For all the purported benefits of the electronic health record (EHR), an unintended adverse effect is “electronic siloing.”

I define electronic siloing as the isolating effect of the EHR on clinical workflow that drives caregivers to work in silos, ie, alone at their workstations, thereby discouraging spontaneous interaction. To the extent that increasing evidence supports the importance of interaction among clinical colleagues and of teamwork to optimize clinical outcomes, electronic siloing threatens optimal practice and quality.

See related editorial

Mindfulness that the EHR can foster siloing will help mitigate the risk, as can novel solutions such as using “viewbox watering holes”¹ and embedding secure social messaging functions within the EHR, thereby allowing clinicians to reach out to colleagues with clinical challenges in the moment.

THE EHR BRINGS CHANGES, GOOD AND BAD

The EHR represents a major change in health care, with reported benefits that include standardized ordering, reduced medical errors, embedded protocols for guideline-based care, data access to analyze clinical practice patterns and outcomes, and enhanced communication among colleagues who are geographically separated (eg, virtual consults²). On the basis of these benefits and the federal Medicare and Medicaid financial incentives associated with “meaningful use,” the EHR is being increasingly adopted.^3–5

Yet for all these benefits and the promise that technology can enhance interaction among health care providers, unintended risks of the EHR paradoxically threaten optimal clinical care.⁶ Recognized risks include the threat to care should the EHR fail,⁶ the time and inefficiency costs of typing and multiple log-ons, and the perpetuation of errors in the medical record caused by the cutting and pasting of clinical notes.

Indeed, a substantial body of literature on sociotechnical interactions—how technology affects human patterns of practice—informs analyses of the impact of changing from a paper medical chart to an EHR.^6,8–12 For example, in a review of the impact of computerized physician order entry on inpatient clinical workflow, Niazkhani et al¹¹ noted that computerized ordering can change communication channels and collaboration mechanisms. More specifically, they point out that these systems can “replace interpersonal contacts that may result in fewer opportunities for team-wide negotiations.”¹¹

Similarly, Ash et al⁸ cited the unintended consequences of patient care information systems, especially increased overreliance on the system to communicate, which can undermine direct communication between healthcare providers.

Finally, Dykstra¹⁰ described the “reciprocal impact” of computerized physician order entry systems on communication between physicians and nurses. One observer stated, “[You] start doing physician order entry and direct entry of notes and you move that away from the ward into a room and now you eliminate the sense of team, and the kind of human communication that really was essential… You create physician separation.”¹⁰ Taken together, these observations suggest that the EHR and computerized order entry in particular can disrupt interaction between physicians and other health care providers, such as nurses and pharmacists.

BENEFITS OF TEAMWORK

A growing body of evidence indicates that teamwork and collaboration among health care providers—which involve frequent, critical face-to-face interaction—has clinical benefit. Demonstrated benefits of teamwork in health care¹¹ include lower surgical and intensive care unit mortality rates, fewer errors in emergency room management, better neonatal resuscitation, and enhanced diagnostic accuracy in interpreting images and biopsies.^12,13

As a specific example of the benefits of face-to-face conversation for interpreting chest images, O’Donovan et al¹⁴ showed that the diagnostic accuracy of a pulmonologist and thoracic radiologist in assessing rounded atelectasis was better when they reviewed chest CT scans together than when they interpreted the images solo.

Similarly, Flaherty et al¹⁵ showed that the level of agreement among pulmonologists, chest radiologists, and lung pathologists progressively increased as interaction and conversation increased when assessing the etiology of patients’ interstitial lung diseases.

As yet another demonstrable benefit of teamwork that should command interest in the current reimbursement-attentive era, analyses by Press Ganey¹⁶ and by Gallup have shown that the single best correlate of high patient satisfaction scores regarding hospitalization (including Hospital Consumer Assessment of Healthcare Providers and Systems ratings) is patients’ perception that their caregivers functioned as a team serving their needs.

The current perspective extends this observation about the unintended adverse effects of the EHR by suggesting that the EHR can inadvertently lessen spontaneous interaction between physicians as they care for outpatients. I have proposed the term electronic siloing to reflect the isolating impact of the EHR on clinical workflow that drives caregivers to work alone at their workstations, thereby discouraging spontaneous interaction between colleagues (eg, between primary care physicians and subspecialists, and between subspecialists in different disciplines). Because spontaneous face-to-face encounters and conversations among clinicians can encourage clinical insights that benefit patient care, electronic siloing can undermine optimal care. My thesis here is that the EHR predisposes to electronic siloing and that the solution is to first recognize and then to design care to prevent this effect.

DECLINE OF THE ‘CURBSIDE’ CONSULT

How does the subtle but sinister effect of electronic siloing really manifest itself at the bedside? I’ll offer an example from my personal clinical experience and then review similar examples from other clinical settings.

First, consider the following real change in clinical workflow that was caused by implementing the EHR in a pulmonary outpatient clinic and its impact on clinical hallway discussions among pulmonologists caring for their outpatients (Figure 1).

The pre-EHR scene was a straight corridor of examination rooms with a long desk outside the rooms and a bank of x-ray viewboxes where clinicians would review films, gather their thoughts, and write notes before re-entering the patient’s room to discuss recommendations. This scene was undoubtedly common in outpatient clinics of all types around the world.

In the bygone era of paper charting and printed x-ray films, the pulmonologists seeing their patients in examination rooms along this corridor and seated next to one another while they wrote their notes would frequently turn to a colleague seated next to them and request a “curbside” consult, ie, an opinion on the films and the case. Typically, a brief, spontaneous conversation would follow, either confirming the requester’s impressions or raising some new, unconsidered approaches. The effect of these brief, spontaneous conversations was either a new diagnostic or treatment consideration or enhanced clinician confidence in the current plan of care. Each outcome has great merit.

