cause mortality.¹⁷ This, along with a declining incidence of this disease and changes in how it is treated (with endovascular repair on the rise and open surgical repair declining), has led some to question if we should continue to screen for it.¹⁸

CHEMOPREVENTION: NO FREE LUNCH

Finasteride

In 2013, an analysis¹⁹ that looked at all of the outcomes laid to rest 10 years of debate over the Prostate Cancer Prevention Trial, which had randomized more than 18,000 healthy men over age 55 with no signs or symptoms of prostate cancer to receive finasteride or placebo, with the end point of prostate cancer incidence. The initial results, published in 2003,²⁰ had found that the drug decreased the rate of incident prostate cancer but paradoxically increased the rate of high-grade (Gleason score ≥ 7) tumors. Whether these results were real or an artifact of ascertainment was debated, as was whether the adverse effects—decreases in sexual potency, libido, and ejaculation—were worth the 25% reduction in prostate cancer incidence.

Much of the debate ended with the 2013 publication, which showed that regardless of finasteride’s effect on prostate cancer, overall mortality curves at 18-year follow-up were absolutely indistinguishable.¹⁹ Healthy patients hoping that finasteride will help them live longer or better can be safely told that it does neither.

Statins as primary prevention

As for statin therapy as primary prevention, the best meta-analysis to date (which meticulously excluded secondary-prevention patients after analyzing individual patient-level data) found no improvement in overall mortality despite more than 240,000 patient-years of follow-up.²¹ Because of this, and because the harms of statin therapy are being increasingly (but still poorly) documented, widespread use of statins has been questioned.²²

Proponents point to the ability of statins to reduce end points such as revascularization, stroke, and nonfatal myocardial infarction.²³ But the main question facing healthy users is whether improvement in these end points translates to longer life or better quality of life. These questions remain unresolved.

Aspirin as primary prevention

Another example of the importance of considering all the outcomes is the issue of aspirin as primary prevention.

Enthusiasm for aspirin as primary prevention has been recently reinvigorated, with data showing it can prevent colorectal cancers that overexpress cyclooxygenase-2.²⁴ But a meta-analysis of nine randomized trials of aspirin²⁵ with more than 1,000 participants found that, although aspirin decreases the rate of nonfatal myocardial infarction (odds ratio [OR] 0.80, 95% CI 0.67–0.96), it does not significantly reduce cancer mortality (OR 0.93, 95% CI 0.84–1.03), and it increases the risk of nontrivial bleeding (OR 1.31; 95% CI 1.14–1.50). Its effects on overall mortality were not statistically significant but were possibly favorable (OR 0.94, 95% CI 0.88–1.00), so this requires further study.

After broad consideration of the risks and benefits of aspirin, the US Food and Drug Administration has issued a statement that aspirin is not recommended as primary prevention.²⁶

WHY STUDIES LOOK ONLY AT SOME OUTCOMES

There are many reasons why researchers favor examining some outcomes over others, but there is no clear justification for ignoring overall mortality. Overall mortality should routinely be examined in large population studies of diet and supplements and in trials of medications²⁷ and cancer screening.

Healthy people do not care about some outcomes; they care about all outcomes

With regard to large observational studies, it is hard to understand why some would not include survival analyses, unless the results would fail to support the study’s hypothesis. In fact, some studies do report overall survival results,²⁸ but others do not. The omission of overall survival in large data-set research should raise concerns of multiple hypothesis testing and selective reporting. Eating peaches as opposed to grapefruit may not be associated with differences in rates of all-cause mortality, myocardial infarction, pneumonia, or lung cancer, but if you look at 20 different variables, chances are that one will have a P value less than .05, and an investigator might be tempted to report it as statistically significant and even meaningful.

Empirical studies support this claim. One group found that for 80% of ingredients randomly selected from a cookbook, there existed Medline-indexed articles assessing cancer risk, with 65% of studies finding nominally significant differences in the risk of some type of cancer.²⁹

An excess of significant findings such as this argues that significance-chasing and selective reporting are common in this field and has led to calls for methodologic improvements, including routine falsification testing³⁰ and up-front registration of observational studies.³¹

WHY ALL OUTCOMES MATTER

Healthy people do not care about some outcomes; they care about all outcomes. Some patients may truly have unique priorities (quality of life vs quantity of life), but others may overestimate their risk of death from some causes and underestimate their risk from others, and practitioners have the obligation to counsel them appropriately.

