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We believe medications can safely be prescribed to most patients who leave against medical advice (AMA), and that follow‐up should be offered to most if not all such patients. Why should we do this? Consider a wheezing asthma patient who leaves AMA. She or he is probably more likely to return to the emergency department (somewhere) or be readmitted (somewhere) and cost more money (to the system) than if given an inhaler and steroid taper.
Dr. Querques et al. suggest that doctors should potentially not prescribe and should not offer follow‐up to certain patients who want to leave AMA, particularly those who show disinterest in heeding the doctor's advice and have already demonstrated a lack of adherence. How should doctors make those judgments? Patients leave AMA for a variety of reasons: for example to avoid cost, because they feel better, or poor communication. Certainly, not all patients who want to leave AMA are categorically nonadherent. Conversely, up to 50% of all continuity patients are not fully adherent to the lifestyle changes and medications their physicians prescribe,[1] yet they would rarely if ever threaten AMA. Is withholding treatments that are likely to be effective and have minimal risk worth the potential benefit of increasing a patient's priority on their own healthcare? As emphasized by Berger (2008),[2] interventions with low risk and high potential for efficacy (assistance with establishing a follow‐up) should be pursued, and those with potential risks (starting new long‐term medications) should be avoided. At minimum, considering these options is an ethical requirement in the care of patients. We maintain that this reasoning should be explained and documented, which often is not being done in healthcare today.
How many AMAs are avoided by truly collaborative relationships with patients (nonevents), and how many are fueled by a more paternalistic relationship? For example, if a patient truly has a sick family member or child to take care of or has financial problems or no insurance, then it seems reasonable, perhaps even responsible, to leave the hospital even if maximal benefits of care have not been reached. In a collaborative relationship, providers may then tailor treatment to the patient's circumstances, even if this means the patient is not getting the best possible care.
- , . Medication adherence: WHO cares? Mayo Clin Proc. 2011;86(4):304–314.
- . Discharge against medical advice: ethical considerations and professional obligations. J Hosp Med. 2008;3(5):403–408.
We believe medications can safely be prescribed to most patients who leave against medical advice (AMA), and that follow‐up should be offered to most if not all such patients. Why should we do this? Consider a wheezing asthma patient who leaves AMA. She or he is probably more likely to return to the emergency department (somewhere) or be readmitted (somewhere) and cost more money (to the system) than if given an inhaler and steroid taper.
Dr. Querques et al. suggest that doctors should potentially not prescribe and should not offer follow‐up to certain patients who want to leave AMA, particularly those who show disinterest in heeding the doctor's advice and have already demonstrated a lack of adherence. How should doctors make those judgments? Patients leave AMA for a variety of reasons: for example to avoid cost, because they feel better, or poor communication. Certainly, not all patients who want to leave AMA are categorically nonadherent. Conversely, up to 50% of all continuity patients are not fully adherent to the lifestyle changes and medications their physicians prescribe,[1] yet they would rarely if ever threaten AMA. Is withholding treatments that are likely to be effective and have minimal risk worth the potential benefit of increasing a patient's priority on their own healthcare? As emphasized by Berger (2008),[2] interventions with low risk and high potential for efficacy (assistance with establishing a follow‐up) should be pursued, and those with potential risks (starting new long‐term medications) should be avoided. At minimum, considering these options is an ethical requirement in the care of patients. We maintain that this reasoning should be explained and documented, which often is not being done in healthcare today.
How many AMAs are avoided by truly collaborative relationships with patients (nonevents), and how many are fueled by a more paternalistic relationship? For example, if a patient truly has a sick family member or child to take care of or has financial problems or no insurance, then it seems reasonable, perhaps even responsible, to leave the hospital even if maximal benefits of care have not been reached. In a collaborative relationship, providers may then tailor treatment to the patient's circumstances, even if this means the patient is not getting the best possible care.
We believe medications can safely be prescribed to most patients who leave against medical advice (AMA), and that follow‐up should be offered to most if not all such patients. Why should we do this? Consider a wheezing asthma patient who leaves AMA. She or he is probably more likely to return to the emergency department (somewhere) or be readmitted (somewhere) and cost more money (to the system) than if given an inhaler and steroid taper.
Dr. Querques et al. suggest that doctors should potentially not prescribe and should not offer follow‐up to certain patients who want to leave AMA, particularly those who show disinterest in heeding the doctor's advice and have already demonstrated a lack of adherence. How should doctors make those judgments? Patients leave AMA for a variety of reasons: for example to avoid cost, because they feel better, or poor communication. Certainly, not all patients who want to leave AMA are categorically nonadherent. Conversely, up to 50% of all continuity patients are not fully adherent to the lifestyle changes and medications their physicians prescribe,[1] yet they would rarely if ever threaten AMA. Is withholding treatments that are likely to be effective and have minimal risk worth the potential benefit of increasing a patient's priority on their own healthcare? As emphasized by Berger (2008),[2] interventions with low risk and high potential for efficacy (assistance with establishing a follow‐up) should be pursued, and those with potential risks (starting new long‐term medications) should be avoided. At minimum, considering these options is an ethical requirement in the care of patients. We maintain that this reasoning should be explained and documented, which often is not being done in healthcare today.
How many AMAs are avoided by truly collaborative relationships with patients (nonevents), and how many are fueled by a more paternalistic relationship? For example, if a patient truly has a sick family member or child to take care of or has financial problems or no insurance, then it seems reasonable, perhaps even responsible, to leave the hospital even if maximal benefits of care have not been reached. In a collaborative relationship, providers may then tailor treatment to the patient's circumstances, even if this means the patient is not getting the best possible care.
- , . Medication adherence: WHO cares? Mayo Clin Proc. 2011;86(4):304–314.
- . Discharge against medical advice: ethical considerations and professional obligations. J Hosp Med. 2008;3(5):403–408.
- , . Medication adherence: WHO cares? Mayo Clin Proc. 2011;86(4):304–314.
- . Discharge against medical advice: ethical considerations and professional obligations. J Hosp Med. 2008;3(5):403–408.
Why social media are here to stay
A new year holds so much potential. It’s often when we’re at our most ambitious and optimistic. A time when we’re more likely to try something new – learn a language, take up CrossFit, or, even, dive into the social media ocean.
In this column over the last year, I have written about many different social media platforms including Facebook, YouTube, and Pinterest. Many physicians have e-mailed me asking, "Do I really need to be doing social media? Is it more than just a fad?" My answer was and still is, Yes!
The medical landscape is continually evolving, and social media continue to disrupt the traditional roles of doctor and patient. We now have "e-patients," "digital doctors," and doctor-rating sites; hospitals have Facebook pages, and surgeons are tweeting live surgery. Never has the field of medicine been so transparent.
Although I don’t have a crystal ball, I can assure you that social media are here to stay for a long time. So, if you’ve only dipped your toe in the social media waters so far, keep reading; you might find some inspiration to take the plunge in 2014:
• 90% of adults aged 18-24 said they would trust medical information shared by others in their social media networks. Social media communications are simply word of mouth enhanced by technology. Instead of telling their immediate family about you at the dinner table, your patients now have the ability to tell hundreds or thousands of people about you on social media. Create compelling content, make it shareable, and you’ll help build positive word of mouth.
• Social media users are more likely to trust health-related content written by physicians than by any other group. There is a tremendous amount of health care information online, much of it inaccurate. That means content produced by you (for example, through Facebook updates, YouTube videos, and blog posts) is likely to be shared more frequently and to help build your brand as a trusted physician.
• 47% of patients share their medical information online with doctors, and 43% do so with hospitals.
• 77% of patients used search engines prior to booking their medical appointment. If you’re not online, patients won’t find you.
• 41% of patients said social media would affect their choice of a specific doctor, hospital, or medical facility. Online word of mouth has an impact on you and your practice.
• 58% of health care marketers use blogs vs. 74% of all marketers. Maintaining a blog helps you build brand loyalty and gives you a competitive edge against physicians who aren’t online.
• YouTube traffic to hospital websites has increased 119% year to year. Because they’re visual, videos tend to be more memorable for social media users. Whether videos are used to share poignant patient stories, educate patients about specific diseases and treatments, or show how a clinical procedure is performed, they allow you to connect more intimately with patients and prospective patients, and put a human face on your practice.
• Parents are more likely to seek medical information online. Data show that 22% of parents use Facebook vs. 14% of nonparents, and 20% of parents use YouTube vs. 12% of nonparents. Parents want online information they can trust; that means information created by you.
• 51% of patients said they would feel more valued if their health care provider communicated with them digitally. This means exploring other modes of communication such as e-mail, newsletters, blog posts, and Facebook updates.
• 60% of physicians surveyed said social media improve the quality of care delivered to their patients. From physician online communities to Google hangouts, physicians are learning from one another, and often from patients, making them better clinicians.
Sources include DC Interactive Group, Demi and Cooper Advertising, Media Bistro, PWC Health Research Institute, and TeleVox.
Dr. Benabio is a practicing dermatologist and physician director of health care transformation at Kaiser Permanente in San Diego. Connect with him on Twitter @Dermdoc or drop him a line at [email protected].
A new year holds so much potential. It’s often when we’re at our most ambitious and optimistic. A time when we’re more likely to try something new – learn a language, take up CrossFit, or, even, dive into the social media ocean.
In this column over the last year, I have written about many different social media platforms including Facebook, YouTube, and Pinterest. Many physicians have e-mailed me asking, "Do I really need to be doing social media? Is it more than just a fad?" My answer was and still is, Yes!
The medical landscape is continually evolving, and social media continue to disrupt the traditional roles of doctor and patient. We now have "e-patients," "digital doctors," and doctor-rating sites; hospitals have Facebook pages, and surgeons are tweeting live surgery. Never has the field of medicine been so transparent.
Although I don’t have a crystal ball, I can assure you that social media are here to stay for a long time. So, if you’ve only dipped your toe in the social media waters so far, keep reading; you might find some inspiration to take the plunge in 2014:
• 90% of adults aged 18-24 said they would trust medical information shared by others in their social media networks. Social media communications are simply word of mouth enhanced by technology. Instead of telling their immediate family about you at the dinner table, your patients now have the ability to tell hundreds or thousands of people about you on social media. Create compelling content, make it shareable, and you’ll help build positive word of mouth.
• Social media users are more likely to trust health-related content written by physicians than by any other group. There is a tremendous amount of health care information online, much of it inaccurate. That means content produced by you (for example, through Facebook updates, YouTube videos, and blog posts) is likely to be shared more frequently and to help build your brand as a trusted physician.
• 47% of patients share their medical information online with doctors, and 43% do so with hospitals.
• 77% of patients used search engines prior to booking their medical appointment. If you’re not online, patients won’t find you.
• 41% of patients said social media would affect their choice of a specific doctor, hospital, or medical facility. Online word of mouth has an impact on you and your practice.
• 58% of health care marketers use blogs vs. 74% of all marketers. Maintaining a blog helps you build brand loyalty and gives you a competitive edge against physicians who aren’t online.
• YouTube traffic to hospital websites has increased 119% year to year. Because they’re visual, videos tend to be more memorable for social media users. Whether videos are used to share poignant patient stories, educate patients about specific diseases and treatments, or show how a clinical procedure is performed, they allow you to connect more intimately with patients and prospective patients, and put a human face on your practice.
• Parents are more likely to seek medical information online. Data show that 22% of parents use Facebook vs. 14% of nonparents, and 20% of parents use YouTube vs. 12% of nonparents. Parents want online information they can trust; that means information created by you.
• 51% of patients said they would feel more valued if their health care provider communicated with them digitally. This means exploring other modes of communication such as e-mail, newsletters, blog posts, and Facebook updates.
• 60% of physicians surveyed said social media improve the quality of care delivered to their patients. From physician online communities to Google hangouts, physicians are learning from one another, and often from patients, making them better clinicians.
Sources include DC Interactive Group, Demi and Cooper Advertising, Media Bistro, PWC Health Research Institute, and TeleVox.
Dr. Benabio is a practicing dermatologist and physician director of health care transformation at Kaiser Permanente in San Diego. Connect with him on Twitter @Dermdoc or drop him a line at [email protected].
A new year holds so much potential. It’s often when we’re at our most ambitious and optimistic. A time when we’re more likely to try something new – learn a language, take up CrossFit, or, even, dive into the social media ocean.
In this column over the last year, I have written about many different social media platforms including Facebook, YouTube, and Pinterest. Many physicians have e-mailed me asking, "Do I really need to be doing social media? Is it more than just a fad?" My answer was and still is, Yes!
The medical landscape is continually evolving, and social media continue to disrupt the traditional roles of doctor and patient. We now have "e-patients," "digital doctors," and doctor-rating sites; hospitals have Facebook pages, and surgeons are tweeting live surgery. Never has the field of medicine been so transparent.
Although I don’t have a crystal ball, I can assure you that social media are here to stay for a long time. So, if you’ve only dipped your toe in the social media waters so far, keep reading; you might find some inspiration to take the plunge in 2014:
• 90% of adults aged 18-24 said they would trust medical information shared by others in their social media networks. Social media communications are simply word of mouth enhanced by technology. Instead of telling their immediate family about you at the dinner table, your patients now have the ability to tell hundreds or thousands of people about you on social media. Create compelling content, make it shareable, and you’ll help build positive word of mouth.
• Social media users are more likely to trust health-related content written by physicians than by any other group. There is a tremendous amount of health care information online, much of it inaccurate. That means content produced by you (for example, through Facebook updates, YouTube videos, and blog posts) is likely to be shared more frequently and to help build your brand as a trusted physician.
• 47% of patients share their medical information online with doctors, and 43% do so with hospitals.
• 77% of patients used search engines prior to booking their medical appointment. If you’re not online, patients won’t find you.
• 41% of patients said social media would affect their choice of a specific doctor, hospital, or medical facility. Online word of mouth has an impact on you and your practice.
• 58% of health care marketers use blogs vs. 74% of all marketers. Maintaining a blog helps you build brand loyalty and gives you a competitive edge against physicians who aren’t online.