Now consider the same scenario in the EHR era. Printed films and viewboxes are gone (which has the benefits of lower production cost and better film retrieval), and images are now reviewed digitally on computer workstations. Workstations are characteristically spread out along the corridor at distances or may be mounted on mobile platforms. Often, physicians now retreat to their nearby offices to write notes, allowing easier access to workstations or to use voice transcription software to record notes. The net effect of this physical separation and of the subtle but powerful change in workflow is that spontaneous curbside consults over a chest film are less likely to occur and, to the extent that such interactions enhance diagnostic accuracy, beneficial face-to-face clinical discussions are less likely. This is the risk of electronic siloing realized.

Defenders of the EHR will point out that the EHR does not preclude such face-to-face encounters. While technically this is correct, it is also equally true that such encounters are less likely because they no longer flow naturally from the workflow of writing a note side-by-side with colleagues with the films displayed nearby. Pressured for time, clinicians learn efficiency of motion and are simply less likely to leave their workstations to seek another colleague who, in turn, may be tethered to a workstation and absorbed in keyboarding and monitor-watching. The net effect is that such spontaneous face-to-face encounters are clearly less common in the EHR era.

Electronic siloing undoubtedly occurs in many other outpatient and inpatient settings in other specialties. For example, consults between orthopedic surgeons seeing outpatients must be similarly affected, as might be discussions between pathologists reviewing tissue slides on a multiheaded microscope vs individually at their own microscopes or work stations. Indeed, observations that computerized order entry isolates physicians from nurses and that the EHR undermines communication between inpatient health care providers^6,8–11 represent other manifestations of electronic siloing.

Another variant of siloing occurs when there are not enough computers to go around. When clinicians seek but cannot find available workstations on the hospital ward, they move from the ward to their offices or other locations, separating them from the nurses and other physicians caring for those patients and, thereby, creating isolation and another form of siloing. A related theme is the importance of architecture in driving desirable interactions in the workplace in general and in hospitals in particular,^17,18 where interchanges between health care providers are critical to enhancing quality of care.

OUT OF THE SILO, INTO THE FIELD

So, given the many clear benefits of the EHR and its current wave of adoption in health care, how can we maximize the benefits of the EHR while minimizing the adverse effects of electronic siloing?

The key point is that we must realize, appreciate, and prioritize the value of face-toface interaction among providers as we try to offer optimal care to patients with ever more complex clinical problems.

In doing so, clinical workspaces and the number and placement of workstations must be designed with an explicit intent and priority to encourage interchange between providers and to avoid electronic siloing. As an example related to reviewing images, imaging suites and clinics should be designed with the concept of a viewbox watering hole¹ in which clinicians arrayed in a common space could review images on their individual computers but could easily prompt colleagues and send an image to a large, centrally visible monitor for the group’s review and comment. Furthermore, the EHR workflows themselves should drive caregivers to the patient rather than requiring their attention to the keyboard and the monitor. One could also imagine embedding secure social messaging within the EHR to encourage interactions among clinicians about pressing clinical challenges they are facing in the moment.

Overall, only through mindfulness of electronic siloing and of its subtle but adverse effects will we break out of the silos and emerge onto the fields of optimal health care.

For all the purported benefits of the electronic health record (EHR), an unintended adverse effect is “electronic siloing.”

I define electronic siloing as the isolating effect of the EHR on clinical workflow that drives caregivers to work in silos, ie, alone at their workstations, thereby discouraging spontaneous interaction. To the extent that increasing evidence supports the importance of interaction among clinical colleagues and of teamwork to optimize clinical outcomes, electronic siloing threatens optimal practice and quality.

See related editorial

Mindfulness that the EHR can foster siloing will help mitigate the risk, as can novel solutions such as using “viewbox watering holes”¹ and embedding secure social messaging functions within the EHR, thereby allowing clinicians to reach out to colleagues with clinical challenges in the moment.

THE EHR BRINGS CHANGES, GOOD AND BAD

The EHR represents a major change in health care, with reported benefits that include standardized ordering, reduced medical errors, embedded protocols for guideline-based care, data access to analyze clinical practice patterns and outcomes, and enhanced communication among colleagues who are geographically separated (eg, virtual consults²). On the basis of these benefits and the federal Medicare and Medicaid financial incentives associated with “meaningful use,” the EHR is being increasingly adopted.^3–5

Yet for all these benefits and the promise that technology can enhance interaction among health care providers, unintended risks of the EHR paradoxically threaten optimal clinical care.⁶ Recognized risks include the threat to care should the EHR fail,⁶ the time and inefficiency costs of typing and multiple log-ons, and the perpetuation of errors in the medical record caused by the cutting and pasting of clinical notes.

Indeed, a substantial body of literature on sociotechnical interactions—how technology affects human patterns of practice—informs analyses of the impact of changing from a paper medical chart to an EHR.^6,8–12 For example, in a review of the impact of computerized physician order entry on inpatient clinical workflow, Niazkhani et al¹¹ noted that computerized ordering can change communication channels and collaboration mechanisms. More specifically, they point out that these systems can “replace interpersonal contacts that may result in fewer opportunities for team-wide negotiations.”¹¹

Similarly, Ash et al⁸ cited the unintended consequences of patient care information systems, especially increased overreliance on the system to communicate, which can undermine direct communication between healthcare providers.

Finally, Dykstra¹⁰ described the “reciprocal impact” of computerized physician order entry systems on communication between physicians and nurses. One observer stated, “[You] start doing physician order entry and direct entry of notes and you move that away from the ward into a room and now you eliminate the sense of team, and the kind of human communication that really was essential… You create physician separation.”¹⁰ Taken together, these observations suggest that the EHR and computerized order entry in particular can disrupt interaction between physicians and other health care providers, such as nurses and pharmacists.