For instance, a patient who watches a brother pass away from pancreatic adenocarcinoma may wish to do everything possible to avoid that illness. But often, as in this case, fear may surpass risk. The patient’s risk of pancreatic cancer is no different than that in the general population: the best data show³² an odds ratio of 1.8, with a confidence interval spanning 1. As such, pancreatic cancer is still not among his five most likely causes of death.

Some patients may care about their bone mineral density or cholesterol level. But again, physicians have an obligation to direct patients’ attention to all of the outcomes that should be of interest to them.

OBJECTIONS TO INCLUDING ALL OUTCOMES

There are important objections to the argument I am presenting here.

First, including all outcomes is expensive. For studies involving retrospective analysis of existing data, looking at overall mortality would not incur additional costs, only an additional analysis. But for prospective trials to have statistical power to detect a difference in overall mortality, larger sample sizes or longer follow-up might be needed—either of which would add to the cost.

In chemoprevention trials, the rate of incident cancer has been called the gold standard end point.³³ To design a thrifty chemoprevention study, investigators can either target a broad population and aim for incident malignancy, or target a restricted, high-risk population and aim for overall mortality. The latter is preferable because although it can inform the decisions of only some people, the former cannot inform any people, as was seen with difficulties in interpreting the Prostate Cancer Prevention Trial and trials showing reduced breast cancer incidence from tamoxifen, raloxifene, and exemestane.

In large cancer screening trials, the cost of powering the trial for overall mortality would be greater, and though a carefully selected, high-risk population can be enrolled, historically this has not been popular. In cancer screening, it is a mistake to contrast the costs of trials powered for overall mortality with those of lesser studies examining disease-specific death. Instead, we must consider the larger societal costs incurred by cancer screening that does not truly improve quantity or quality of life.³⁴

The recent reversal of recommendations for prostate-specific antigen testing by the United States Preventive Services Task Force³⁵ suggests that erroneous recommendations, practiced for decades, can cost society hundreds of billions of dollars but fail to improve meaningful outcomes.

The history of medicine is replete with examples of widely recommended practices and interventions that not only failed to improve the outcomes they claimed to improve, but at times increased the rate of all-cause mortality or carried harms that far outweighed benefits.^36,37 The costs of conducting research to fully understand all outcomes are only a fraction of the costs of a practice that is widely disseminated.³⁸

The history of medicine is replete with practices that harmed more than helped

A second objection to my analysis is that there is more to life than survival, and outcomes besides overall mortality are important. This is a self-evident truth. That an intervention improves the rate of overall mortality is neither necessary nor sufficient for its recommendation. Practices may improve survival but worsen quality of life to such a degree that they should not be recommended. Conversely, practices that improve quality of life should be endorsed even if they fail to prolong life.

Thus, overall mortality and quality of life must be considered together, but the end points that are favored currently (disease-specific death, incident cancer, diabetes mellitus, myocardial infarction) do not do a good job of capturing either. Disease-specific death is not meaningful to any patient if deaths from other causes are increased so that overall mortality is unchanged. Furthermore, preventing a diagnosis of cancer or diabetes may offer some psychological comfort, but well-crafted quality-of-life instruments are best suited to capture just how great that benefit is and whether it justifies the cost of such interventions, particularly if the rate of survival is unchanged.

Preventing stroke or myocardial infarction is important, but we should be cautious of interpreting data when decreasing the rate of these morbid events does not lead to commensurate improvements in survival. Alternatively, if morbid events are truly avoided but survival analyses are underpowered, quality-of-life measurements should demonstrate the benefit. But the end points currently used capture neither survival nor quality of life in a meaningful way.

WHEN ADVISING HEALTHY PEOPLE

Looking at all outcomes is important when caring for patients who are sick, but even more so for patients who are well. We need to know an intervention has a net benefit before we recommend it to a healthy person. Overall mortality should be reported routinely in this population, particularly in settings where the cost to do so is trivial (ie, in observational studies). Designers of thrifty trials should try to include people at high risk and power the trial for definite end points, rather than being broadly inclusive and reaching disputed conclusions. Research and decision-making should look at all outcomes. Healthy people deserve no less.

Before we dispense advice about staying healthy, we should know the effect of whatever we are recommending—be it diet, supplements, chemoprevention, or screening—on all meaningful outcomes, including overall mortality, quality of life, harms, inconveniences, and cost. Even though looking at all these outcomes may seem self-evidently wise, many research studies do not do it, and health care providers do not do it enough.

How would looking at all the outcomes change our opinion of health practices?