• YouTube traffic to hospital websites has increased 119% year to year. Because they’re visual, videos tend to be more memorable for social media users. Whether videos are used to share poignant patient stories, educate patients about specific diseases and treatments, or show how a clinical procedure is performed, they allow you to connect more intimately with patients and prospective patients, and put a human face on your practice.
• Parents are more likely to seek medical information online. Data show that 22% of parents use Facebook vs. 14% of nonparents, and 20% of parents use YouTube vs. 12% of nonparents. Parents want online information they can trust; that means information created by you.
• 51% of patients said they would feel more valued if their health care provider communicated with them digitally. This means exploring other modes of communication such as e-mail, newsletters, blog posts, and Facebook updates.
• 60% of physicians surveyed said social media improve the quality of care delivered to their patients. From physician online communities to Google hangouts, physicians are learning from one another, and often from patients, making them better clinicians.
Sources include DC Interactive Group, Demi and Cooper Advertising, Media Bistro, PWC Health Research Institute, and TeleVox.
Dr. Benabio is a practicing dermatologist and physician director of health care transformation at Kaiser Permanente in San Diego. Connect with him on Twitter @Dermdoc or drop him a line at [email protected].
Promises, promises
For many, the making and breaking of New Year’s resolutions have become a humorless cliché. Still, the beginning of a new year is as good a time as any for reflection and inspiration; and if you restrict your fix-it list to a few realistic promises that can actually be kept, resolution time does not have to remain an exercise in futility.
I can’t presume to know what needs improving in your practice, but I do know the issues I get the most questions about. Perhaps the following Top Ten list will inspire you to create a realistic list of your own.
1. Do a HIPAA risk assessment. The new HIPAA rules are now in effect, as I discussed a few months ago. Is your office up to speed? Review every procedure that involves confidential information; make sure there are no violations. Penalties for carelessness are much stiffer now.
2. Encrypt your mobile devices. This is a subset of item 1. The biggest HIPAA vulnerability in many practices is laptops and tablets that carry confidential patient information; losing one could be a disaster. Encryption software is cheap and readily available, and a lost or stolen mobile device will probably not be treated as a HIPAA breach if it is properly encrypted.
3. Reduce your accounts receivable by keeping a credit card number on file for each patient, and charging patient-owed balances as they come in. A series of my past columns in the archives at edermatologynews.com explains exactly how to do it. Every hotel in the world does this, and you should too.
4. Review your coding habits. For example, are you billing for 99213 each and every time your evaluation and treatment meet the criteria for that code? If not, you’re leaving money on the table; and that will become a more and more significant issue if reimbursements tighten up in the next few years – as they almost surely will.
5. Clear your "horizontal file cabinet." That’s the mess on your desk, all the paperwork you never seem to get to (probably because you’re tweeting or answering e-mail). Set aside an hour or two and get it all done. You’ll find some interesting stuff in there. Then, for every piece of paper that arrives on your desk from now on, follow the DDD Rule: Do it, Delegate it, or Destroy it. Don’t start a new mess.
6. Keep a closer eye on your office finances. Most physicians delegate the bookkeeping, and that’s fine. But ignoring the financial side creates an atmosphere that facilitates embezzlement. Set aside a few hours each month to review the books personally. And make sure your employees know you’re doing it.
7. Make sure your long-range financial planning is on track. This is another task physicians tend to "set and forget," but the Great Recession was an eye-opener for many of us. Once a year, sit down with your accountant and planner and make sure your investments are well diversified and all other aspects of your finances – budgets, credit ratings, insurance coverage, tax situations, college savings, estate plans, and retirement accounts – are in the best shape possible. Now would be a good time.
8. Back up your data. Now is also an excellent time to verify that the information on your office and personal computers is being backed up – locally and online – on a regular schedule. Don’t wait until something crashes.
9. Take more vacations. Remember Eastern’s First Law: Your last words will not be, "I wish I had spent more time in the office." This is the year to start spending more time enjoying your life, your friends and family, and the world. As John Lennon said, "Life is what happens to you while you’re busy making other plans."
10. Look at yourself. A private practice lives or dies on the personalities of its physicians, and your staff copies your personality and style. Take a hard, honest look at yourself. Identify your negative personality traits and work to eliminate them. If you have any difficulty finding the things that need changing ... ask your spouse. He or she will be happy to outline them for you in great detail.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is a clinical associate professor of dermatology at Seton Hall University School of Graduate Medical Education in South Orange, N.J. Dr. Eastern is a two-time past president of the Dermatological Society of New Jersey, and currently serves on its executive board. He holds teaching positions at several hospitals and has delivered more than 500 academic speaking presentations. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.
For many, the making and breaking of New Year’s resolutions have become a humorless cliché. Still, the beginning of a new year is as good a time as any for reflection and inspiration; and if you restrict your fix-it list to a few realistic promises that can actually be kept, resolution time does not have to remain an exercise in futility.
I can’t presume to know what needs improving in your practice, but I do know the issues I get the most questions about. Perhaps the following Top Ten list will inspire you to create a realistic list of your own.
1. Do a HIPAA risk assessment. The new HIPAA rules are now in effect, as I discussed a few months ago. Is your office up to speed? Review every procedure that involves confidential information; make sure there are no violations. Penalties for carelessness are much stiffer now.
2. Encrypt your mobile devices. This is a subset of item 1. The biggest HIPAA vulnerability in many practices is laptops and tablets that carry confidential patient information; losing one could be a disaster. Encryption software is cheap and readily available, and a lost or stolen mobile device will probably not be treated as a HIPAA breach if it is properly encrypted.
3. Reduce your accounts receivable by keeping a credit card number on file for each patient, and charging patient-owed balances as they come in. A series of my past columns in the archives at edermatologynews.com explains exactly how to do it. Every hotel in the world does this, and you should too.
4. Review your coding habits. For example, are you billing for 99213 each and every time your evaluation and treatment meet the criteria for that code? If not, you’re leaving money on the table; and that will become a more and more significant issue if reimbursements tighten up in the next few years – as they almost surely will.
5. Clear your "horizontal file cabinet." That’s the mess on your desk, all the paperwork you never seem to get to (probably because you’re tweeting or answering e-mail). Set aside an hour or two and get it all done. You’ll find some interesting stuff in there. Then, for every piece of paper that arrives on your desk from now on, follow the DDD Rule: Do it, Delegate it, or Destroy it. Don’t start a new mess.
6. Keep a closer eye on your office finances. Most physicians delegate the bookkeeping, and that’s fine. But ignoring the financial side creates an atmosphere that facilitates embezzlement. Set aside a few hours each month to review the books personally. And make sure your employees know you’re doing it.
7. Make sure your long-range financial planning is on track. This is another task physicians tend to "set and forget," but the Great Recession was an eye-opener for many of us. Once a year, sit down with your accountant and planner and make sure your investments are well diversified and all other aspects of your finances – budgets, credit ratings, insurance coverage, tax situations, college savings, estate plans, and retirement accounts – are in the best shape possible. Now would be a good time.
8. Back up your data. Now is also an excellent time to verify that the information on your office and personal computers is being backed up – locally and online – on a regular schedule. Don’t wait until something crashes.
9. Take more vacations. Remember Eastern’s First Law: Your last words will not be, "I wish I had spent more time in the office." This is the year to start spending more time enjoying your life, your friends and family, and the world. As John Lennon said, "Life is what happens to you while you’re busy making other plans."
10. Look at yourself. A private practice lives or dies on the personalities of its physicians, and your staff copies your personality and style. Take a hard, honest look at yourself. Identify your negative personality traits and work to eliminate them. If you have any difficulty finding the things that need changing ... ask your spouse. He or she will be happy to outline them for you in great detail.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is a clinical associate professor of dermatology at Seton Hall University School of Graduate Medical Education in South Orange, N.J. Dr. Eastern is a two-time past president of the Dermatological Society of New Jersey, and currently serves on its executive board. He holds teaching positions at several hospitals and has delivered more than 500 academic speaking presentations. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.
For many, the making and breaking of New Year’s resolutions have become a humorless cliché. Still, the beginning of a new year is as good a time as any for reflection and inspiration; and if you restrict your fix-it list to a few realistic promises that can actually be kept, resolution time does not have to remain an exercise in futility.
I can’t presume to know what needs improving in your practice, but I do know the issues I get the most questions about. Perhaps the following Top Ten list will inspire you to create a realistic list of your own.
1. Do a HIPAA risk assessment. The new HIPAA rules are now in effect, as I discussed a few months ago. Is your office up to speed? Review every procedure that involves confidential information; make sure there are no violations. Penalties for carelessness are much stiffer now.
2. Encrypt your mobile devices. This is a subset of item 1. The biggest HIPAA vulnerability in many practices is laptops and tablets that carry confidential patient information; losing one could be a disaster. Encryption software is cheap and readily available, and a lost or stolen mobile device will probably not be treated as a HIPAA breach if it is properly encrypted.
3. Reduce your accounts receivable by keeping a credit card number on file for each patient, and charging patient-owed balances as they come in. A series of my past columns in the archives at edermatologynews.com explains exactly how to do it. Every hotel in the world does this, and you should too.
4. Review your coding habits. For example, are you billing for 99213 each and every time your evaluation and treatment meet the criteria for that code? If not, you’re leaving money on the table; and that will become a more and more significant issue if reimbursements tighten up in the next few years – as they almost surely will.
5. Clear your "horizontal file cabinet." That’s the mess on your desk, all the paperwork you never seem to get to (probably because you’re tweeting or answering e-mail). Set aside an hour or two and get it all done. You’ll find some interesting stuff in there. Then, for every piece of paper that arrives on your desk from now on, follow the DDD Rule: Do it, Delegate it, or Destroy it. Don’t start a new mess.
6. Keep a closer eye on your office finances. Most physicians delegate the bookkeeping, and that’s fine. But ignoring the financial side creates an atmosphere that facilitates embezzlement. Set aside a few hours each month to review the books personally. And make sure your employees know you’re doing it.
7. Make sure your long-range financial planning is on track. This is another task physicians tend to "set and forget," but the Great Recession was an eye-opener for many of us. Once a year, sit down with your accountant and planner and make sure your investments are well diversified and all other aspects of your finances – budgets, credit ratings, insurance coverage, tax situations, college savings, estate plans, and retirement accounts – are in the best shape possible. Now would be a good time.
8. Back up your data. Now is also an excellent time to verify that the information on your office and personal computers is being backed up – locally and online – on a regular schedule. Don’t wait until something crashes.
9. Take more vacations. Remember Eastern’s First Law: Your last words will not be, "I wish I had spent more time in the office." This is the year to start spending more time enjoying your life, your friends and family, and the world. As John Lennon said, "Life is what happens to you while you’re busy making other plans."
10. Look at yourself. A private practice lives or dies on the personalities of its physicians, and your staff copies your personality and style. Take a hard, honest look at yourself. Identify your negative personality traits and work to eliminate them. If you have any difficulty finding the things that need changing ... ask your spouse. He or she will be happy to outline them for you in great detail.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is a clinical associate professor of dermatology at Seton Hall University School of Graduate Medical Education in South Orange, N.J. Dr. Eastern is a two-time past president of the Dermatological Society of New Jersey, and currently serves on its executive board. He holds teaching positions at several hospitals and has delivered more than 500 academic speaking presentations. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.
Vitamin D deficiency in ethnic populations
Many clinicians are unaware that ethnic populations in North America do not achieve optimal serum 25-hydroxyvitamin D (abbreviated 25[OH]D) because of the increased pigmentation in their skin, which reduces vitamin D production. Vitamin D insufficiency is more prevalent among individuals with darker skin, compared with those with lighter skin at any time of year, even during the winter months. Contributing to the deficiency, the dietary intake of vitamin D intake among African Americans in particular is often below the recommended intakes in every age group after puberty. However, data have shown vitamin D protects against Sjögren’s syndrome, psoriasis, type 1 and type 2 diabetes, multiple sclerosis, and rheumatoid arthritis.
Vitamin D also may protect against cardiovascular disease through its anti-inflammatory effects and may reduce the risk for colorectal cancer, breast cancer, and prostate cancer by promoting cell differentiation and down-regulating hyperproliferative cell growth. Most of these conditions have been shown to be as prevalent, if not more prevalent, among blacks than whites.
While vitamin D can be obtained from sun exposure, this is not always a viable option. UV exposure is linked to skin cancer, which leads clinicians to encourage sun avoidance, but they may disregard the need for vitamin D. In addition, darker pigmentation of the skin reduces vitamin D synthesis in the skin.
How can you help your skin of color patients get enough vitamin D, especially in the winter? Nutritional sources of vitamin D include salmon, sardines, and cows’ milk; however, many individuals do not achieve optimal vitamin D status from food intake alone.
Since UV exposure and diet are not sufficient sources of vitamin D, supplementation has become crucial to our patients, particularly those with darker skin. Dietary reference intakes for vitamin D have been under considerable scrutiny, and many experts now believe that intakes of 25 mcg/d (1,000 IU) or more may be needed for most people to achieve optimal blood levels of 25(OH)D. The two forms of vitamin D used in dietary supplements are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Cholecalciferol, the D3 form of the vitamin, is the form of choice when supplementing with vitamin D. Types of D3 supplements include gel caps, liquid, powders, and tablets. Vitamin D is often measured in International Units (IU) or mcg. One mcg of cholecalciferol is equal to 40 IU of vitamin D.
The debate continues over the most effective forms of vitamin D acquisition; however, many health professionals agree that vitamin D supplementation, particularly in winter months, should be an integral part of our armamentarium of therapeutics for ethnic patients, and especially those who suffer from psoriasis and other autoimmune and inflammatory skin conditions.
Dr. Talakoub is in private practice in McLean, Va.
Do you have questions about treating patients with dark skin? If so, send them to [email protected].
Many clinicians are unaware that ethnic populations in North America do not achieve optimal serum 25-hydroxyvitamin D (abbreviated 25[OH]D) because of the increased pigmentation in their skin, which reduces vitamin D production. Vitamin D insufficiency is more prevalent among individuals with darker skin, compared with those with lighter skin at any time of year, even during the winter months. Contributing to the deficiency, the dietary intake of vitamin D intake among African Americans in particular is often below the recommended intakes in every age group after puberty. However, data have shown vitamin D protects against Sjögren’s syndrome, psoriasis, type 1 and type 2 diabetes, multiple sclerosis, and rheumatoid arthritis.