BENEFITS OF TEAMWORK

A growing body of evidence indicates that teamwork and collaboration among health care providers—which involve frequent, critical face-to-face interaction—has clinical benefit. Demonstrated benefits of teamwork in health care¹¹ include lower surgical and intensive care unit mortality rates, fewer errors in emergency room management, better neonatal resuscitation, and enhanced diagnostic accuracy in interpreting images and biopsies.^12,13

As a specific example of the benefits of face-to-face conversation for interpreting chest images, O’Donovan et al¹⁴ showed that the diagnostic accuracy of a pulmonologist and thoracic radiologist in assessing rounded atelectasis was better when they reviewed chest CT scans together than when they interpreted the images solo.

Similarly, Flaherty et al¹⁵ showed that the level of agreement among pulmonologists, chest radiologists, and lung pathologists progressively increased as interaction and conversation increased when assessing the etiology of patients’ interstitial lung diseases.

As yet another demonstrable benefit of teamwork that should command interest in the current reimbursement-attentive era, analyses by Press Ganey¹⁶ and by Gallup have shown that the single best correlate of high patient satisfaction scores regarding hospitalization (including Hospital Consumer Assessment of Healthcare Providers and Systems ratings) is patients’ perception that their caregivers functioned as a team serving their needs.

The current perspective extends this observation about the unintended adverse effects of the EHR by suggesting that the EHR can inadvertently lessen spontaneous interaction between physicians as they care for outpatients. I have proposed the term electronic siloing to reflect the isolating impact of the EHR on clinical workflow that drives caregivers to work alone at their workstations, thereby discouraging spontaneous interaction between colleagues (eg, between primary care physicians and subspecialists, and between subspecialists in different disciplines). Because spontaneous face-to-face encounters and conversations among clinicians can encourage clinical insights that benefit patient care, electronic siloing can undermine optimal care. My thesis here is that the EHR predisposes to electronic siloing and that the solution is to first recognize and then to design care to prevent this effect.

DECLINE OF THE ‘CURBSIDE’ CONSULT

How does the subtle but sinister effect of electronic siloing really manifest itself at the bedside? I’ll offer an example from my personal clinical experience and then review similar examples from other clinical settings.

First, consider the following real change in clinical workflow that was caused by implementing the EHR in a pulmonary outpatient clinic and its impact on clinical hallway discussions among pulmonologists caring for their outpatients (Figure 1).

The pre-EHR scene was a straight corridor of examination rooms with a long desk outside the rooms and a bank of x-ray viewboxes where clinicians would review films, gather their thoughts, and write notes before re-entering the patient’s room to discuss recommendations. This scene was undoubtedly common in outpatient clinics of all types around the world.

In the bygone era of paper charting and printed x-ray films, the pulmonologists seeing their patients in examination rooms along this corridor and seated next to one another while they wrote their notes would frequently turn to a colleague seated next to them and request a “curbside” consult, ie, an opinion on the films and the case. Typically, a brief, spontaneous conversation would follow, either confirming the requester’s impressions or raising some new, unconsidered approaches. The effect of these brief, spontaneous conversations was either a new diagnostic or treatment consideration or enhanced clinician confidence in the current plan of care. Each outcome has great merit.

Now consider the same scenario in the EHR era. Printed films and viewboxes are gone (which has the benefits of lower production cost and better film retrieval), and images are now reviewed digitally on computer workstations. Workstations are characteristically spread out along the corridor at distances or may be mounted on mobile platforms. Often, physicians now retreat to their nearby offices to write notes, allowing easier access to workstations or to use voice transcription software to record notes. The net effect of this physical separation and of the subtle but powerful change in workflow is that spontaneous curbside consults over a chest film are less likely to occur and, to the extent that such interactions enhance diagnostic accuracy, beneficial face-to-face clinical discussions are less likely. This is the risk of electronic siloing realized.

Defenders of the EHR will point out that the EHR does not preclude such face-to-face encounters. While technically this is correct, it is also equally true that such encounters are less likely because they no longer flow naturally from the workflow of writing a note side-by-side with colleagues with the films displayed nearby. Pressured for time, clinicians learn efficiency of motion and are simply less likely to leave their workstations to seek another colleague who, in turn, may be tethered to a workstation and absorbed in keyboarding and monitor-watching. The net effect is that such spontaneous face-to-face encounters are clearly less common in the EHR era.

Electronic siloing undoubtedly occurs in many other outpatient and inpatient settings in other specialties. For example, consults between orthopedic surgeons seeing outpatients must be similarly affected, as might be discussions between pathologists reviewing tissue slides on a multiheaded microscope vs individually at their own microscopes or work stations. Indeed, observations that computerized order entry isolates physicians from nurses and that the EHR undermines communication between inpatient health care providers^6,8–11 represent other manifestations of electronic siloing.

Another variant of siloing occurs when there are not enough computers to go around. When clinicians seek but cannot find available workstations on the hospital ward, they move from the ward to their offices or other locations, separating them from the nurses and other physicians caring for those patients and, thereby, creating isolation and another form of siloing. A related theme is the importance of architecture in driving desirable interactions in the workplace in general and in hospitals in particular,^17,18 where interchanges between health care providers are critical to enhancing quality of care.

OUT OF THE SILO, INTO THE FIELD

So, given the many clear benefits of the EHR and its current wave of adoption in health care, how can we maximize the benefits of the EHR while minimizing the adverse effects of electronic siloing?

The key point is that we must realize, appreciate, and prioritize the value of face-toface interaction among providers as we try to offer optimal care to patients with ever more complex clinical problems.

In doing so, clinical workspaces and the number and placement of workstations must be designed with an explicit intent and priority to encourage interchange between providers and to avoid electronic siloing. As an example related to reviewing images, imaging suites and clinics should be designed with the concept of a viewbox watering hole¹ in which clinicians arrayed in a common space could review images on their individual computers but could easily prompt colleagues and send an image to a large, centrally visible monitor for the group’s review and comment. Furthermore, the EHR workflows themselves should drive caregivers to the patient rather than requiring their attention to the keyboard and the monitor. One could also imagine embedding secure social messaging within the EHR to encourage interactions among clinicians about pressing clinical challenges they are facing in the moment.