COMPARING GRAPEFRUIT AND PEACHES

A 2013 study linked eating berries with lower rates of myocardial infarction in women,¹ another found that people who ate some fruits (blackberries and grapefruit) but not others (peaches and oranges) had a lower rate of incident diabetes,² and a third linked a healthy diet to a lower incidence of pancreatic cancer.³ However, none of these studies examined all-cause mortality rates. A fourth study found that drinking green tea was associated with a lower risk of death from pneumonia in Japanese women, but not men.⁴

For the sake of argument, let us put aside concern about whether observational studies can reliably inform recommendations for clinical practice⁵ and concede that they can. The point is that studies such as those above look at some but not all meaningful outcomes, undermining the utility of their findings. If healthy people conclude that they should eat grapefruit instead of peaches, they may miss out on benefits of peaches that the study did not examine. Eating a healthy diet remains prudent, but the study linking it to a lower rate of pancreatic cancer is no tipping point, as pancreatic cancer is just one way to die. And advocating green tea to Japanese women but not men, to avoid pneumonia, would be a questionable public health strategy. Pneumonia is the sixth leading cause of death and accounts for 3.9% of disability-adjusted life-years lost,⁶ but what about the first five causes, which account for 96.1%?

We should know the effect of what we recommend on all meaningful outcomes

These and many other studies of dietary habits of people who are well fail to consider end points that healthy people care about. Suppose that drinking more coffee would prevent all deaths from pancreatic cancer but would modestly increase cardiovascular deaths—say, by 5%. On a population level, recommending more coffee would be wrong, because it would result in far more deaths. Suppose that drinking tea decreased deaths from pneumonia—we should still not advise patients to drink tea, as we do not know whether tea’s net effect is beneficial.

Some may argue that these epidemiologic studies are merely hypothesis-generating, but my colleagues and I analyzed all the nonrandomized studies published in several leading medical journals in 1 year and found that 59% made specific practice recommendations.⁵ Other studies may be misused in this fashion, even though the authors refrained from doing so.

CALCIUM PROTECTS BONES, BUT WHAT ABOUT THE HEART?

Narrow end points are not limited to dietary studies. Calcium supplementation with or without vitamin D has been vigorously promoted for decades⁷ to treat and prevent osteoporosis in pre- and postmenopausal women, and data confirm that these agents decrease the risk of fracture.⁸

But bone health is only one end point important to women, and long-term supplementation of a mineral or vitamin with the goal of strengthening bones may have unforeseen adverse effects.

In 2010, calcium supplementation without vitamin D was linked to higher rates of myocardial infarction (with some suggestion of increased rates of all-cause death) in pooled analyses of 15 trials.⁹ In 2011, a higher risk of cardiovascular events (stroke and myocardial infarction) was found in recipients of calcium with vitamin D in a reanalysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study,¹⁰ adjusting for the widespread use of these supplements at baseline, and this was corroborated by a meta-analysis of eight other studies.¹⁰ A more recent study confirmed that supplemental calcium increases cardiovascular risk in men.¹¹

Although the increase in cardiovascular risk seems to be modest, millions of people take calcium supplements; thus, many people may be harmed. Our exuberance for bone health suggests that, at times, a single outcome can distract.

DOES SCREENING IMPROVE SURVIVAL?

On the whole, the evidence for screening continues to focus only on certain outcomes. With the exception of the National Lung Cancer Screening Trial,¹² to date, no cancer screening trial has shown an improvement in the overall survival rate.

In fact, a 2013 Cochrane review¹³ found that mammographic screening failed to lower the rate of death from all cancers, including breast cancer, after 10 years (relative risk [RR] 1.02, 95% confidence interval [CI] 0.95–1.10) and the rate of death from all causes after 13 years (RR 0.99, 95% CI 0.95–1.03). Although screening lowered the breast cancer mortality rate, the authors argued that we should not look at only some outcomes and concluded that “breast cancer mortality was an unreliable outcome” that was biased in favor of screening, mainly because of “differential misclassification of cause of death.”¹³

Significance-chasing and selective reporting are common in observational studies

Black et al¹⁴ found that of 12 major cancer screening trials examining both disease-specific mortality and all-cause mortality, 5 had differences in mortality rates that went in opposite directions (eg, the rate of disease-specific mortality improved while overall survival was harmed, or vice-versa), suggesting paradoxical effects. In another 2 studies, differences in all-cause mortality exceeded gains in disease-specific mortality. Thus, in 7 (58%) of the 12 trials, inconsistencies existed between rates of disease-specific mortality and all-cause mortality, prompting doubt about the conclusions of the studies.¹⁴

For some cancers, data suggest that screening increases deaths from other causes, and these extra deaths are not included in the data on disease-specific mortality. For instance, men who are screened for prostate cancer have higher rates of death from cardiovascular disease and suicide,¹⁵ which might negate the tenuous benefits of screening in terms of deaths from prostate cancer.