Vitamin D also may protect against cardiovascular disease through its anti-inflammatory effects and may reduce the risk for colorectal cancer, breast cancer, and prostate cancer by promoting cell differentiation and down-regulating hyperproliferative cell growth. Most of these conditions have been shown to be as prevalent, if not more prevalent, among blacks than whites.
While vitamin D can be obtained from sun exposure, this is not always a viable option. UV exposure is linked to skin cancer, which leads clinicians to encourage sun avoidance, but they may disregard the need for vitamin D. In addition, darker pigmentation of the skin reduces vitamin D synthesis in the skin.
How can you help your skin of color patients get enough vitamin D, especially in the winter? Nutritional sources of vitamin D include salmon, sardines, and cows’ milk; however, many individuals do not achieve optimal vitamin D status from food intake alone.
Since UV exposure and diet are not sufficient sources of vitamin D, supplementation has become crucial to our patients, particularly those with darker skin. Dietary reference intakes for vitamin D have been under considerable scrutiny, and many experts now believe that intakes of 25 mcg/d (1,000 IU) or more may be needed for most people to achieve optimal blood levels of 25(OH)D. The two forms of vitamin D used in dietary supplements are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Cholecalciferol, the D3 form of the vitamin, is the form of choice when supplementing with vitamin D. Types of D3 supplements include gel caps, liquid, powders, and tablets. Vitamin D is often measured in International Units (IU) or mcg. One mcg of cholecalciferol is equal to 40 IU of vitamin D.
The debate continues over the most effective forms of vitamin D acquisition; however, many health professionals agree that vitamin D supplementation, particularly in winter months, should be an integral part of our armamentarium of therapeutics for ethnic patients, and especially those who suffer from psoriasis and other autoimmune and inflammatory skin conditions.
Dr. Talakoub is in private practice in McLean, Va.
Do you have questions about treating patients with dark skin? If so, send them to [email protected].
Many clinicians are unaware that ethnic populations in North America do not achieve optimal serum 25-hydroxyvitamin D (abbreviated 25[OH]D) because of the increased pigmentation in their skin, which reduces vitamin D production. Vitamin D insufficiency is more prevalent among individuals with darker skin, compared with those with lighter skin at any time of year, even during the winter months. Contributing to the deficiency, the dietary intake of vitamin D intake among African Americans in particular is often below the recommended intakes in every age group after puberty. However, data have shown vitamin D protects against Sjögren’s syndrome, psoriasis, type 1 and type 2 diabetes, multiple sclerosis, and rheumatoid arthritis.
Vitamin D also may protect against cardiovascular disease through its anti-inflammatory effects and may reduce the risk for colorectal cancer, breast cancer, and prostate cancer by promoting cell differentiation and down-regulating hyperproliferative cell growth. Most of these conditions have been shown to be as prevalent, if not more prevalent, among blacks than whites.
While vitamin D can be obtained from sun exposure, this is not always a viable option. UV exposure is linked to skin cancer, which leads clinicians to encourage sun avoidance, but they may disregard the need for vitamin D. In addition, darker pigmentation of the skin reduces vitamin D synthesis in the skin.
How can you help your skin of color patients get enough vitamin D, especially in the winter? Nutritional sources of vitamin D include salmon, sardines, and cows’ milk; however, many individuals do not achieve optimal vitamin D status from food intake alone.
Since UV exposure and diet are not sufficient sources of vitamin D, supplementation has become crucial to our patients, particularly those with darker skin. Dietary reference intakes for vitamin D have been under considerable scrutiny, and many experts now believe that intakes of 25 mcg/d (1,000 IU) or more may be needed for most people to achieve optimal blood levels of 25(OH)D. The two forms of vitamin D used in dietary supplements are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Cholecalciferol, the D3 form of the vitamin, is the form of choice when supplementing with vitamin D. Types of D3 supplements include gel caps, liquid, powders, and tablets. Vitamin D is often measured in International Units (IU) or mcg. One mcg of cholecalciferol is equal to 40 IU of vitamin D.
The debate continues over the most effective forms of vitamin D acquisition; however, many health professionals agree that vitamin D supplementation, particularly in winter months, should be an integral part of our armamentarium of therapeutics for ethnic patients, and especially those who suffer from psoriasis and other autoimmune and inflammatory skin conditions.
Dr. Talakoub is in private practice in McLean, Va.
Do you have questions about treating patients with dark skin? If so, send them to [email protected].
Cost and response criteria are the new challenges
Although the concept of using immunotherapy to target an immune response against tumors is not new, this treatment modality is only now beginning to realize its full potential. Here, we take a look at the role of immunotherapy in cancer and some of the most exciting areas of clinical development.
*Click on the link to the left for a PDF of the full article.
Although the concept of using immunotherapy to target an immune response against tumors is not new, this treatment modality is only now beginning to realize its full potential. Here, we take a look at the role of immunotherapy in cancer and some of the most exciting areas of clinical development.
*Click on the link to the left for a PDF of the full article.
Although the concept of using immunotherapy to target an immune response against tumors is not new, this treatment modality is only now beginning to realize its full potential. Here, we take a look at the role of immunotherapy in cancer and some of the most exciting areas of clinical development.
*Click on the link to the left for a PDF of the full article.
Key issues in the management of gastrointestinal immune-related adverse events associated with ipilimumab administration
Ipilimumab is an anticytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody that attenuates negative signaling from CTLA-4 and potentiates T-cell activation and proliferation. Two phase 3 randomized trials in advanced melanoma demonstrated a significant improvement in overall survival, the first of which led to regulatory approval in the United States and Europe for treatment of unresectable or metastatic melanoma. Ipilimumab administration is associated with immune-related adverse events (irAEs). Gastrointestinal (GI) irAEs are among the most common and although they are typically mild to moderate in severity, if they are left unrecognized or untreated, they can become life-threatening. These toxicities can be managed effectively in almost all patients by using established guidelines that stress vigilance and the use of corticosteroids and other immunosuppressive agents when necessary. The goal of this review is to educate physicians on the recognition and challenges associated with management of GI irAEs.
*Click on the link to the left for a PDF of the full article.
Ipilimumab is an anticytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody that attenuates negative signaling from CTLA-4 and potentiates T-cell activation and proliferation. Two phase 3 randomized trials in advanced melanoma demonstrated a significant improvement in overall survival, the first of which led to regulatory approval in the United States and Europe for treatment of unresectable or metastatic melanoma. Ipilimumab administration is associated with immune-related adverse events (irAEs). Gastrointestinal (GI) irAEs are among the most common and although they are typically mild to moderate in severity, if they are left unrecognized or untreated, they can become life-threatening. These toxicities can be managed effectively in almost all patients by using established guidelines that stress vigilance and the use of corticosteroids and other immunosuppressive agents when necessary. The goal of this review is to educate physicians on the recognition and challenges associated with management of GI irAEs.
*Click on the link to the left for a PDF of the full article.
Ipilimumab is an anticytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody that attenuates negative signaling from CTLA-4 and potentiates T-cell activation and proliferation. Two phase 3 randomized trials in advanced melanoma demonstrated a significant improvement in overall survival, the first of which led to regulatory approval in the United States and Europe for treatment of unresectable or metastatic melanoma. Ipilimumab administration is associated with immune-related adverse events (irAEs). Gastrointestinal (GI) irAEs are among the most common and although they are typically mild to moderate in severity, if they are left unrecognized or untreated, they can become life-threatening. These toxicities can be managed effectively in almost all patients by using established guidelines that stress vigilance and the use of corticosteroids and other immunosuppressive agents when necessary. The goal of this review is to educate physicians on the recognition and challenges associated with management of GI irAEs.
*Click on the link to the left for a PDF of the full article.
Multimodality therapy for uterine serous carcinoma and the association with overall and relapse-free survival
Objective To identify prognostic factors for overall survival (OS) and relapse-free survival (RFS) for patients with uterine serous carcinoma.
Methods From January 1, 2000 to January 1, 2010, 44 patients with uterine serous carcinoma were analyzed to determine prognostic and predictive factors for OS and RFS using the Kaplan-Meier product-limit method and log-rank tests.
Results Median follow-up was 4.1 years, median OS was 4.2 years, 2-year OS was 83% and decreased to 48% at 5 years. Two-year RFS was 82% and decreased to 75% at 5 years. Age, stage, tumor size, tumor not arising from a polyp, parametrial involvement, lymphovascular invasion, and no adjuvant treatment were prognostic factors associated with shorter OS. Higher stage and parametrial involvement were prognostic factors associated with shorter RFS. Combined adjuvant chemotherapy and radiation therapy was significantly associated with longer OS rates.
Conclusions Adjuvant chemotherapy and radiation therapy as well as tumors arising from a polyp are associated with increased overall survival in patients with uterine serous carcinoma. Early-stage disease is associated with increased relapse-free and overall survival. Adjuvant chemotherapy with a platinum and paclitaxol-based regimen and radiation therapy should be attempted in patients with uterine serous carcinoma.
*To read the full article, click on the PDF icon at the top of this introduction.
Objective To identify prognostic factors for overall survival (OS) and relapse-free survival (RFS) for patients with uterine serous carcinoma.
Methods From January 1, 2000 to January 1, 2010, 44 patients with uterine serous carcinoma were analyzed to determine prognostic and predictive factors for OS and RFS using the Kaplan-Meier product-limit method and log-rank tests.
Results Median follow-up was 4.1 years, median OS was 4.2 years, 2-year OS was 83% and decreased to 48% at 5 years. Two-year RFS was 82% and decreased to 75% at 5 years. Age, stage, tumor size, tumor not arising from a polyp, parametrial involvement, lymphovascular invasion, and no adjuvant treatment were prognostic factors associated with shorter OS. Higher stage and parametrial involvement were prognostic factors associated with shorter RFS. Combined adjuvant chemotherapy and radiation therapy was significantly associated with longer OS rates.
Conclusions Adjuvant chemotherapy and radiation therapy as well as tumors arising from a polyp are associated with increased overall survival in patients with uterine serous carcinoma. Early-stage disease is associated with increased relapse-free and overall survival. Adjuvant chemotherapy with a platinum and paclitaxol-based regimen and radiation therapy should be attempted in patients with uterine serous carcinoma.
*To read the full article, click on the PDF icon at the top of this introduction.
Objective To identify prognostic factors for overall survival (OS) and relapse-free survival (RFS) for patients with uterine serous carcinoma.
Methods From January 1, 2000 to January 1, 2010, 44 patients with uterine serous carcinoma were analyzed to determine prognostic and predictive factors for OS and RFS using the Kaplan-Meier product-limit method and log-rank tests.
Results Median follow-up was 4.1 years, median OS was 4.2 years, 2-year OS was 83% and decreased to 48% at 5 years. Two-year RFS was 82% and decreased to 75% at 5 years. Age, stage, tumor size, tumor not arising from a polyp, parametrial involvement, lymphovascular invasion, and no adjuvant treatment were prognostic factors associated with shorter OS. Higher stage and parametrial involvement were prognostic factors associated with shorter RFS. Combined adjuvant chemotherapy and radiation therapy was significantly associated with longer OS rates.
Conclusions Adjuvant chemotherapy and radiation therapy as well as tumors arising from a polyp are associated with increased overall survival in patients with uterine serous carcinoma. Early-stage disease is associated with increased relapse-free and overall survival. Adjuvant chemotherapy with a platinum and paclitaxol-based regimen and radiation therapy should be attempted in patients with uterine serous carcinoma.
*To read the full article, click on the PDF icon at the top of this introduction.
Enzastaurin no better than placebo in DLBCL
Convention Center, site of the
2013 ASH Annual Meeting
NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.
All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.
The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.
Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.
Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.
“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.
“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.”
With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.
Patient population
The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.
The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.
The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively).
Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).
Survival outcomes
The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).
The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).
The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).
The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.
Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).
“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”
“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.”
Adverse events
Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.
Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).
Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.
Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers. 
Convention Center, site of the
2013 ASH Annual Meeting
NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.
All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.
The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.
Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.
Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.
“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.
“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.”
With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.
Patient population
The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.
The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.
The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively).
Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).
Survival outcomes
The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).
The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).
The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).
The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.
Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).
“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”
“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.”
Adverse events
Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.
Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).
Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.
Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.
Convention Center, site of the
2013 ASH Annual Meeting
NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.
All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.
The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.
Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.
Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.
“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.
“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.”
With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.
Patient population
The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.
The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.
The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively).
Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).
Survival outcomes
The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).
The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).
The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).
The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.
Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).
“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”
“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.”
Adverse events
Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.
Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).
Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.
Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.
Letters to the Editor
Mohamed‐Kalib et al. illustrate 2 important caveats to penicillin skin testing (PST): (1) there is an exceptionally rare potential for resensitization, a phenomenon in which a previously reactive patient is proven tolerant, then develops sensitivity and has a positive PST; (2) consider repeating PST prior to a parenteral ‐lactam prescription in patients who previously reported severe anaphylactic reactions.
Our negative predictive value of 100% does not abate the tentative concern for resensitization.[1] Similar to the likelihood of becoming allergic initially, 0% to 3.2% of PST‐negative patients can become allergic again, more commonly with parenteral therapy and among children.[2, 3, 4]
The author describes a seemingly resensitized patient who reacted in an outpatient setting. Theoretically, anyone could resensitize, regardless of their setting or whether a single dose or full course was given after the PST. Individuals with a proven tolerance by PST and repeated courses are at a very low risk of future immunoglobulin E‐mediated reactions, a risk similar to that of the general population.
Whether previously reactive or not, patients receiving medicinal therapies should always be monitored for allergic reactions. Although PST may not be prudent in the minority of patients who report recent or severe reactions, a repeat PST prior to prescribing parenteral ‐lactam may potentially avoid instances described by Mohamed‐Kalib et al.
- , , , et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8(6):342–345.
- , , . Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med. 2002;162(7):822–826.
- . Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes. J Allergy Clin Immunol. 1998;102(2):281–285.
- , . Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259–273.