Overall, only through mindfulness of electronic siloing and of its subtle but adverse effects will we break out of the silos and emerge onto the fields of optimal health care.

For all the purported benefits of the electronic health record (EHR), an unintended adverse effect is “electronic siloing.”

I define electronic siloing as the isolating effect of the EHR on clinical workflow that drives caregivers to work in silos, ie, alone at their workstations, thereby discouraging spontaneous interaction. To the extent that increasing evidence supports the importance of interaction among clinical colleagues and of teamwork to optimize clinical outcomes, electronic siloing threatens optimal practice and quality.

See related editorial

Mindfulness that the EHR can foster siloing will help mitigate the risk, as can novel solutions such as using “viewbox watering holes”¹ and embedding secure social messaging functions within the EHR, thereby allowing clinicians to reach out to colleagues with clinical challenges in the moment.

THE EHR BRINGS CHANGES, GOOD AND BAD

The EHR represents a major change in health care, with reported benefits that include standardized ordering, reduced medical errors, embedded protocols for guideline-based care, data access to analyze clinical practice patterns and outcomes, and enhanced communication among colleagues who are geographically separated (eg, virtual consults²). On the basis of these benefits and the federal Medicare and Medicaid financial incentives associated with “meaningful use,” the EHR is being increasingly adopted.^3–5

Yet for all these benefits and the promise that technology can enhance interaction among health care providers, unintended risks of the EHR paradoxically threaten optimal clinical care.⁶ Recognized risks include the threat to care should the EHR fail,⁶ the time and inefficiency costs of typing and multiple log-ons, and the perpetuation of errors in the medical record caused by the cutting and pasting of clinical notes.

Indeed, a substantial body of literature on sociotechnical interactions—how technology affects human patterns of practice—informs analyses of the impact of changing from a paper medical chart to an EHR.^6,8–12 For example, in a review of the impact of computerized physician order entry on inpatient clinical workflow, Niazkhani et al¹¹ noted that computerized ordering can change communication channels and collaboration mechanisms. More specifically, they point out that these systems can “replace interpersonal contacts that may result in fewer opportunities for team-wide negotiations.”¹¹

Similarly, Ash et al⁸ cited the unintended consequences of patient care information systems, especially increased overreliance on the system to communicate, which can undermine direct communication between healthcare providers.

Finally, Dykstra¹⁰ described the “reciprocal impact” of computerized physician order entry systems on communication between physicians and nurses. One observer stated, “[You] start doing physician order entry and direct entry of notes and you move that away from the ward into a room and now you eliminate the sense of team, and the kind of human communication that really was essential… You create physician separation.”¹⁰ Taken together, these observations suggest that the EHR and computerized order entry in particular can disrupt interaction between physicians and other health care providers, such as nurses and pharmacists.

BENEFITS OF TEAMWORK

A growing body of evidence indicates that teamwork and collaboration among health care providers—which involve frequent, critical face-to-face interaction—has clinical benefit. Demonstrated benefits of teamwork in health care¹¹ include lower surgical and intensive care unit mortality rates, fewer errors in emergency room management, better neonatal resuscitation, and enhanced diagnostic accuracy in interpreting images and biopsies.^12,13

As a specific example of the benefits of face-to-face conversation for interpreting chest images, O’Donovan et al¹⁴ showed that the diagnostic accuracy of a pulmonologist and thoracic radiologist in assessing rounded atelectasis was better when they reviewed chest CT scans together than when they interpreted the images solo.

Similarly, Flaherty et al¹⁵ showed that the level of agreement among pulmonologists, chest radiologists, and lung pathologists progressively increased as interaction and conversation increased when assessing the etiology of patients’ interstitial lung diseases.

As yet another demonstrable benefit of teamwork that should command interest in the current reimbursement-attentive era, analyses by Press Ganey¹⁶ and by Gallup have shown that the single best correlate of high patient satisfaction scores regarding hospitalization (including Hospital Consumer Assessment of Healthcare Providers and Systems ratings) is patients’ perception that their caregivers functioned as a team serving their needs.

The current perspective extends this observation about the unintended adverse effects of the EHR by suggesting that the EHR can inadvertently lessen spontaneous interaction between physicians as they care for outpatients. I have proposed the term electronic siloing to reflect the isolating impact of the EHR on clinical workflow that drives caregivers to work alone at their workstations, thereby discouraging spontaneous interaction between colleagues (eg, between primary care physicians and subspecialists, and between subspecialists in different disciplines). Because spontaneous face-to-face encounters and conversations among clinicians can encourage clinical insights that benefit patient care, electronic siloing can undermine optimal care. My thesis here is that the EHR predisposes to electronic siloing and that the solution is to first recognize and then to design care to prevent this effect.

DECLINE OF THE ‘CURBSIDE’ CONSULT

How does the subtle but sinister effect of electronic siloing really manifest itself at the bedside? I’ll offer an example from my personal clinical experience and then review similar examples from other clinical settings.

First, consider the following real change in clinical workflow that was caused by implementing the EHR in a pulmonary outpatient clinic and its impact on clinical hallway discussions among pulmonologists caring for their outpatients (Figure 1).

The pre-EHR scene was a straight corridor of examination rooms with a long desk outside the rooms and a bank of x-ray viewboxes where clinicians would review films, gather their thoughts, and write notes before re-entering the patient’s room to discuss recommendations. This scene was undoubtedly common in outpatient clinics of all types around the world.

In the bygone era of paper charting and printed x-ray films, the pulmonologists seeing their patients in examination rooms along this corridor and seated next to one another while they wrote their notes would frequently turn to a colleague seated next to them and request a “curbside” consult, ie, an opinion on the films and the case. Typically, a brief, spontaneous conversation would follow, either confirming the requester’s impressions or raising some new, unconsidered approaches. The effect of these brief, spontaneous conversations was either a new diagnostic or treatment consideration or enhanced clinician confidence in the current plan of care. Each outcome has great merit.