Studies of screening for diseases other than cancer have also focused on only some outcomes. For example, the United States Preventive Services Task Force supports screening for abdominal aortic aneurysm once with ultrasonography in men ages 65 to 75 who have ever smoked,¹⁶ but the recommendation is based on improvements in the death rate from abdominal aortic aneurysm, not in all-cause mortality.¹⁷ This, along with a declining incidence of this disease and changes in how it is treated (with endovascular repair on the rise and open surgical repair declining), has led some to question if we should continue to screen for it.¹⁸

CHEMOPREVENTION: NO FREE LUNCH

Finasteride

In 2013, an analysis¹⁹ that looked at all of the outcomes laid to rest 10 years of debate over the Prostate Cancer Prevention Trial, which had randomized more than 18,000 healthy men over age 55 with no signs or symptoms of prostate cancer to receive finasteride or placebo, with the end point of prostate cancer incidence. The initial results, published in 2003,²⁰ had found that the drug decreased the rate of incident prostate cancer but paradoxically increased the rate of high-grade (Gleason score ≥ 7) tumors. Whether these results were real or an artifact of ascertainment was debated, as was whether the adverse effects—decreases in sexual potency, libido, and ejaculation—were worth the 25% reduction in prostate cancer incidence.

Much of the debate ended with the 2013 publication, which showed that regardless of finasteride’s effect on prostate cancer, overall mortality curves at 18-year follow-up were absolutely indistinguishable.¹⁹ Healthy patients hoping that finasteride will help them live longer or better can be safely told that it does neither.

Statins as primary prevention

As for statin therapy as primary prevention, the best meta-analysis to date (which meticulously excluded secondary-prevention patients after analyzing individual patient-level data) found no improvement in overall mortality despite more than 240,000 patient-years of follow-up.²¹ Because of this, and because the harms of statin therapy are being increasingly (but still poorly) documented, widespread use of statins has been questioned.²²

Proponents point to the ability of statins to reduce end points such as revascularization, stroke, and nonfatal myocardial infarction.²³ But the main question facing healthy users is whether improvement in these end points translates to longer life or better quality of life. These questions remain unresolved.

Aspirin as primary prevention

Another example of the importance of considering all the outcomes is the issue of aspirin as primary prevention.

Enthusiasm for aspirin as primary prevention has been recently reinvigorated, with data showing it can prevent colorectal cancers that overexpress cyclooxygenase-2.²⁴ But a meta-analysis of nine randomized trials of aspirin²⁵ with more than 1,000 participants found that, although aspirin decreases the rate of nonfatal myocardial infarction (odds ratio [OR] 0.80, 95% CI 0.67–0.96), it does not significantly reduce cancer mortality (OR 0.93, 95% CI 0.84–1.03), and it increases the risk of nontrivial bleeding (OR 1.31; 95% CI 1.14–1.50). Its effects on overall mortality were not statistically significant but were possibly favorable (OR 0.94, 95% CI 0.88–1.00), so this requires further study.

After broad consideration of the risks and benefits of aspirin, the US Food and Drug Administration has issued a statement that aspirin is not recommended as primary prevention.²⁶

WHY STUDIES LOOK ONLY AT SOME OUTCOMES

There are many reasons why researchers favor examining some outcomes over others, but there is no clear justification for ignoring overall mortality. Overall mortality should routinely be examined in large population studies of diet and supplements and in trials of medications²⁷ and cancer screening.

Healthy people do not care about some outcomes; they care about all outcomes

With regard to large observational studies, it is hard to understand why some would not include survival analyses, unless the results would fail to support the study’s hypothesis. In fact, some studies do report overall survival results,²⁸ but others do not. The omission of overall survival in large data-set research should raise concerns of multiple hypothesis testing and selective reporting. Eating peaches as opposed to grapefruit may not be associated with differences in rates of all-cause mortality, myocardial infarction, pneumonia, or lung cancer, but if you look at 20 different variables, chances are that one will have a P value less than .05, and an investigator might be tempted to report it as statistically significant and even meaningful.