Mohamed‐Kalib et al. illustrate 2 important caveats to penicillin skin testing (PST): (1) there is an exceptionally rare potential for resensitization, a phenomenon in which a previously reactive patient is proven tolerant, then develops sensitivity and has a positive PST; (2) consider repeating PST prior to a parenteral ‐lactam prescription in patients who previously reported severe anaphylactic reactions.
Our negative predictive value of 100% does not abate the tentative concern for resensitization.[1] Similar to the likelihood of becoming allergic initially, 0% to 3.2% of PST‐negative patients can become allergic again, more commonly with parenteral therapy and among children.[2, 3, 4]
The author describes a seemingly resensitized patient who reacted in an outpatient setting. Theoretically, anyone could resensitize, regardless of their setting or whether a single dose or full course was given after the PST. Individuals with a proven tolerance by PST and repeated courses are at a very low risk of future immunoglobulin E‐mediated reactions, a risk similar to that of the general population.
Whether previously reactive or not, patients receiving medicinal therapies should always be monitored for allergic reactions. Although PST may not be prudent in the minority of patients who report recent or severe reactions, a repeat PST prior to prescribing parenteral ‐lactam may potentially avoid instances described by Mohamed‐Kalib et al.
Mohamed‐Kalib et al. illustrate 2 important caveats to penicillin skin testing (PST): (1) there is an exceptionally rare potential for resensitization, a phenomenon in which a previously reactive patient is proven tolerant, then develops sensitivity and has a positive PST; (2) consider repeating PST prior to a parenteral ‐lactam prescription in patients who previously reported severe anaphylactic reactions.
Our negative predictive value of 100% does not abate the tentative concern for resensitization.[1] Similar to the likelihood of becoming allergic initially, 0% to 3.2% of PST‐negative patients can become allergic again, more commonly with parenteral therapy and among children.[2, 3, 4]
The author describes a seemingly resensitized patient who reacted in an outpatient setting. Theoretically, anyone could resensitize, regardless of their setting or whether a single dose or full course was given after the PST. Individuals with a proven tolerance by PST and repeated courses are at a very low risk of future immunoglobulin E‐mediated reactions, a risk similar to that of the general population.
Whether previously reactive or not, patients receiving medicinal therapies should always be monitored for allergic reactions. Although PST may not be prudent in the minority of patients who report recent or severe reactions, a repeat PST prior to prescribing parenteral ‐lactam may potentially avoid instances described by Mohamed‐Kalib et al.
- , , , et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8(6):342–345.
- , , . Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med. 2002;162(7):822–826.
- . Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes. J Allergy Clin Immunol. 1998;102(2):281–285.
- , . Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259–273.
- , , , et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8(6):342–345.
- , , . Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med. 2002;162(7):822–826.
- . Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes. J Allergy Clin Immunol. 1998;102(2):281–285.
- , . Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259–273.
Treatment and Outcomes of SPFD
Over the past decade, the use of chest computed tomography scans with pulmonary angiography (CTPA) for diagnosis of pulmonary embolism (PE) has soared due to the ease of acquisition, the desire for the additional information that CT scanning may provide, and heightened sensitivity to medical liability.[1, 2, 3, 4, 5, 6] In parallel with this shift, the incidence of PE has nearly doubled, despite no recorded increase in the pretest probability of the disease, increasing from 62 per 100,000 to 112 per 100,000 during the period of 1993 to 2006.6 One major explanation for this increase is that the improvement in CTPA resolution has enabled radiologists to identify more small peripheral (ie, segmental and subsegmental) filling defects. When confronted with the finding of a small peripheral filling defect on CTPA, clinicians often face a management quandary. Case series and retrospective series on outcomes of these patients do not support treatment, but they are limited by having small numbers of patients; the largest examined 93 patients and provided no insight into the treatment decision.[7] Uncertainty exists, furthermore, about the pathologic meaning of small peripheral filling defects.[8] Clinicians must weigh these arguments and the risk of anticoagulation against concerns about the consequences of untreated pulmonary thromboemboli. More information is needed, therefore, on the outcomes of patients with peripheral filling defects, and on variables impacting the treatment decision, in order to help clinicians manage these patients.[9]
In this study, we analyzed cases of patients with a single peripheral filling defect (SPFD). We choose to look at patients with a SPFD because they represent the starkest decision‐making treatment dilemma and are not infrequent. We assessed the 90‐day mortality and rate of postdischarge venous thromboembolism (VTE) of treated and untreated patients and identified characteristics of treated and untreated patients with a SPFD. We wished to determine the incidence of SPFD among patients evaluated with CTPA and to determine how often the defect is called a PE by the radiologist. We also aimed to determine what role secondary studies play in helping to clarify the diagnosis and management of SPFD and to identify other factors that may influence the decision to treat patients with this finding.
METHODS
Site
This retrospective cohort study was conducted at a community hospital in Norwalk, CT. The hospital is a 328‐bed, not‐for‐profit, acute‐care community teaching hospital that serves a population of 250,000 in lower Fairfield County, Connecticut, and is affiliated with the Yale School of Medicine.
Subjects
The reports of all CTPAs done over a 66‐month period from 2006 to 2010 were individually reviewed. Any study that had a filling defect reported in the body of the radiology report was selected for initial consideration. A second round of review was conducted, extracting only CTPAs with a SPFD for study inclusion. We then excluded from the primary analysis those studies in which the patient had a concurrently positive lower‐extremity ultrasound, the medical records could not be located, and the patient age was <18 years. The study was approved by the investigational review board of the hospital.
Radiographic Methods
The CTPAs were performed using the SOMATOM Definition scanner, a 128‐slice CT scanner with 0.5‐cm collimation (Siemens, Erlangen, Germany). The CT‐scanner technology did not change over the 66 months of the study period.
Data Collection
Clinical data were abstracted from the physical charts and from the computerized practitioner order‐entry system (PowerChart electronic medical record system; Cerner Corp, Kansas City, MO). Three abstractors were trained in the process of chart abstraction using training sets of 10 records. The Fleiss was used to assess concordance. The Fleiss was 0.6 at the initial training set, and after 3 training sets it improved to 0.9. In‐hospital all‐cause mortality was determined using the hospital death records, and out‐of‐hospital mortality data were obtained from the online statewide death records.[10] Postdischarge VTE was assessed by interrogating the hospital radiology database for repeat ventilation perfusion scan, conventional pulmonary angiography, lower‐limb compression ultrasound (CUS) or CTPA studies that were positive within 90 days of the index event. Treatment was defined as either anticoagulation, ascertained from medication list at discharge, or inferior vena cava (IVC) filter placement, documented at the index visit.
To better understand the variation in interpretation of SPFD, all CTPA studies that showed a SPFD were also over‐read by 2 radiologists who reached a consensus opinion regarding whether the finding was a PE. The radiologists who over‐read the studies were blinded to the final impression of the initial radiologist. Our study group comprised 3 radiologists; 1 read <20% of the initial studies and the other 2 had no input in the initial readings. One of the radiologists was an attending and the other 2 were fourth‐year radiology residents.
Baseline Variables and Outcome Measures
A peripheral filling defect was defined as a single filling defect located in either the segmental or subsegmental pulmonary artery. The primary variables of interest were patient demographics (age, sex, and race), insurance status, the presence of pulmonary input in the management of the patient, history of comorbid conditions (prior VTE, congestive heart failure, chronic lung disease, pulmonary hypertension, coronary artery disease, surgery within the last 6 months, active malignancy, and acute pulmonary edema or syncope at presentation) and risk class as assessed by the Pulmonary Embolism Severity Index (PESI) score.[11] The PESI scoring system is a risk‐stratification tool for patients with acute PE. It uses 11 prognostic variables to predict in‐hospital and all‐cause mortality: age, sex, heart rate 110 bpm, systolic blood pressure <90 mm Hg, congestive heart failure, presence of malignancy, chronic lung disease, respiratory rate <30/minute, temperature <36C, altered mental status, and oxygen saturation <90%. Additional variables of interest were the proportion of patients in the treated and untreated arms who had a pulmonary consultation at the index visit and the role, if any, of a second test for VTE at the index visit. The primary outcomes investigated were all‐cause 90‐day mortality and 90‐day incidence of postdischarge VTE from the index visit in the treated and untreated groups. Those patients whose studies had a SPFD that was concluded by the initial radiologist to be a PE on the final impression of the report were analyzed as a subgroup.
Statistical Analysis
Bivariate analysis was conducted to compare patient baseline characteristics between treated and untreated groups. The 2 test was used for comparing binary or categorical variables and the Student t test was used for comparing continuous variables. A logistic regression model utilizing the Markov chain Monte Carlo (MCMC) method was employed for assessing the differences in 90‐day mortality and 90‐day postdischarge VTE between the treated group and untreated group, adjusting for patient baseline characteristics. This model was also used for identifying factors associated with the decision to treat. We reported the odds ratio (OR) and its corresponding 95% confidence interval (CI) for each estimate identified from the model. All analyses were conducted using SAS version 9.3 64‐bit software (SAS Institute Inc, Cary, NC).
RESULTS
A total of 4906 CTPAs were screened during the 66 months reviewed, identifying 518 (10.6%) with any filling defect and 153 (3.1%) with a SPFD. Thirteen patients were excluded from the primary analysis because their records could not be located, and another 6 were excluded because they had a concurrently positive CUS. The primary analysis was performed, therefore, with 134 patients. The inpatient service ordered 78% of the CTPAs. The initial radiologist stated in the impression section of the report that a PE was present in 99 of 134 (73.9%) studies. On over‐read of the 134 studies, 100 of these were considered to be positive for a PE. There was modest agreement between the initial impression and the consensus impression at over‐read (=0.69).
Association of Treatment With Mortality and Recurrence
In the primary‐analysis group, 61 (45.5%) patients were treated: 50 patients had warfarin alone, 10 patients had an IVC filter alone, and 1 patient had both warfarin and an IVC filter. No patient was treated solely with low‐molecular‐weight heparin long‐term. Whenever low‐molecular‐weight heparin was used, it was as a bridge to warfarin. The characteristics of the patients in the treatment groups were similar (Table 1). Four of the treated patients had a CTPA with SPFD that was not called a PE in the initial reading. Ten patients died, 5 each in the treated and untreated groups, yielding an overall mortality rate at 90 days of 7.4% (Table 2). Analysis of the 134 patients showed no difference in adjusted 90‐day mortality between treated and untreated groups (OR: 1.0, 95% CI: 0.25‐3.98). The number of patients with postdischarge VTE within 90 days was 5 of 134 (3.7%) patients, 3 treated and 2 untreated, and too few to show a treatment effect. Among the 99 cases considered by the initial radiologist to be definite for a PE, 59 (59.6%) were treated and 40 (40.4%) untreated. In this subgroup, no mortality benefit was observed with treatment (OR: 1.42, 95% CI: 0.28‐8.05).
| Characteristic | Treated, n=61 | Untreated, n=73 | P Value |
|---|---|---|---|
| |||
| Age, y, mean (SD) | 67 (20) | 62 (21) | 0.056 |
| Sex, M | 29 (48) | 34 (47) | 0.831 |
| Race/ethnicity | 0.426 | ||
| White | 43 (70) | 57 (78) | |
| Black | 12 (20) | 8 (11) | |
| Hispanic | 6 (10) | 7 (10) | |
| Other | 0 | 1 (2) | |
| Primary insurance | 0.231 | ||
| Medicare | 30 (50) | 29 (40) | |
| Medicaid | 2 (3) | 8 (11) | |
| Commercial | 27 (44) | 30 (41) | |
| Self‐pay | 2 (3) | 6 (8) | |
| Pulmonary consultation | 29 (48) | 28 (38) | 0.482 |
| Comorbid illnesses | 0.119 | ||
| Cancera | 13 (21) | 17 (23) | |
| Surgery/traumab | 16 (26) | 2 (3) | |
| Chronic lung disease | 17 (28) | 15 (21) | |
| CHF | 12 (20) | 9 (12) | |
| Ischemic heart disease | 12 (20) | 7 (10) | |
| Pulmonary hypertension | 0 | 1 (1) | |
| Collagen vascular disease | 1 (2) | 2 (3) | |
| PESI classc | 0.840 | ||
| I | 15 (25) | 24 (33) | |
| II | 13 (21) | 16 (22) | |
| III | 12 (20) | 13 (18) | |
| IV | 9 (15) | 8 (11) | |
| V | 12 (20) | 12 (16) | |
| Treatment | Combined Outcome | 90‐Day All‐Cause Mortality | 90‐Day All‐Cause Recurrence | |||
|---|---|---|---|---|---|---|
| Death or Recurrent VTE, n (% All Patients) | Adjusted OR for Combined Outcome (95% CI)a | Mortality, n (% All Patients) | Adjusted OR (95% CI)a | Recurrence, n (% All Patients) | Adjusted OR (95% CI)a | |
| ||||||
| Any treatment, n=61 | 8 (6.0) | 1.50 (0.435.20) | 5 (3.7) | 1.00 (0.253.98) | 3 (2.2) | 1.10 (0.129.92) |
| Warfarin, n=51 | 5 (3.7) | 0.75 (0.202.85) | 2 (1.5) | 0.26 (0.041.51) | 3 (2.2) | 2.04 (0.2318.04) |
| IVC filter, n=10 | 3 (2.2) | 5.77 (1.2227.36) | 3 (2.2) | 10.60 (2.1053.56) | 0 | NA |
| None, n=73 | 7 (5.2) | Referent | 5 (3.7) | Referent | 2 (1.5%) | Referent |
Use of Secondary Diagnostic Tests
A CUS was performed on 42 of the 153 patients (27%) with studies noting a SPFD. Six CUSs were positive, with 5 of the patients receiving anticoagulation and the sixth an IVC filter. A second lung‐imaging study was done in 10 (7%) of the 134 patients in the primary‐analysis group: 1 conventional pulmonary angiogram that was normal and 9 ventilation‐perfusion scans, among which 4 were normal, 2 were intermediate probability for PE, 2 were low probability for PE, and 1 was very low probability for PE. The 2 patients whose scans were read as intermediate probability and 1 patient whose scan was read as low probability was treated, and none of the patients with normal scans received treatment. None of these 10 patients died or had a postdischarge VTE during the 90‐day follow‐up period.