Now consider the same scenario in the EHR era. Printed films and viewboxes are gone (which has the benefits of lower production cost and better film retrieval), and images are now reviewed digitally on computer workstations. Workstations are characteristically spread out along the corridor at distances or may be mounted on mobile platforms. Often, physicians now retreat to their nearby offices to write notes, allowing easier access to workstations or to use voice transcription software to record notes. The net effect of this physical separation and of the subtle but powerful change in workflow is that spontaneous curbside consults over a chest film are less likely to occur and, to the extent that such interactions enhance diagnostic accuracy, beneficial face-to-face clinical discussions are less likely. This is the risk of electronic siloing realized.

Defenders of the EHR will point out that the EHR does not preclude such face-to-face encounters. While technically this is correct, it is also equally true that such encounters are less likely because they no longer flow naturally from the workflow of writing a note side-by-side with colleagues with the films displayed nearby. Pressured for time, clinicians learn efficiency of motion and are simply less likely to leave their workstations to seek another colleague who, in turn, may be tethered to a workstation and absorbed in keyboarding and monitor-watching. The net effect is that such spontaneous face-to-face encounters are clearly less common in the EHR era.

Electronic siloing undoubtedly occurs in many other outpatient and inpatient settings in other specialties. For example, consults between orthopedic surgeons seeing outpatients must be similarly affected, as might be discussions between pathologists reviewing tissue slides on a multiheaded microscope vs individually at their own microscopes or work stations. Indeed, observations that computerized order entry isolates physicians from nurses and that the EHR undermines communication between inpatient health care providers^6,8–11 represent other manifestations of electronic siloing.

Another variant of siloing occurs when there are not enough computers to go around. When clinicians seek but cannot find available workstations on the hospital ward, they move from the ward to their offices or other locations, separating them from the nurses and other physicians caring for those patients and, thereby, creating isolation and another form of siloing. A related theme is the importance of architecture in driving desirable interactions in the workplace in general and in hospitals in particular,^17,18 where interchanges between health care providers are critical to enhancing quality of care.

OUT OF THE SILO, INTO THE FIELD

So, given the many clear benefits of the EHR and its current wave of adoption in health care, how can we maximize the benefits of the EHR while minimizing the adverse effects of electronic siloing?

The key point is that we must realize, appreciate, and prioritize the value of face-toface interaction among providers as we try to offer optimal care to patients with ever more complex clinical problems.

In doing so, clinical workspaces and the number and placement of workstations must be designed with an explicit intent and priority to encourage interchange between providers and to avoid electronic siloing. As an example related to reviewing images, imaging suites and clinics should be designed with the concept of a viewbox watering hole¹ in which clinicians arrayed in a common space could review images on their individual computers but could easily prompt colleagues and send an image to a large, centrally visible monitor for the group’s review and comment. Furthermore, the EHR workflows themselves should drive caregivers to the patient rather than requiring their attention to the keyboard and the monitor. One could also imagine embedding secure social messaging within the EHR to encourage interactions among clinicians about pressing clinical challenges they are facing in the moment.

Overall, only through mindfulness of electronic siloing and of its subtle but adverse effects will we break out of the silos and emerge onto the fields of optimal health care.

The promise of the electronic health record (EHR) has not yet been realized. I find it extremely beneficial to have access to shared, accurate information during each patient encounter, but my expectations are still far ahead of reality. We should demand more-flexible software with more clinician-tailored utilities—more bang for the click. However, we users also need to improve.

Benefits and challenges of computers in the examination room

With the EHR, the monitor and keyboard have been interposed between the physician and patient. Physicians now must type or dictate their office notes, enter electronic orders and prescriptions, and remember to use specific phrases to fulfill compliance regulations. Many physicians have to see more patients in less time while incorporating the EHR into each visit. Under these new pressures, some have chosen to retire early or to drastically change the scope of their practice.

I too experience these challenges. I have more electronic tasks to do during each visit and wonder if this is really the best use of my time. I run even further behind than I used to, and I almost uniformly have to apologize to my patients for being late. I am not the world’s best typist. Patients note my clerical challenges, and some of them offer to type in their information for me—a bonding experience I could do without.

Lest the computer become the primary object of my attention, I push back from the keyboard intermittently, with my hands in my lap, or make physical contact with my (human) patient. I try to make eye contact as we converse, and patients leave with a legible—albeit possibly misspelled—summary. During visits, I can share graphs of my patient’s lab tests or vital signs over time, and I hope that more sophisticated EHRs will correlate this information with medication changes and other events. I have less work to do at the end of the day than I used to, since during my clinic time, multitasking as I go, I send prescriptions to pharmacies, review test results, and send letters to my patients and their referring physicians about their test results and my suggestions. I encourage patients to e-mail me directly with their questions or problems as they arise—an opportunity that many have used and none have abused. Technology is not all bad.

How the EHR needs to improve

The EHR is still evolving, and it needs to be better honed to the needs of the user. My EHR still does not give me reminders for routine screening and monitoring. It is not yet tailored to the specific problems shared by many of my patients. It does not yet provide snapshots or specifics about tailored measures of quality of my practice.

As nicely summarized by Dr. William Morris in this issue, we need to get the EHR to work for us, not mainly for those responsible for billing and regulatory compliance. But all groups can be served equally; “alerts” can be activated as screen pop-ups to drive physician behavior towards best practice—with the caveat that alerts must be meaningful, triggered intelligently, and individualized to avoid pop-up fatigue.

In addition, as Dr. James Stoller discusses in this issue, the solitary work involved in using the EHR has also affected the natural collegial interchange that took place around the chart rack in the past. He, Dr. Morris, and I agree that direct physician-physician communication has diminished in our medical centers. But I believe that this is the result of many pressures, not simply the renewed emphasis¹ on the physician’s role as scribe and more-cloistered physician keyboarding. We all extol the value of the phone call and face-to-face conversation between consultants and primary care providers, and at times this is necessary to reach decisions of care. But physicians are more strapped for time than ever. In this era of the “flash mob” and instant texting and tweeting, we should be able to promote effective digital dialogue between physicians. We should embrace and facilitate digital communication.