Empirical studies support this claim. One group found that for 80% of ingredients randomly selected from a cookbook, there existed Medline-indexed articles assessing cancer risk, with 65% of studies finding nominally significant differences in the risk of some type of cancer.²⁹

An excess of significant findings such as this argues that significance-chasing and selective reporting are common in this field and has led to calls for methodologic improvements, including routine falsification testing³⁰ and up-front registration of observational studies.³¹

WHY ALL OUTCOMES MATTER

Healthy people do not care about some outcomes; they care about all outcomes. Some patients may truly have unique priorities (quality of life vs quantity of life), but others may overestimate their risk of death from some causes and underestimate their risk from others, and practitioners have the obligation to counsel them appropriately.

For instance, a patient who watches a brother pass away from pancreatic adenocarcinoma may wish to do everything possible to avoid that illness. But often, as in this case, fear may surpass risk. The patient’s risk of pancreatic cancer is no different than that in the general population: the best data show³² an odds ratio of 1.8, with a confidence interval spanning 1. As such, pancreatic cancer is still not among his five most likely causes of death.

Some patients may care about their bone mineral density or cholesterol level. But again, physicians have an obligation to direct patients’ attention to all of the outcomes that should be of interest to them.

OBJECTIONS TO INCLUDING ALL OUTCOMES

There are important objections to the argument I am presenting here.

First, including all outcomes is expensive. For studies involving retrospective analysis of existing data, looking at overall mortality would not incur additional costs, only an additional analysis. But for prospective trials to have statistical power to detect a difference in overall mortality, larger sample sizes or longer follow-up might be needed—either of which would add to the cost.

In chemoprevention trials, the rate of incident cancer has been called the gold standard end point.³³ To design a thrifty chemoprevention study, investigators can either target a broad population and aim for incident malignancy, or target a restricted, high-risk population and aim for overall mortality. The latter is preferable because although it can inform the decisions of only some people, the former cannot inform any people, as was seen with difficulties in interpreting the Prostate Cancer Prevention Trial and trials showing reduced breast cancer incidence from tamoxifen, raloxifene, and exemestane.

In large cancer screening trials, the cost of powering the trial for overall mortality would be greater, and though a carefully selected, high-risk population can be enrolled, historically this has not been popular. In cancer screening, it is a mistake to contrast the costs of trials powered for overall mortality with those of lesser studies examining disease-specific death. Instead, we must consider the larger societal costs incurred by cancer screening that does not truly improve quantity or quality of life.³⁴

The recent reversal of recommendations for prostate-specific antigen testing by the United States Preventive Services Task Force³⁵ suggests that erroneous recommendations, practiced for decades, can cost society hundreds of billions of dollars but fail to improve meaningful outcomes.

The history of medicine is replete with examples of widely recommended practices and interventions that not only failed to improve the outcomes they claimed to improve, but at times increased the rate of all-cause mortality or carried harms that far outweighed benefits.^36,37 The costs of conducting research to fully understand all outcomes are only a fraction of the costs of a practice that is widely disseminated.³⁸

The history of medicine is replete with practices that harmed more than helped

A second objection to my analysis is that there is more to life than survival, and outcomes besides overall mortality are important. This is a self-evident truth. That an intervention improves the rate of overall mortality is neither necessary nor sufficient for its recommendation. Practices may improve survival but worsen quality of life to such a degree that they should not be recommended. Conversely, practices that improve quality of life should be endorsed even if they fail to prolong life.

Thus, overall mortality and quality of life must be considered together, but the end points that are favored currently (disease-specific death, incident cancer, diabetes mellitus, myocardial infarction) do not do a good job of capturing either. Disease-specific death is not meaningful to any patient if deaths from other causes are increased so that overall mortality is unchanged. Furthermore, preventing a diagnosis of cancer or diabetes may offer some psychological comfort, but well-crafted quality-of-life instruments are best suited to capture just how great that benefit is and whether it justifies the cost of such interventions, particularly if the rate of survival is unchanged.

Preventing stroke or myocardial infarction is important, but we should be cautious of interpreting data when decreasing the rate of these morbid events does not lead to commensurate improvements in survival. Alternatively, if morbid events are truly avoided but survival analyses are underpowered, quality-of-life measurements should demonstrate the benefit. But the end points currently used capture neither survival nor quality of life in a meaningful way.

WHEN ADVISING HEALTHY PEOPLE

Looking at all outcomes is important when caring for patients who are sick, but even more so for patients who are well. We need to know an intervention has a net benefit before we recommend it to a healthy person. Overall mortality should be reported routinely in this population, particularly in settings where the cost to do so is trivial (ie, in observational studies). Designers of thrifty trials should try to include people at high risk and power the trial for definite end points, rather than being broadly inclusive and reaching disputed conclusions. Research and decision-making should look at all outcomes. Healthy people deserve no less.