Factors Associated With Treatment
In the risk‐adjusted model, patient characteristics associated with treatment were immobility, previous VTE, and acute mental‐status change (Table 3). When the radiologist concluded that the SPFD was a PE, there was a highly increased likelihood of being treated. These factors were selected based on the MCMC simulation and the final model had a goodness‐of‐fit P value of 0.69, indicating it was fitted well. Vital‐sign abnormalities, comorbid illnesses, history of cancer, ethnicity, insurance status, and the presence of pulmonary consultation were not associated with the decision to treat. The 3 patient factorsimmobility, previous VTE, and absence of mental‐status changecombined with the initial impression of the radiologist, were strongly predictive of the decision to treat (C statistic: 0.87). None of the subset of patients who had a negative CUS and normal or very low probability ventilation‐perfusion scan received treatment. Eighty of the 134 (60%) patients had an active malignancy, chronic lung disease, heart failure, or evidence of ischemic heart disease; all 10 patients who died were from this subset of patients.
| Factors | Adjusted OR | 95% CI | Probability of Being Statistically Associated With the Decision to Treat |
|---|---|---|---|
| |||
| Immobility | 3.9 | 1.4510.6 | 0.78 |
| Acute mental‐status change | 0.14 | 0.020.84 | 0.64 |
| Initial impression of radiologist | 24.68 | 5.4112.89 | 0.86 |
| Prior VTE | 3.72 | 1.1811.67 | 0.70 |
DISCUSSION
This very large retrospective study examines treatment and outcomes in patients with a SPFD. We found that SPFDs were common, showing up in approximately 3% of all the CTPAs performed. Among the studies that were deemed positive for PE, SPFD comprised nearly one‐third. Treatment of SPFD, whether concluded as PE or not, was not associated with a mortality benefit or difference in postdischarge VTE within 90 days. Our results add to the weight of smaller case‐control and retrospective series that also found no benefit from treating small PE.[7, 12, 13, 14, 15]
Given this data, why might physicians choose to treat? Physicians may feel compelled to anticoagulate due to extrapolation of data from the early studies showing a fatality rate of up to 30% in untreated PE.[2] Also, physicians may harbor the concern that, though small emboli may pose no immediate danger, they serve as a marker of hypercoagulability and as such are a harbinger of subsequent large clots. A reflexive treatment response to the radiologist's conclusion that the filling defect is a PE may also play a part. Balancing this concern is the recognition that the treatment for acute PE is not benign. The age‐adjusted incidence of major bleeding (eg, gastrointestinal or intracranial) with warfarin has increased by 71%, from 3.1 to 5.3 per 100,000, since the introduction of CTPA.[6] Also, as seen in this study, a substantial percentage of patients will incur the morbidity and cost of IVC‐filter placement.
When physicians face management uncertainty, they consider risk factors for the condition investigated, consult experts, employ additional studies, and weigh patient preference. In this study, history of immobility and VTE were, indeed, positively associated with treatment, but change in mental status was negatively so. Given that the PESI score is higher with change in mental status, this finding is superficially paradoxical but unsurprising. Mental‐status change could not likely stem from a SPFD and its presence heightens the risks of anticoagulation, hence dissuading treatment. Pulmonary consultations were documented in less than half of the cases and did not clearly sway the treatment decision. Determining whether more patients would have been treated if pulmonologists were not involved would require a prospective study.
The most important association with treatment was how the radiologist interpreted the SPFD. Even then, the influence of the radiologist's interpretation was far from complete: 40% of the cases in which PE was called went untreated, and 4 cases received treatment despite PE not being called. The value of the radiologist's interpretation is further undercut by the modest interobserver agreement found on over‐read, which is line with previous reports and reflective of lack of a gold standard for diagnosing isolated peripheral PE.[3, 12, 16]
Even if radiologists could agree upon what they are seeing, the question remains about the pathological importance. Unrecognized PE incidental to the cause of death are commonly found at autopsy. Autopsy studies reveal that up to 52% to 64% of patients have PE; and, if multiple blocks of lung tissue are studied, the prevalence increases up to 90%.[17, 18] In the series by Freiman et al., 59% of the identified thrombi were small enough not to be recognized on routine gross examination.[17] Furthermore, an unknown percentage of small clots, especially in the upper lobes, are in situ thrombi rather than emboli.[18] In the case of small dot‐like clots, Suh and colleagues have speculated that they represent normal embolic activity from the lower limbs, which are cleared routinely by the lung serving in its role as a filter.[19] Although our study only examined SPFD, the accumulation of small emboli could have pathologic consequences. In their review, Gali and Kim reported that 12% of patients with chronic thromboembolic pulmonary hypertension who underwent pulmonary endarterectomy had disease confined to the distal segmental and subsegmental arteries.[13]
Use of secondary studies could mitigate some of the diagnostic and management uncertainty, but they were obtained in only about a quarter of the cases. The use of a second lung‐imaging study following CTPA is not recommended in guidelines or diagnostic algorithms, but in our institution a significant minority of physicians were employing these tests to clarify the nature of the filling defects.[20] Tapson, speaking to the treatment dilemma that small PEs present, has suggested that prospective trials on this topic employ tests that investigate risk for poor outcome if untreated including cardiopulmonary reserve, D‐dimer, and presence of lower‐limb thrombus.[21] Indeed, a study is ongoing examining the outcome at 90 days of patients with single or multiple subsegmental embolism with negative CUS.[22]
Ten of the 134 patients (7.4%) with peripheral filling defects died within 90 days. It is difficult to establish whether these deaths were PE‐specific mortalities because there was a high degree of comorbid illness in this cohort. Five of the 134 (3.7%) had recurrent VTE, which is comparable to the outcomes in other studies.[23]
There are limitations to this study. This study is the first to limit analysis of the filling defects to single defects in the segmental or subsegmental pulmonary arteries. This subset of patients includes those with the least clot burden, therefore representing the starkest decision‐making treatment dilemma, and the incidence of these clots is not insignificant. As a retrospective study, we could not fully capture all of the considerations that may have factored into the clinicians' decision‐making regarding treatment, including patient preference. Because of inadequate documentation, especially in the emergency department notes, we were unable to calculate pretest probability. Also, we cannot exclude that subclinical VTEs were occurring that would later harm the patients. We did not analyze the role of D‐dimer testing because that test is validated to guide the decision to obtain lung‐imaging studies and not to inform the treatment decision. In our cohort, 89 of 134 (66%) of our patients were already hospitalized for other diagnoses prior to PE being queried. Moreover, many of these patients had active malignancy or were being treated for pneumonia, which would decrease the positive predictive value of the D‐dimer test. D‐dimer performs poorly when used for prognosis.[24] This is a single‐center study, therefore the comparability of our findings to other centers may be an issue, although our findings generally accord with those from other single‐center studies.[7, 12, 24, 25] We determined the recurrence rate from the hospital records and could have missed cases diagnosed elsewhere. However, our hospital is the only one in the city and serves the vast majority of patients in the area, and 88% of our cohort had a repeat visit to our hospital subsequently. In addition, the radiology service is the only one in the area that provides outpatient CUS, CTPA, and ventilation‐perfusion scan studies. Our study is the largest to date on this issue. However, our sample size is somewhat modest, and consequently the factors associated with treatment have large confidence intervals. We are therefore constrained in recommending empiric application of our findings. Nonetheless, our results in terms of no difference in mortality and recurrence between treated and untreated patients are in keeping with other studies on this topic. Also, our simulation analysis did reveal factors that were highly associated with the decision to treat. These findings as a whole strongly point to the need for a larger study on this issue, because, as we and other authors have argued, the consequences of treatment are not benign.[6]
In conclusion, this study shows that SPFDs are common and that there was no difference in 90‐day mortality between treated and untreated patients, regardless of whether the defects were interpreted as PE or not. Physicians appear to rely heavily on the radiologist's interpretation for their treatment decision, but they will also treat when the interpretation is not PE and not infrequently abstain when it is. Treatment remains common despite the modest agreement among radiologists whether the peripheral filling defect even represents PE. When secondary imaging studies are obtained and negative, physicians forgo treatment. Larger studies are needed to help clarify our findings and should include decision‐making algorithms that include secondary imaging studies, because these studies may provide enough reassurance when negative to sway physicians against treatment.
Disclosure
Nothing to report.
- , , . The mortality of untreated pulmonary embolism in emergency department patients. Ann Emerg Med. 2005;45:302–310.
- . Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest. 2002;122:1400–1456.
- , , , et al. Subsegmental pulmonary emboli: improved detection with thin‐collimation multi‐detector row spiral CT. Radiology. 2002;222:483–490.
- , , . Trends in the use of diagnostic imaging in patients hospitalized with acute pulmonary embolism. Am J Cardiol. 2004;93:1316–1317.
- , , , , . The effect of helical computed tomography on diagnostic and treatment strategies in patients with suspected pulmonary embolism. Am J Med. 2004;116:84–90.
- , , . Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171:831–837.
- , , , . Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res. 2010;126:e266–e270.
- , , , et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29:2276–2315.
- , , , , . Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost. 2012;18:20–26.
- Intelius. Available at: http://www.intelius.com. Accessed September 30, 2010.
- , , . The validation and reproducibility of the pulmonary embolism severity index. J Thromb Haemost. 2010;8:1509–1514.
- , , . Clinicians' response to radiologists' reports of isolated subsegmental pulmonary embolism or inconclusive interpretation of pulmonary embolism using MDCT. AJR Am J Roentgenol. 2005;184:623–628.
- , . Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3:571–576.
- . Small pulmonary emboli: what do we know? Radiology. 2005;234:654–658.
- , , . Reassessment of pulmonary angiography for the diagnosis of pulmonary embolism: relation of interpreter agreement to the order of the involved pulmonary arterial branch. Radiology. 1999;210:689–691.
- , . Helical CT for the evaluation of acute pulmonary embolism. AJR Am J Roentgenol. 2005;185:135–149.
- , , . Frequency of pulmonary thromboembolism in man. N Engl J Med. 1965;272:1278–1280.
- . Pathology of pulmonary thromboembolism. Chest. 1995;107(1 suppl):10S–17S.
- , , . Dots are not clots: the over‐diagnosis and over‐treatment of PE. Emerg Radiol. 2010;17:347–352.
- , , . Current approach to the diagnosis of acute nonmassive pulmonary embolism. Chest. 2011;140:509–518.
- . Acute pulmonary embolism: comment on “time trends in pulmonary embolism in the United States.” Arch Intern Med. 2011;171:837–839.
- National Institutes of Health, ClinicalTrials.gov; Carrier M. A study to evaluate the safety of withholding anticoagulation in patients with subsegmental PE who have a negative serial bilateral lower extremity ultrasound (SSPE). ClinicalTrials.gov identifier: NCT01455818.
- , , . Untreated patients with pulmonary embolism: outcome, clinical, and laboratory assessment. Chest. 1995;107:931–935.
- , , , , , . Prognostic value of D‐dimer in stable patients with pulmonary embolism. Clin Appl Thromb Hemost. 2011;17:E183–E185.
- , , , , . Diagnosis and management of subsegmental pulmonary embolism. J Thromb Hemost. 2006;4:724–731.
Over the past decade, the use of chest computed tomography scans with pulmonary angiography (CTPA) for diagnosis of pulmonary embolism (PE) has soared due to the ease of acquisition, the desire for the additional information that CT scanning may provide, and heightened sensitivity to medical liability.[1, 2, 3, 4, 5, 6] In parallel with this shift, the incidence of PE has nearly doubled, despite no recorded increase in the pretest probability of the disease, increasing from 62 per 100,000 to 112 per 100,000 during the period of 1993 to 2006.6 One major explanation for this increase is that the improvement in CTPA resolution has enabled radiologists to identify more small peripheral (ie, segmental and subsegmental) filling defects. When confronted with the finding of a small peripheral filling defect on CTPA, clinicians often face a management quandary. Case series and retrospective series on outcomes of these patients do not support treatment, but they are limited by having small numbers of patients; the largest examined 93 patients and provided no insight into the treatment decision.[7] Uncertainty exists, furthermore, about the pathologic meaning of small peripheral filling defects.[8] Clinicians must weigh these arguments and the risk of anticoagulation against concerns about the consequences of untreated pulmonary thromboemboli. More information is needed, therefore, on the outcomes of patients with peripheral filling defects, and on variables impacting the treatment decision, in order to help clinicians manage these patients.[9]
In this study, we analyzed cases of patients with a single peripheral filling defect (SPFD). We choose to look at patients with a SPFD because they represent the starkest decision‐making treatment dilemma and are not infrequent. We assessed the 90‐day mortality and rate of postdischarge venous thromboembolism (VTE) of treated and untreated patients and identified characteristics of treated and untreated patients with a SPFD. We wished to determine the incidence of SPFD among patients evaluated with CTPA and to determine how often the defect is called a PE by the radiologist. We also aimed to determine what role secondary studies play in helping to clarify the diagnosis and management of SPFD and to identify other factors that may influence the decision to treat patients with this finding.
METHODS
Site
This retrospective cohort study was conducted at a community hospital in Norwalk, CT. The hospital is a 328‐bed, not‐for‐profit, acute‐care community teaching hospital that serves a population of 250,000 in lower Fairfield County, Connecticut, and is affiliated with the Yale School of Medicine.
Subjects
The reports of all CTPAs done over a 66‐month period from 2006 to 2010 were individually reviewed. Any study that had a filling defect reported in the body of the radiology report was selected for initial consideration. A second round of review was conducted, extracting only CTPAs with a SPFD for study inclusion. We then excluded from the primary analysis those studies in which the patient had a concurrently positive lower‐extremity ultrasound, the medical records could not be located, and the patient age was <18 years. The study was approved by the investigational review board of the hospital.
Radiographic Methods
The CTPAs were performed using the SOMATOM Definition scanner, a 128‐slice CT scanner with 0.5‐cm collimation (Siemens, Erlangen, Germany). The CT‐scanner technology did not change over the 66 months of the study period.