How physicians need to improve

I see many copy-and-paste reiterations of semi-irrelevant (and I suspect, usually not independently confirmed) details of social history and physical examinations from visits gone by. I read completed templates with information that clearly was not collected at the time of the encounter. The potential for misuse and misrepresentation (even without any malevolent intent) with the use of templates and copy-and-paste functions is apparent. These bad practices must stop.

Another problem: some of my colleagues do not read their messages regarding forwarded charts or patient questions within our EHR—“It is just too many e-mails to check.” This reluctance to fully connect in cyberspace is perhaps a case of failing to teach old dogs new tricks, and we do have too much e-mail. But I think it is also partly a result of paranoia over maintaining confidentiality of patient-related communication, at the expense of the efficiency of digital communication. The forwarding of EHR messages to our office e-mail system and phones is blocked by a firewall to ensure privacy—but this makes necessary medical communication more difficult. Is this the right trade-off? If the EHR is to become the hub for tracking patient-centered care, we need to use it to our advantage and to ease access to all aspects of the EHR from multiple venues.

Even when read, our notes leave much to be desired. Beyond the problem with copying and pasting of earlier notes, paragraphs of unfiltered, often irrelevant or untimely lab and imaging reports are repeatedly inserted into multiple notes, while a clearly expressed impression and plan are often nowhere to be found. Some of my colleagues dictate their notes with a delay before uploading, without any concise placeholder summary in the EHR, or they have an assistant or trainee enter a summary, without the nuanced explanation that I need to fully understand the consultant’s reasoning. These behaviors negate the potential power of the EHR.

Bemoaning the new technology and developing work-arounds is not the answer. We need to refine the clinician-computer interface,² and we need to do much better with our documentation.

The basic principles of physician communication are as important now as they were 50 years ago, when notes were illegibly written with pen and paper and discussed by docs seated around the chart rack in the nursing station. We need to take ownership of the EHR and to insist with other stakeholders that all aspects work better for us and for our patients. This includes the software and, maybe more important, the user.

The promise of the electronic health record (EHR) has not yet been realized. I find it extremely beneficial to have access to shared, accurate information during each patient encounter, but my expectations are still far ahead of reality. We should demand more-flexible software with more clinician-tailored utilities—more bang for the click. However, we users also need to improve.

Benefits and challenges of computers in the examination room

With the EHR, the monitor and keyboard have been interposed between the physician and patient. Physicians now must type or dictate their office notes, enter electronic orders and prescriptions, and remember to use specific phrases to fulfill compliance regulations. Many physicians have to see more patients in less time while incorporating the EHR into each visit. Under these new pressures, some have chosen to retire early or to drastically change the scope of their practice.

I too experience these challenges. I have more electronic tasks to do during each visit and wonder if this is really the best use of my time. I run even further behind than I used to, and I almost uniformly have to apologize to my patients for being late. I am not the world’s best typist. Patients note my clerical challenges, and some of them offer to type in their information for me—a bonding experience I could do without.

Lest the computer become the primary object of my attention, I push back from the keyboard intermittently, with my hands in my lap, or make physical contact with my (human) patient. I try to make eye contact as we converse, and patients leave with a legible—albeit possibly misspelled—summary. During visits, I can share graphs of my patient’s lab tests or vital signs over time, and I hope that more sophisticated EHRs will correlate this information with medication changes and other events. I have less work to do at the end of the day than I used to, since during my clinic time, multitasking as I go, I send prescriptions to pharmacies, review test results, and send letters to my patients and their referring physicians about their test results and my suggestions. I encourage patients to e-mail me directly with their questions or problems as they arise—an opportunity that many have used and none have abused. Technology is not all bad.

How the EHR needs to improve

The EHR is still evolving, and it needs to be better honed to the needs of the user. My EHR still does not give me reminders for routine screening and monitoring. It is not yet tailored to the specific problems shared by many of my patients. It does not yet provide snapshots or specifics about tailored measures of quality of my practice.

As nicely summarized by Dr. William Morris in this issue, we need to get the EHR to work for us, not mainly for those responsible for billing and regulatory compliance. But all groups can be served equally; “alerts” can be activated as screen pop-ups to drive physician behavior towards best practice—with the caveat that alerts must be meaningful, triggered intelligently, and individualized to avoid pop-up fatigue.

In addition, as Dr. James Stoller discusses in this issue, the solitary work involved in using the EHR has also affected the natural collegial interchange that took place around the chart rack in the past. He, Dr. Morris, and I agree that direct physician-physician communication has diminished in our medical centers. But I believe that this is the result of many pressures, not simply the renewed emphasis¹ on the physician’s role as scribe and more-cloistered physician keyboarding. We all extol the value of the phone call and face-to-face conversation between consultants and primary care providers, and at times this is necessary to reach decisions of care. But physicians are more strapped for time than ever. In this era of the “flash mob” and instant texting and tweeting, we should be able to promote effective digital dialogue between physicians. We should embrace and facilitate digital communication.

How physicians need to improve

I see many copy-and-paste reiterations of semi-irrelevant (and I suspect, usually not independently confirmed) details of social history and physical examinations from visits gone by. I read completed templates with information that clearly was not collected at the time of the encounter. The potential for misuse and misrepresentation (even without any malevolent intent) with the use of templates and copy-and-paste functions is apparent. These bad practices must stop.

Another problem: some of my colleagues do not read their messages regarding forwarded charts or patient questions within our EHR—“It is just too many e-mails to check.” This reluctance to fully connect in cyberspace is perhaps a case of failing to teach old dogs new tricks, and we do have too much e-mail. But I think it is also partly a result of paranoia over maintaining confidentiality of patient-related communication, at the expense of the efficiency of digital communication. The forwarding of EHR messages to our office e-mail system and phones is blocked by a firewall to ensure privacy—but this makes necessary medical communication more difficult. Is this the right trade-off? If the EHR is to become the hub for tracking patient-centered care, we need to use it to our advantage and to ease access to all aspects of the EHR from multiple venues.

Even when read, our notes leave much to be desired. Beyond the problem with copying and pasting of earlier notes, paragraphs of unfiltered, often irrelevant or untimely lab and imaging reports are repeatedly inserted into multiple notes, while a clearly expressed impression and plan are often nowhere to be found. Some of my colleagues dictate their notes with a delay before uploading, without any concise placeholder summary in the EHR, or they have an assistant or trainee enter a summary, without the nuanced explanation that I need to fully understand the consultant’s reasoning. These behaviors negate the potential power of the EHR.

Bemoaning the new technology and developing work-arounds is not the answer. We need to refine the clinician-computer interface,² and we need to do much better with our documentation.

The basic principles of physician communication are as important now as they were 50 years ago, when notes were illegibly written with pen and paper and discussed by docs seated around the chart rack in the nursing station. We need to take ownership of the EHR and to insist with other stakeholders that all aspects work better for us and for our patients. This includes the software and, maybe more important, the user.

The promise of the electronic health record (EHR) has not yet been realized. I find it extremely beneficial to have access to shared, accurate information during each patient encounter, but my expectations are still far ahead of reality. We should demand more-flexible software with more clinician-tailored utilities—more bang for the click. However, we users also need to improve.

Benefits and challenges of computers in the examination room

With the EHR, the monitor and keyboard have been interposed between the physician and patient. Physicians now must type or dictate their office notes, enter electronic orders and prescriptions, and remember to use specific phrases to fulfill compliance regulations. Many physicians have to see more patients in less time while incorporating the EHR into each visit. Under these new pressures, some have chosen to retire early or to drastically change the scope of their practice.

I too experience these challenges. I have more electronic tasks to do during each visit and wonder if this is really the best use of my time. I run even further behind than I used to, and I almost uniformly have to apologize to my patients for being late. I am not the world’s best typist. Patients note my clerical challenges, and some of them offer to type in their information for me—a bonding experience I could do without.

Lest the computer become the primary object of my attention, I push back from the keyboard intermittently, with my hands in my lap, or make physical contact with my (human) patient. I try to make eye contact as we converse, and patients leave with a legible—albeit possibly misspelled—summary. During visits, I can share graphs of my patient’s lab tests or vital signs over time, and I hope that more sophisticated EHRs will correlate this information with medication changes and other events. I have less work to do at the end of the day than I used to, since during my clinic time, multitasking as I go, I send prescriptions to pharmacies, review test results, and send letters to my patients and their referring physicians about their test results and my suggestions. I encourage patients to e-mail me directly with their questions or problems as they arise—an opportunity that many have used and none have abused. Technology is not all bad.

How the EHR needs to improve

The EHR is still evolving, and it needs to be better honed to the needs of the user. My EHR still does not give me reminders for routine screening and monitoring. It is not yet tailored to the specific problems shared by many of my patients. It does not yet provide snapshots or specifics about tailored measures of quality of my practice.

As nicely summarized by Dr. William Morris in this issue, we need to get the EHR to work for us, not mainly for those responsible for billing and regulatory compliance. But all groups can be served equally; “alerts” can be activated as screen pop-ups to drive physician behavior towards best practice—with the caveat that alerts must be meaningful, triggered intelligently, and individualized to avoid pop-up fatigue.

In addition, as Dr. James Stoller discusses in this issue, the solitary work involved in using the EHR has also affected the natural collegial interchange that took place around the chart rack in the past. He, Dr. Morris, and I agree that direct physician-physician communication has diminished in our medical centers. But I believe that this is the result of many pressures, not simply the renewed emphasis¹ on the physician’s role as scribe and more-cloistered physician keyboarding. We all extol the value of the phone call and face-to-face conversation between consultants and primary care providers, and at times this is necessary to reach decisions of care. But physicians are more strapped for time than ever. In this era of the “flash mob” and instant texting and tweeting, we should be able to promote effective digital dialogue between physicians. We should embrace and facilitate digital communication.

How physicians need to improve

I see many copy-and-paste reiterations of semi-irrelevant (and I suspect, usually not independently confirmed) details of social history and physical examinations from visits gone by. I read completed templates with information that clearly was not collected at the time of the encounter. The potential for misuse and misrepresentation (even without any malevolent intent) with the use of templates and copy-and-paste functions is apparent. These bad practices must stop.

Another problem: some of my colleagues do not read their messages regarding forwarded charts or patient questions within our EHR—“It is just too many e-mails to check.” This reluctance to fully connect in cyberspace is perhaps a case of failing to teach old dogs new tricks, and we do have too much e-mail. But I think it is also partly a result of paranoia over maintaining confidentiality of patient-related communication, at the expense of the efficiency of digital communication. The forwarding of EHR messages to our office e-mail system and phones is blocked by a firewall to ensure privacy—but this makes necessary medical communication more difficult. Is this the right trade-off? If the EHR is to become the hub for tracking patient-centered care, we need to use it to our advantage and to ease access to all aspects of the EHR from multiple venues.

Even when read, our notes leave much to be desired. Beyond the problem with copying and pasting of earlier notes, paragraphs of unfiltered, often irrelevant or untimely lab and imaging reports are repeatedly inserted into multiple notes, while a clearly expressed impression and plan are often nowhere to be found. Some of my colleagues dictate their notes with a delay before uploading, without any concise placeholder summary in the EHR, or they have an assistant or trainee enter a summary, without the nuanced explanation that I need to fully understand the consultant’s reasoning. These behaviors negate the potential power of the EHR.

Bemoaning the new technology and developing work-arounds is not the answer. We need to refine the clinician-computer interface,² and we need to do much better with our documentation.

The basic principles of physician communication are as important now as they were 50 years ago, when notes were illegibly written with pen and paper and discussed by docs seated around the chart rack in the nursing station. We need to take ownership of the EHR and to insist with other stakeholders that all aspects work better for us and for our patients. This includes the software and, maybe more important, the user.