Data Collection
Clinical data were abstracted from the physical charts and from the computerized practitioner order‐entry system (PowerChart electronic medical record system; Cerner Corp, Kansas City, MO). Three abstractors were trained in the process of chart abstraction using training sets of 10 records. The Fleiss was used to assess concordance. The Fleiss was 0.6 at the initial training set, and after 3 training sets it improved to 0.9. In‐hospital all‐cause mortality was determined using the hospital death records, and out‐of‐hospital mortality data were obtained from the online statewide death records.[10] Postdischarge VTE was assessed by interrogating the hospital radiology database for repeat ventilation perfusion scan, conventional pulmonary angiography, lower‐limb compression ultrasound (CUS) or CTPA studies that were positive within 90 days of the index event. Treatment was defined as either anticoagulation, ascertained from medication list at discharge, or inferior vena cava (IVC) filter placement, documented at the index visit.
To better understand the variation in interpretation of SPFD, all CTPA studies that showed a SPFD were also over‐read by 2 radiologists who reached a consensus opinion regarding whether the finding was a PE. The radiologists who over‐read the studies were blinded to the final impression of the initial radiologist. Our study group comprised 3 radiologists; 1 read <20% of the initial studies and the other 2 had no input in the initial readings. One of the radiologists was an attending and the other 2 were fourth‐year radiology residents.
Baseline Variables and Outcome Measures
A peripheral filling defect was defined as a single filling defect located in either the segmental or subsegmental pulmonary artery. The primary variables of interest were patient demographics (age, sex, and race), insurance status, the presence of pulmonary input in the management of the patient, history of comorbid conditions (prior VTE, congestive heart failure, chronic lung disease, pulmonary hypertension, coronary artery disease, surgery within the last 6 months, active malignancy, and acute pulmonary edema or syncope at presentation) and risk class as assessed by the Pulmonary Embolism Severity Index (PESI) score.[11] The PESI scoring system is a risk‐stratification tool for patients with acute PE. It uses 11 prognostic variables to predict in‐hospital and all‐cause mortality: age, sex, heart rate 110 bpm, systolic blood pressure <90 mm Hg, congestive heart failure, presence of malignancy, chronic lung disease, respiratory rate <30/minute, temperature <36C, altered mental status, and oxygen saturation <90%. Additional variables of interest were the proportion of patients in the treated and untreated arms who had a pulmonary consultation at the index visit and the role, if any, of a second test for VTE at the index visit. The primary outcomes investigated were all‐cause 90‐day mortality and 90‐day incidence of postdischarge VTE from the index visit in the treated and untreated groups. Those patients whose studies had a SPFD that was concluded by the initial radiologist to be a PE on the final impression of the report were analyzed as a subgroup.
Statistical Analysis
Bivariate analysis was conducted to compare patient baseline characteristics between treated and untreated groups. The 2 test was used for comparing binary or categorical variables and the Student t test was used for comparing continuous variables. A logistic regression model utilizing the Markov chain Monte Carlo (MCMC) method was employed for assessing the differences in 90‐day mortality and 90‐day postdischarge VTE between the treated group and untreated group, adjusting for patient baseline characteristics. This model was also used for identifying factors associated with the decision to treat. We reported the odds ratio (OR) and its corresponding 95% confidence interval (CI) for each estimate identified from the model. All analyses were conducted using SAS version 9.3 64‐bit software (SAS Institute Inc, Cary, NC).
RESULTS
A total of 4906 CTPAs were screened during the 66 months reviewed, identifying 518 (10.6%) with any filling defect and 153 (3.1%) with a SPFD. Thirteen patients were excluded from the primary analysis because their records could not be located, and another 6 were excluded because they had a concurrently positive CUS. The primary analysis was performed, therefore, with 134 patients. The inpatient service ordered 78% of the CTPAs. The initial radiologist stated in the impression section of the report that a PE was present in 99 of 134 (73.9%) studies. On over‐read of the 134 studies, 100 of these were considered to be positive for a PE. There was modest agreement between the initial impression and the consensus impression at over‐read (=0.69).
Association of Treatment With Mortality and Recurrence
In the primary‐analysis group, 61 (45.5%) patients were treated: 50 patients had warfarin alone, 10 patients had an IVC filter alone, and 1 patient had both warfarin and an IVC filter. No patient was treated solely with low‐molecular‐weight heparin long‐term. Whenever low‐molecular‐weight heparin was used, it was as a bridge to warfarin. The characteristics of the patients in the treatment groups were similar (Table 1). Four of the treated patients had a CTPA with SPFD that was not called a PE in the initial reading. Ten patients died, 5 each in the treated and untreated groups, yielding an overall mortality rate at 90 days of 7.4% (Table 2). Analysis of the 134 patients showed no difference in adjusted 90‐day mortality between treated and untreated groups (OR: 1.0, 95% CI: 0.25‐3.98). The number of patients with postdischarge VTE within 90 days was 5 of 134 (3.7%) patients, 3 treated and 2 untreated, and too few to show a treatment effect. Among the 99 cases considered by the initial radiologist to be definite for a PE, 59 (59.6%) were treated and 40 (40.4%) untreated. In this subgroup, no mortality benefit was observed with treatment (OR: 1.42, 95% CI: 0.28‐8.05).
| Characteristic | Treated, n=61 | Untreated, n=73 | P Value |
|---|---|---|---|
| |||
| Age, y, mean (SD) | 67 (20) | 62 (21) | 0.056 |
| Sex, M | 29 (48) | 34 (47) | 0.831 |
| Race/ethnicity | 0.426 | ||
| White | 43 (70) | 57 (78) | |
| Black | 12 (20) | 8 (11) | |
| Hispanic | 6 (10) | 7 (10) | |
| Other | 0 | 1 (2) | |
| Primary insurance | 0.231 | ||
| Medicare | 30 (50) | 29 (40) | |
| Medicaid | 2 (3) | 8 (11) | |
| Commercial | 27 (44) | 30 (41) | |
| Self‐pay | 2 (3) | 6 (8) | |
| Pulmonary consultation | 29 (48) | 28 (38) | 0.482 |
| Comorbid illnesses | 0.119 | ||
| Cancera | 13 (21) | 17 (23) | |
| Surgery/traumab | 16 (26) | 2 (3) | |
| Chronic lung disease | 17 (28) | 15 (21) | |
| CHF | 12 (20) | 9 (12) | |
| Ischemic heart disease | 12 (20) | 7 (10) | |
| Pulmonary hypertension | 0 | 1 (1) | |
| Collagen vascular disease | 1 (2) | 2 (3) | |
| PESI classc | 0.840 | ||
| I | 15 (25) | 24 (33) | |
| II | 13 (21) | 16 (22) | |
| III | 12 (20) | 13 (18) | |
| IV | 9 (15) | 8 (11) | |
| V | 12 (20) | 12 (16) | |
| Treatment | Combined Outcome | 90‐Day All‐Cause Mortality | 90‐Day All‐Cause Recurrence | |||
|---|---|---|---|---|---|---|
| Death or Recurrent VTE, n (% All Patients) | Adjusted OR for Combined Outcome (95% CI)a | Mortality, n (% All Patients) | Adjusted OR (95% CI)a | Recurrence, n (% All Patients) | Adjusted OR (95% CI)a | |
| ||||||
| Any treatment, n=61 | 8 (6.0) | 1.50 (0.435.20) | 5 (3.7) | 1.00 (0.253.98) | 3 (2.2) | 1.10 (0.129.92) |
| Warfarin, n=51 | 5 (3.7) | 0.75 (0.202.85) | 2 (1.5) | 0.26 (0.041.51) | 3 (2.2) | 2.04 (0.2318.04) |
| IVC filter, n=10 | 3 (2.2) | 5.77 (1.2227.36) | 3 (2.2) | 10.60 (2.1053.56) | 0 | NA |
| None, n=73 | 7 (5.2) | Referent | 5 (3.7) | Referent | 2 (1.5%) | Referent |
Use of Secondary Diagnostic Tests
A CUS was performed on 42 of the 153 patients (27%) with studies noting a SPFD. Six CUSs were positive, with 5 of the patients receiving anticoagulation and the sixth an IVC filter. A second lung‐imaging study was done in 10 (7%) of the 134 patients in the primary‐analysis group: 1 conventional pulmonary angiogram that was normal and 9 ventilation‐perfusion scans, among which 4 were normal, 2 were intermediate probability for PE, 2 were low probability for PE, and 1 was very low probability for PE. The 2 patients whose scans were read as intermediate probability and 1 patient whose scan was read as low probability was treated, and none of the patients with normal scans received treatment. None of these 10 patients died or had a postdischarge VTE during the 90‐day follow‐up period.
Factors Associated With Treatment
In the risk‐adjusted model, patient characteristics associated with treatment were immobility, previous VTE, and acute mental‐status change (Table 3). When the radiologist concluded that the SPFD was a PE, there was a highly increased likelihood of being treated. These factors were selected based on the MCMC simulation and the final model had a goodness‐of‐fit P value of 0.69, indicating it was fitted well. Vital‐sign abnormalities, comorbid illnesses, history of cancer, ethnicity, insurance status, and the presence of pulmonary consultation were not associated with the decision to treat. The 3 patient factorsimmobility, previous VTE, and absence of mental‐status changecombined with the initial impression of the radiologist, were strongly predictive of the decision to treat (C statistic: 0.87). None of the subset of patients who had a negative CUS and normal or very low probability ventilation‐perfusion scan received treatment. Eighty of the 134 (60%) patients had an active malignancy, chronic lung disease, heart failure, or evidence of ischemic heart disease; all 10 patients who died were from this subset of patients.
| Factors | Adjusted OR | 95% CI | Probability of Being Statistically Associated With the Decision to Treat |
|---|---|---|---|
| |||
| Immobility | 3.9 | 1.4510.6 | 0.78 |
| Acute mental‐status change | 0.14 | 0.020.84 | 0.64 |
| Initial impression of radiologist | 24.68 | 5.4112.89 | 0.86 |
| Prior VTE | 3.72 | 1.1811.67 | 0.70 |
DISCUSSION
This very large retrospective study examines treatment and outcomes in patients with a SPFD. We found that SPFDs were common, showing up in approximately 3% of all the CTPAs performed. Among the studies that were deemed positive for PE, SPFD comprised nearly one‐third. Treatment of SPFD, whether concluded as PE or not, was not associated with a mortality benefit or difference in postdischarge VTE within 90 days. Our results add to the weight of smaller case‐control and retrospective series that also found no benefit from treating small PE.[7, 12, 13, 14, 15]
Given this data, why might physicians choose to treat? Physicians may feel compelled to anticoagulate due to extrapolation of data from the early studies showing a fatality rate of up to 30% in untreated PE.[2] Also, physicians may harbor the concern that, though small emboli may pose no immediate danger, they serve as a marker of hypercoagulability and as such are a harbinger of subsequent large clots. A reflexive treatment response to the radiologist's conclusion that the filling defect is a PE may also play a part. Balancing this concern is the recognition that the treatment for acute PE is not benign. The age‐adjusted incidence of major bleeding (eg, gastrointestinal or intracranial) with warfarin has increased by 71%, from 3.1 to 5.3 per 100,000, since the introduction of CTPA.[6] Also, as seen in this study, a substantial percentage of patients will incur the morbidity and cost of IVC‐filter placement.
When physicians face management uncertainty, they consider risk factors for the condition investigated, consult experts, employ additional studies, and weigh patient preference. In this study, history of immobility and VTE were, indeed, positively associated with treatment, but change in mental status was negatively so. Given that the PESI score is higher with change in mental status, this finding is superficially paradoxical but unsurprising. Mental‐status change could not likely stem from a SPFD and its presence heightens the risks of anticoagulation, hence dissuading treatment. Pulmonary consultations were documented in less than half of the cases and did not clearly sway the treatment decision. Determining whether more patients would have been treated if pulmonologists were not involved would require a prospective study.
The most important association with treatment was how the radiologist interpreted the SPFD. Even then, the influence of the radiologist's interpretation was far from complete: 40% of the cases in which PE was called went untreated, and 4 cases received treatment despite PE not being called. The value of the radiologist's interpretation is further undercut by the modest interobserver agreement found on over‐read, which is line with previous reports and reflective of lack of a gold standard for diagnosing isolated peripheral PE.[3, 12, 16]
Even if radiologists could agree upon what they are seeing, the question remains about the pathological importance. Unrecognized PE incidental to the cause of death are commonly found at autopsy. Autopsy studies reveal that up to 52% to 64% of patients have PE; and, if multiple blocks of lung tissue are studied, the prevalence increases up to 90%.[17, 18] In the series by Freiman et al., 59% of the identified thrombi were small enough not to be recognized on routine gross examination.[17] Furthermore, an unknown percentage of small clots, especially in the upper lobes, are in situ thrombi rather than emboli.[18] In the case of small dot‐like clots, Suh and colleagues have speculated that they represent normal embolic activity from the lower limbs, which are cleared routinely by the lung serving in its role as a filter.[19] Although our study only examined SPFD, the accumulation of small emboli could have pathologic consequences. In their review, Gali and Kim reported that 12% of patients with chronic thromboembolic pulmonary hypertension who underwent pulmonary endarterectomy had disease confined to the distal segmental and subsegmental arteries.[13]
Use of secondary studies could mitigate some of the diagnostic and management uncertainty, but they were obtained in only about a quarter of the cases. The use of a second lung‐imaging study following CTPA is not recommended in guidelines or diagnostic algorithms, but in our institution a significant minority of physicians were employing these tests to clarify the nature of the filling defects.[20] Tapson, speaking to the treatment dilemma that small PEs present, has suggested that prospective trials on this topic employ tests that investigate risk for poor outcome if untreated including cardiopulmonary reserve, D‐dimer, and presence of lower‐limb thrombus.[21] Indeed, a study is ongoing examining the outcome at 90 days of patients with single or multiple subsegmental embolism with negative CUS.[22]
Ten of the 134 patients (7.4%) with peripheral filling defects died within 90 days. It is difficult to establish whether these deaths were PE‐specific mortalities because there was a high degree of comorbid illness in this cohort. Five of the 134 (3.7%) had recurrent VTE, which is comparable to the outcomes in other studies.[23]
There are limitations to this study. This study is the first to limit analysis of the filling defects to single defects in the segmental or subsegmental pulmonary arteries. This subset of patients includes those with the least clot burden, therefore representing the starkest decision‐making treatment dilemma, and the incidence of these clots is not insignificant. As a retrospective study, we could not fully capture all of the considerations that may have factored into the clinicians' decision‐making regarding treatment, including patient preference. Because of inadequate documentation, especially in the emergency department notes, we were unable to calculate pretest probability. Also, we cannot exclude that subclinical VTEs were occurring that would later harm the patients. We did not analyze the role of D‐dimer testing because that test is validated to guide the decision to obtain lung‐imaging studies and not to inform the treatment decision. In our cohort, 89 of 134 (66%) of our patients were already hospitalized for other diagnoses prior to PE being queried. Moreover, many of these patients had active malignancy or were being treated for pneumonia, which would decrease the positive predictive value of the D‐dimer test. D‐dimer performs poorly when used for prognosis.[24] This is a single‐center study, therefore the comparability of our findings to other centers may be an issue, although our findings generally accord with those from other single‐center studies.[7, 12, 24, 25] We determined the recurrence rate from the hospital records and could have missed cases diagnosed elsewhere. However, our hospital is the only one in the city and serves the vast majority of patients in the area, and 88% of our cohort had a repeat visit to our hospital subsequently. In addition, the radiology service is the only one in the area that provides outpatient CUS, CTPA, and ventilation‐perfusion scan studies. Our study is the largest to date on this issue. However, our sample size is somewhat modest, and consequently the factors associated with treatment have large confidence intervals. We are therefore constrained in recommending empiric application of our findings. Nonetheless, our results in terms of no difference in mortality and recurrence between treated and untreated patients are in keeping with other studies on this topic. Also, our simulation analysis did reveal factors that were highly associated with the decision to treat. These findings as a whole strongly point to the need for a larger study on this issue, because, as we and other authors have argued, the consequences of treatment are not benign.[6]
In conclusion, this study shows that SPFDs are common and that there was no difference in 90‐day mortality between treated and untreated patients, regardless of whether the defects were interpreted as PE or not. Physicians appear to rely heavily on the radiologist's interpretation for their treatment decision, but they will also treat when the interpretation is not PE and not infrequently abstain when it is. Treatment remains common despite the modest agreement among radiologists whether the peripheral filling defect even represents PE. When secondary imaging studies are obtained and negative, physicians forgo treatment. Larger studies are needed to help clarify our findings and should include decision‐making algorithms that include secondary imaging studies, because these studies may provide enough reassurance when negative to sway physicians against treatment.
Disclosure
Nothing to report.
Over the past decade, the use of chest computed tomography scans with pulmonary angiography (CTPA) for diagnosis of pulmonary embolism (PE) has soared due to the ease of acquisition, the desire for the additional information that CT scanning may provide, and heightened sensitivity to medical liability.[1, 2, 3, 4, 5, 6] In parallel with this shift, the incidence of PE has nearly doubled, despite no recorded increase in the pretest probability of the disease, increasing from 62 per 100,000 to 112 per 100,000 during the period of 1993 to 2006.6 One major explanation for this increase is that the improvement in CTPA resolution has enabled radiologists to identify more small peripheral (ie, segmental and subsegmental) filling defects. When confronted with the finding of a small peripheral filling defect on CTPA, clinicians often face a management quandary. Case series and retrospective series on outcomes of these patients do not support treatment, but they are limited by having small numbers of patients; the largest examined 93 patients and provided no insight into the treatment decision.[7] Uncertainty exists, furthermore, about the pathologic meaning of small peripheral filling defects.[8] Clinicians must weigh these arguments and the risk of anticoagulation against concerns about the consequences of untreated pulmonary thromboemboli. More information is needed, therefore, on the outcomes of patients with peripheral filling defects, and on variables impacting the treatment decision, in order to help clinicians manage these patients.[9]
In this study, we analyzed cases of patients with a single peripheral filling defect (SPFD). We choose to look at patients with a SPFD because they represent the starkest decision‐making treatment dilemma and are not infrequent. We assessed the 90‐day mortality and rate of postdischarge venous thromboembolism (VTE) of treated and untreated patients and identified characteristics of treated and untreated patients with a SPFD. We wished to determine the incidence of SPFD among patients evaluated with CTPA and to determine how often the defect is called a PE by the radiologist. We also aimed to determine what role secondary studies play in helping to clarify the diagnosis and management of SPFD and to identify other factors that may influence the decision to treat patients with this finding.
METHODS
Site
This retrospective cohort study was conducted at a community hospital in Norwalk, CT. The hospital is a 328‐bed, not‐for‐profit, acute‐care community teaching hospital that serves a population of 250,000 in lower Fairfield County, Connecticut, and is affiliated with the Yale School of Medicine.
Subjects
The reports of all CTPAs done over a 66‐month period from 2006 to 2010 were individually reviewed. Any study that had a filling defect reported in the body of the radiology report was selected for initial consideration. A second round of review was conducted, extracting only CTPAs with a SPFD for study inclusion. We then excluded from the primary analysis those studies in which the patient had a concurrently positive lower‐extremity ultrasound, the medical records could not be located, and the patient age was <18 years. The study was approved by the investigational review board of the hospital.
Radiographic Methods
The CTPAs were performed using the SOMATOM Definition scanner, a 128‐slice CT scanner with 0.5‐cm collimation (Siemens, Erlangen, Germany). The CT‐scanner technology did not change over the 66 months of the study period.
Data Collection
Clinical data were abstracted from the physical charts and from the computerized practitioner order‐entry system (PowerChart electronic medical record system; Cerner Corp, Kansas City, MO). Three abstractors were trained in the process of chart abstraction using training sets of 10 records. The Fleiss was used to assess concordance. The Fleiss was 0.6 at the initial training set, and after 3 training sets it improved to 0.9. In‐hospital all‐cause mortality was determined using the hospital death records, and out‐of‐hospital mortality data were obtained from the online statewide death records.[10] Postdischarge VTE was assessed by interrogating the hospital radiology database for repeat ventilation perfusion scan, conventional pulmonary angiography, lower‐limb compression ultrasound (CUS) or CTPA studies that were positive within 90 days of the index event. Treatment was defined as either anticoagulation, ascertained from medication list at discharge, or inferior vena cava (IVC) filter placement, documented at the index visit.
To better understand the variation in interpretation of SPFD, all CTPA studies that showed a SPFD were also over‐read by 2 radiologists who reached a consensus opinion regarding whether the finding was a PE. The radiologists who over‐read the studies were blinded to the final impression of the initial radiologist. Our study group comprised 3 radiologists; 1 read <20% of the initial studies and the other 2 had no input in the initial readings. One of the radiologists was an attending and the other 2 were fourth‐year radiology residents.
Baseline Variables and Outcome Measures
A peripheral filling defect was defined as a single filling defect located in either the segmental or subsegmental pulmonary artery. The primary variables of interest were patient demographics (age, sex, and race), insurance status, the presence of pulmonary input in the management of the patient, history of comorbid conditions (prior VTE, congestive heart failure, chronic lung disease, pulmonary hypertension, coronary artery disease, surgery within the last 6 months, active malignancy, and acute pulmonary edema or syncope at presentation) and risk class as assessed by the Pulmonary Embolism Severity Index (PESI) score.[11] The PESI scoring system is a risk‐stratification tool for patients with acute PE. It uses 11 prognostic variables to predict in‐hospital and all‐cause mortality: age, sex, heart rate 110 bpm, systolic blood pressure <90 mm Hg, congestive heart failure, presence of malignancy, chronic lung disease, respiratory rate <30/minute, temperature <36C, altered mental status, and oxygen saturation <90%. Additional variables of interest were the proportion of patients in the treated and untreated arms who had a pulmonary consultation at the index visit and the role, if any, of a second test for VTE at the index visit. The primary outcomes investigated were all‐cause 90‐day mortality and 90‐day incidence of postdischarge VTE from the index visit in the treated and untreated groups. Those patients whose studies had a SPFD that was concluded by the initial radiologist to be a PE on the final impression of the report were analyzed as a subgroup.
Statistical Analysis
Bivariate analysis was conducted to compare patient baseline characteristics between treated and untreated groups. The 2 test was used for comparing binary or categorical variables and the Student t test was used for comparing continuous variables. A logistic regression model utilizing the Markov chain Monte Carlo (MCMC) method was employed for assessing the differences in 90‐day mortality and 90‐day postdischarge VTE between the treated group and untreated group, adjusting for patient baseline characteristics. This model was also used for identifying factors associated with the decision to treat. We reported the odds ratio (OR) and its corresponding 95% confidence interval (CI) for each estimate identified from the model. All analyses were conducted using SAS version 9.3 64‐bit software (SAS Institute Inc, Cary, NC).
RESULTS
A total of 4906 CTPAs were screened during the 66 months reviewed, identifying 518 (10.6%) with any filling defect and 153 (3.1%) with a SPFD. Thirteen patients were excluded from the primary analysis because their records could not be located, and another 6 were excluded because they had a concurrently positive CUS. The primary analysis was performed, therefore, with 134 patients. The inpatient service ordered 78% of the CTPAs. The initial radiologist stated in the impression section of the report that a PE was present in 99 of 134 (73.9%) studies. On over‐read of the 134 studies, 100 of these were considered to be positive for a PE. There was modest agreement between the initial impression and the consensus impression at over‐read (=0.69).
Association of Treatment With Mortality and Recurrence
In the primary‐analysis group, 61 (45.5%) patients were treated: 50 patients had warfarin alone, 10 patients had an IVC filter alone, and 1 patient had both warfarin and an IVC filter. No patient was treated solely with low‐molecular‐weight heparin long‐term. Whenever low‐molecular‐weight heparin was used, it was as a bridge to warfarin. The characteristics of the patients in the treatment groups were similar (Table 1). Four of the treated patients had a CTPA with SPFD that was not called a PE in the initial reading. Ten patients died, 5 each in the treated and untreated groups, yielding an overall mortality rate at 90 days of 7.4% (Table 2). Analysis of the 134 patients showed no difference in adjusted 90‐day mortality between treated and untreated groups (OR: 1.0, 95% CI: 0.25‐3.98). The number of patients with postdischarge VTE within 90 days was 5 of 134 (3.7%) patients, 3 treated and 2 untreated, and too few to show a treatment effect. Among the 99 cases considered by the initial radiologist to be definite for a PE, 59 (59.6%) were treated and 40 (40.4%) untreated. In this subgroup, no mortality benefit was observed with treatment (OR: 1.42, 95% CI: 0.28‐8.05).
| Characteristic | Treated, n=61 | Untreated, n=73 | P Value |
|---|---|---|---|
| |||
| Age, y, mean (SD) | 67 (20) | 62 (21) | 0.056 |
| Sex, M | 29 (48) | 34 (47) | 0.831 |
| Race/ethnicity | 0.426 | ||
| White | 43 (70) | 57 (78) | |
| Black | 12 (20) | 8 (11) | |
| Hispanic | 6 (10) | 7 (10) | |
| Other | 0 | 1 (2) | |
| Primary insurance | 0.231 | ||
| Medicare | 30 (50) | 29 (40) | |
| Medicaid | 2 (3) | 8 (11) | |
| Commercial | 27 (44) | 30 (41) | |
| Self‐pay | 2 (3) | 6 (8) | |
| Pulmonary consultation | 29 (48) | 28 (38) | 0.482 |
| Comorbid illnesses | 0.119 | ||
| Cancera | 13 (21) | 17 (23) | |
| Surgery/traumab | 16 (26) | 2 (3) | |
| Chronic lung disease | 17 (28) | 15 (21) | |
| CHF | 12 (20) | 9 (12) | |
| Ischemic heart disease | 12 (20) | 7 (10) | |
| Pulmonary hypertension | 0 | 1 (1) | |
| Collagen vascular disease | 1 (2) | 2 (3) | |
| PESI classc | 0.840 | ||
| I | 15 (25) | 24 (33) | |
| II | 13 (21) | 16 (22) | |
| III | 12 (20) | 13 (18) | |
| IV | 9 (15) | 8 (11) | |
| V | 12 (20) | 12 (16) | |
| Treatment | Combined Outcome | 90‐Day All‐Cause Mortality | 90‐Day All‐Cause Recurrence | |||
|---|---|---|---|---|---|---|
| Death or Recurrent VTE, n (% All Patients) | Adjusted OR for Combined Outcome (95% CI)a | Mortality, n (% All Patients) | Adjusted OR (95% CI)a | Recurrence, n (% All Patients) | Adjusted OR (95% CI)a | |
| ||||||
| Any treatment, n=61 | 8 (6.0) | 1.50 (0.435.20) | 5 (3.7) | 1.00 (0.253.98) | 3 (2.2) | 1.10 (0.129.92) |
| Warfarin, n=51 | 5 (3.7) | 0.75 (0.202.85) | 2 (1.5) | 0.26 (0.041.51) | 3 (2.2) | 2.04 (0.2318.04) |
| IVC filter, n=10 | 3 (2.2) | 5.77 (1.2227.36) | 3 (2.2) | 10.60 (2.1053.56) | 0 | NA |
| None, n=73 | 7 (5.2) | Referent | 5 (3.7) | Referent | 2 (1.5%) | Referent |
Use of Secondary Diagnostic Tests
A CUS was performed on 42 of the 153 patients (27%) with studies noting a SPFD. Six CUSs were positive, with 5 of the patients receiving anticoagulation and the sixth an IVC filter. A second lung‐imaging study was done in 10 (7%) of the 134 patients in the primary‐analysis group: 1 conventional pulmonary angiogram that was normal and 9 ventilation‐perfusion scans, among which 4 were normal, 2 were intermediate probability for PE, 2 were low probability for PE, and 1 was very low probability for PE. The 2 patients whose scans were read as intermediate probability and 1 patient whose scan was read as low probability was treated, and none of the patients with normal scans received treatment. None of these 10 patients died or had a postdischarge VTE during the 90‐day follow‐up period.
Factors Associated With Treatment
In the risk‐adjusted model, patient characteristics associated with treatment were immobility, previous VTE, and acute mental‐status change (Table 3). When the radiologist concluded that the SPFD was a PE, there was a highly increased likelihood of being treated. These factors were selected based on the MCMC simulation and the final model had a goodness‐of‐fit P value of 0.69, indicating it was fitted well. Vital‐sign abnormalities, comorbid illnesses, history of cancer, ethnicity, insurance status, and the presence of pulmonary consultation were not associated with the decision to treat. The 3 patient factorsimmobility, previous VTE, and absence of mental‐status changecombined with the initial impression of the radiologist, were strongly predictive of the decision to treat (C statistic: 0.87). None of the subset of patients who had a negative CUS and normal or very low probability ventilation‐perfusion scan received treatment. Eighty of the 134 (60%) patients had an active malignancy, chronic lung disease, heart failure, or evidence of ischemic heart disease; all 10 patients who died were from this subset of patients.
| Factors | Adjusted OR | 95% CI | Probability of Being Statistically Associated With the Decision to Treat |
|---|---|---|---|
| |||
| Immobility | 3.9 | 1.4510.6 | 0.78 |
| Acute mental‐status change | 0.14 | 0.020.84 | 0.64 |
| Initial impression of radiologist | 24.68 | 5.4112.89 | 0.86 |
| Prior VTE | 3.72 | 1.1811.67 | 0.70 |
DISCUSSION
This very large retrospective study examines treatment and outcomes in patients with a SPFD. We found that SPFDs were common, showing up in approximately 3% of all the CTPAs performed. Among the studies that were deemed positive for PE, SPFD comprised nearly one‐third. Treatment of SPFD, whether concluded as PE or not, was not associated with a mortality benefit or difference in postdischarge VTE within 90 days. Our results add to the weight of smaller case‐control and retrospective series that also found no benefit from treating small PE.[7, 12, 13, 14, 15]
Given this data, why might physicians choose to treat? Physicians may feel compelled to anticoagulate due to extrapolation of data from the early studies showing a fatality rate of up to 30% in untreated PE.[2] Also, physicians may harbor the concern that, though small emboli may pose no immediate danger, they serve as a marker of hypercoagulability and as such are a harbinger of subsequent large clots. A reflexive treatment response to the radiologist's conclusion that the filling defect is a PE may also play a part. Balancing this concern is the recognition that the treatment for acute PE is not benign. The age‐adjusted incidence of major bleeding (eg, gastrointestinal or intracranial) with warfarin has increased by 71%, from 3.1 to 5.3 per 100,000, since the introduction of CTPA.[6] Also, as seen in this study, a substantial percentage of patients will incur the morbidity and cost of IVC‐filter placement.
When physicians face management uncertainty, they consider risk factors for the condition investigated, consult experts, employ additional studies, and weigh patient preference. In this study, history of immobility and VTE were, indeed, positively associated with treatment, but change in mental status was negatively so. Given that the PESI score is higher with change in mental status, this finding is superficially paradoxical but unsurprising. Mental‐status change could not likely stem from a SPFD and its presence heightens the risks of anticoagulation, hence dissuading treatment. Pulmonary consultations were documented in less than half of the cases and did not clearly sway the treatment decision. Determining whether more patients would have been treated if pulmonologists were not involved would require a prospective study.
The most important association with treatment was how the radiologist interpreted the SPFD. Even then, the influence of the radiologist's interpretation was far from complete: 40% of the cases in which PE was called went untreated, and 4 cases received treatment despite PE not being called. The value of the radiologist's interpretation is further undercut by the modest interobserver agreement found on over‐read, which is line with previous reports and reflective of lack of a gold standard for diagnosing isolated peripheral PE.[3, 12, 16]
Even if radiologists could agree upon what they are seeing, the question remains about the pathological importance. Unrecognized PE incidental to the cause of death are commonly found at autopsy. Autopsy studies reveal that up to 52% to 64% of patients have PE; and, if multiple blocks of lung tissue are studied, the prevalence increases up to 90%.[17, 18] In the series by Freiman et al., 59% of the identified thrombi were small enough not to be recognized on routine gross examination.[17] Furthermore, an unknown percentage of small clots, especially in the upper lobes, are in situ thrombi rather than emboli.[18] In the case of small dot‐like clots, Suh and colleagues have speculated that they represent normal embolic activity from the lower limbs, which are cleared routinely by the lung serving in its role as a filter.[19] Although our study only examined SPFD, the accumulation of small emboli could have pathologic consequences. In their review, Gali and Kim reported that 12% of patients with chronic thromboembolic pulmonary hypertension who underwent pulmonary endarterectomy had disease confined to the distal segmental and subsegmental arteries.[13]
Use of secondary studies could mitigate some of the diagnostic and management uncertainty, but they were obtained in only about a quarter of the cases. The use of a second lung‐imaging study following CTPA is not recommended in guidelines or diagnostic algorithms, but in our institution a significant minority of physicians were employing these tests to clarify the nature of the filling defects.[20] Tapson, speaking to the treatment dilemma that small PEs present, has suggested that prospective trials on this topic employ tests that investigate risk for poor outcome if untreated including cardiopulmonary reserve, D‐dimer, and presence of lower‐limb thrombus.[21] Indeed, a study is ongoing examining the outcome at 90 days of patients with single or multiple subsegmental embolism with negative CUS.[22]
Ten of the 134 patients (7.4%) with peripheral filling defects died within 90 days. It is difficult to establish whether these deaths were PE‐specific mortalities because there was a high degree of comorbid illness in this cohort. Five of the 134 (3.7%) had recurrent VTE, which is comparable to the outcomes in other studies.[23]
There are limitations to this study. This study is the first to limit analysis of the filling defects to single defects in the segmental or subsegmental pulmonary arteries. This subset of patients includes those with the least clot burden, therefore representing the starkest decision‐making treatment dilemma, and the incidence of these clots is not insignificant. As a retrospective study, we could not fully capture all of the considerations that may have factored into the clinicians' decision‐making regarding treatment, including patient preference. Because of inadequate documentation, especially in the emergency department notes, we were unable to calculate pretest probability. Also, we cannot exclude that subclinical VTEs were occurring that would later harm the patients. We did not analyze the role of D‐dimer testing because that test is validated to guide the decision to obtain lung‐imaging studies and not to inform the treatment decision. In our cohort, 89 of 134 (66%) of our patients were already hospitalized for other diagnoses prior to PE being queried. Moreover, many of these patients had active malignancy or were being treated for pneumonia, which would decrease the positive predictive value of the D‐dimer test. D‐dimer performs poorly when used for prognosis.[24] This is a single‐center study, therefore the comparability of our findings to other centers may be an issue, although our findings generally accord with those from other single‐center studies.[7, 12, 24, 25] We determined the recurrence rate from the hospital records and could have missed cases diagnosed elsewhere. However, our hospital is the only one in the city and serves the vast majority of patients in the area, and 88% of our cohort had a repeat visit to our hospital subsequently. In addition, the radiology service is the only one in the area that provides outpatient CUS, CTPA, and ventilation‐perfusion scan studies. Our study is the largest to date on this issue. However, our sample size is somewhat modest, and consequently the factors associated with treatment have large confidence intervals. We are therefore constrained in recommending empiric application of our findings. Nonetheless, our results in terms of no difference in mortality and recurrence between treated and untreated patients are in keeping with other studies on this topic. Also, our simulation analysis did reveal factors that were highly associated with the decision to treat. These findings as a whole strongly point to the need for a larger study on this issue, because, as we and other authors have argued, the consequences of treatment are not benign.[6]
In conclusion, this study shows that SPFDs are common and that there was no difference in 90‐day mortality between treated and untreated patients, regardless of whether the defects were interpreted as PE or not. Physicians appear to rely heavily on the radiologist's interpretation for their treatment decision, but they will also treat when the interpretation is not PE and not infrequently abstain when it is. Treatment remains common despite the modest agreement among radiologists whether the peripheral filling defect even represents PE. When secondary imaging studies are obtained and negative, physicians forgo treatment. Larger studies are needed to help clarify our findings and should include decision‐making algorithms that include secondary imaging studies, because these studies may provide enough reassurance when negative to sway physicians against treatment.
Disclosure
Nothing to report.
- , , . The mortality of untreated pulmonary embolism in emergency department patients. Ann Emerg Med. 2005;45:302–310.
- . Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest. 2002;122:1400–1456.
- , , , et al. Subsegmental pulmonary emboli: improved detection with thin‐collimation multi‐detector row spiral CT. Radiology. 2002;222:483–490.
- , , . Trends in the use of diagnostic imaging in patients hospitalized with acute pulmonary embolism. Am J Cardiol. 2004;93:1316–1317.
- , , , , . The effect of helical computed tomography on diagnostic and treatment strategies in patients with suspected pulmonary embolism. Am J Med. 2004;116:84–90.
- , , . Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171:831–837.
- , , , . Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res. 2010;126:e266–e270.
- , , , et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29:2276–2315.
- , , , , . Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost. 2012;18:20–26.
- Intelius. Available at: http://www.intelius.com. Accessed September 30, 2010.
- , , . The validation and reproducibility of the pulmonary embolism severity index. J Thromb Haemost. 2010;8:1509–1514.
- , , . Clinicians' response to radiologists' reports of isolated subsegmental pulmonary embolism or inconclusive interpretation of pulmonary embolism using MDCT. AJR Am J Roentgenol. 2005;184:623–628.
- , . Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3:571–576.
- . Small pulmonary emboli: what do we know? Radiology. 2005;234:654–658.
- , , . Reassessment of pulmonary angiography for the diagnosis of pulmonary embolism: relation of interpreter agreement to the order of the involved pulmonary arterial branch. Radiology. 1999;210:689–691.
- , . Helical CT for the evaluation of acute pulmonary embolism. AJR Am J Roentgenol. 2005;185:135–149.
- , , . Frequency of pulmonary thromboembolism in man. N Engl J Med. 1965;272:1278–1280.
- . Pathology of pulmonary thromboembolism. Chest. 1995;107(1 suppl):10S–17S.
- , , . Dots are not clots: the over‐diagnosis and over‐treatment of PE. Emerg Radiol. 2010;17:347–352.
- , , . Current approach to the diagnosis of acute nonmassive pulmonary embolism. Chest. 2011;140:509–518.
- . Acute pulmonary embolism: comment on “time trends in pulmonary embolism in the United States.” Arch Intern Med. 2011;171:837–839.
- National Institutes of Health, ClinicalTrials.gov; Carrier M. A study to evaluate the safety of withholding anticoagulation in patients with subsegmental PE who have a negative serial bilateral lower extremity ultrasound (SSPE). ClinicalTrials.gov identifier: NCT01455818.
- , , . Untreated patients with pulmonary embolism: outcome, clinical, and laboratory assessment. Chest. 1995;107:931–935.
- , , , , , . Prognostic value of D‐dimer in stable patients with pulmonary embolism. Clin Appl Thromb Hemost. 2011;17:E183–E185.
- , , , , . Diagnosis and management of subsegmental pulmonary embolism. J Thromb Hemost. 2006;4:724–731.
- , , . The mortality of untreated pulmonary embolism in emergency department patients. Ann Emerg Med. 2005;45:302–310.
- . Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest. 2002;122:1400–1456.
- , , , et al. Subsegmental pulmonary emboli: improved detection with thin‐collimation multi‐detector row spiral CT. Radiology. 2002;222:483–490.
- , , . Trends in the use of diagnostic imaging in patients hospitalized with acute pulmonary embolism. Am J Cardiol. 2004;93:1316–1317.
- , , , , . The effect of helical computed tomography on diagnostic and treatment strategies in patients with suspected pulmonary embolism. Am J Med. 2004;116:84–90.
- , , . Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171:831–837.
- , , , . Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res. 2010;126:e266–e270.
- , , , et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29:2276–2315.
- , , , , . Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost. 2012;18:20–26.
- Intelius. Available at: http://www.intelius.com. Accessed September 30, 2010.
- , , . The validation and reproducibility of the pulmonary embolism severity index. J Thromb Haemost. 2010;8:1509–1514.
- , , . Clinicians' response to radiologists' reports of isolated subsegmental pulmonary embolism or inconclusive interpretation of pulmonary embolism using MDCT. AJR Am J Roentgenol. 2005;184:623–628.
- , . Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3:571–576.
- . Small pulmonary emboli: what do we know? Radiology. 2005;234:654–658.
- , , . Reassessment of pulmonary angiography for the diagnosis of pulmonary embolism: relation of interpreter agreement to the order of the involved pulmonary arterial branch. Radiology. 1999;210:689–691.
- , . Helical CT for the evaluation of acute pulmonary embolism. AJR Am J Roentgenol. 2005;185:135–149.
- , , . Frequency of pulmonary thromboembolism in man. N Engl J Med. 1965;272:1278–1280.
- . Pathology of pulmonary thromboembolism. Chest. 1995;107(1 suppl):10S–17S.
- , , . Dots are not clots: the over‐diagnosis and over‐treatment of PE. Emerg Radiol. 2010;17:347–352.
- , , . Current approach to the diagnosis of acute nonmassive pulmonary embolism. Chest. 2011;140:509–518.
- . Acute pulmonary embolism: comment on “time trends in pulmonary embolism in the United States.” Arch Intern Med. 2011;171:837–839.
- National Institutes of Health, ClinicalTrials.gov; Carrier M. A study to evaluate the safety of withholding anticoagulation in patients with subsegmental PE who have a negative serial bilateral lower extremity ultrasound (SSPE). ClinicalTrials.gov identifier: NCT01455818.
- , , . Untreated patients with pulmonary embolism: outcome, clinical, and laboratory assessment. Chest. 1995;107:931–935.
- , , , , , . Prognostic value of D‐dimer in stable patients with pulmonary embolism. Clin Appl Thromb Hemost. 2011;17:E183–E185.
- , , , , . Diagnosis and management of subsegmental pulmonary embolism. J Thromb Hemost. 2006;4:724–731.
© 2013 Society of Hospital Medicine