Paget disease of bone is a focal disorder of the aging skeleton that can be asymptomatic or can present with pain, bowing deformities, fractures, or nonspecific rheumatic complaints. Physicians often discover it in asymptomatic patients when serum alkaline phosphatase levels are elevated or as an incidental finding on radiography. Despite evidence of germline mutations and polymorphisms that predispose to Paget disease, the environmental determinants that permit disease expression in older people remain unknown.

A STRIKING GEOGRAPHIC DISTRIBUTION

Researchers have been studying the determinants and distribution of Paget disease ever since Sir James Paget first described it in 1877.¹

Paget disease has a predilection for the axial skeleton, particularly the lumbosacral spine and pelvis, as well as the skull, femur, and tibia.² Knowing this, investigators have used screening plain films of the abdomen (kidney-ureter-bladder views) to estimate its prevalence in different populations, as these images capture the lumbosacral spine, pelvis, and proximal femurs. Other means of assessing prevalence have included autopsy series, questionnaires, and screens for biochemical markers of bone turnover, such as elevated serum alkaline phosphatase from bone.^3–6

Using these methods, Paget disease has been estimated to occur in 1% to 3% of people over age 55, and in as many as 8% of people over age 80 in certain countries.⁷

This disease has a striking geographic distribution, being frequent in Europe, Canada, the United States, Australia, New Zealand, and cities of South America, but rare in Scandinavia and Japan. It seems to be equally rare in other countries of the Far East and in India, Russia, and Africa, although its prevalence in these areas has not been thoroughly investigated.⁸

That it is an ancient disease has been corroborated by excavations in churchyards in Great Britain.^9,10 It may be familial or sporadic, but its expression is delayed until late middle age in most persons, and it does not occur in children. For reasons unclear, the prevalence seems to be decreasing in many countries.^11–13

GENETICS IS NOT THE WHOLE STORY

The variable prevalence of Paget disease in different geographic regions and its sometimes-familial expression suggest a genetic predisposition, environmental factor, or both.

Mutations in SQSTM1

In 2002, scientists investigating a cohort of French Canadian families found a mutation in the SQSTM1 gene that was present in almost 50% of people with familial Paget disease and in 16% of those with sporadic Paget disease.¹⁴ Hocking and his colleagues in the United Kingdom subsequently found the same mutation in 19% of cases of familial Paget disease and in 9% of sporadic cases.¹⁵

Further, investigators noted that the mutation was often present on a conserved haplotype, consistent with a stable genetic change occurring in the affected population.¹⁶ This observation of a “founder effect” dovetailed with the epidemiology of Paget disease,¹⁷ but only with this SQSTM1 mutation.

Throughout Europe, Australia, and the United States, comparable rates of the SQSTM1 mutation were reported in or around the ubiquitin-associated domain. Several specific mutations exist, the most common one being P392L, ie, a prolineto-leucine substitution at amino acid 392. Scientists have tried to correlate severity of disease with genotype, but the findings have been inconsistent.^18–21

Investigations into the mechanism of disease have pointed to the role of p62, the product of SQSTM1, in signaling osteoclast activation via nuclear factor kappa B. Since this initial discovery, polymorphisms in the genes affecting osteoclast maturation, activation, and fusion pathways have been shown to predispose to Paget disease. Examples:

• TNFRSF11A, which codes for receptor activator of nuclear factor kappa B, or RANK
• TNFRSF11B, which codes for osteoprotegerin, or OPG
• CSF1, which codes for macrophage colony-stimulating factor 1, and
• OPTN, which codes for optineurin, a member of the nuclear factor kappa B-modulating protein family.

Clinicians interested in these details can read an excellent review of the pathogenesis of Paget disease.²²

Other possible factors

Although there is good evidence that measles and canine distemper virus can infect osteoclasts and modify their phenotype, there is no good evidence that these infections by themselves cause Paget disease.^23–25 It is, however, tempting to think of these RNA paramyxoviruses as precipitating factors; conceivably, an infectious agent might seed the ends of long bones, accounting for the fixed distribution of Paget disease and its late expression.

Epidemiologic studies from around the world have failed to identify conclusively any environmental exposure that predisposes to Paget disease, although a rural setting, trauma, infection, and milk ingestion have all been proposed.^26–28 It is also possible that as bone ages and the marrow becomes less cellular and more fatty, these changes may permit the disease to develop.

The greatest risk factor for Paget disease is perhaps aging, followed by ancestry and a known family history of it. That genetics is not the whole story is evident by reports of people with SQSTM1 mutations who show no clinical evidence of Paget disease in their old age, and patients with Paget disease who have no SQSTM1 mutation.^20,29

CLINICAL PRESENTATION

Most patients with Paget disease have no symptoms and come to medical attention because of an elevated serum alkaline phosphatase level or characteristic findings on radiographs ordered for other indications.¹¹ Paget disease is the second most common disorder of aging bone after osteoporosis. Yet unlike osteoporosis, which presents as a systemic fragility of bone, the clinical manifestations of Paget disease depend on which bones are affected and how enlarged or misshapen they have become.

Common complications

As a consequence of this abnormal bone remodeling and overgrowth, many patients present with bone pain. Bone deformity, headache, and hearing loss may also occur (Figure 1), as well as fractures and nerve compression syndromes (eg, spinal stenosis, sciatica, cauda equina syndrome).

It is important to remember that “pagetic” bone may not be the source of pain, and that functional impairment caused by degenerative changes at affected sites is common (Figure  2).^30,31

In a study from the New England Registry for Paget’s Disease,³² most patients knew fairly well which bones were affected and what complications resulted from this when deformity, fracture, or total joint replacement had occurred.³² Although Paget disease did affect their quality of life as measured by physical functioning on the Short Form-12 assessment, these impairments did not seem to affect their outlook, which was as good as or better than that in other people their age.

Metabolic complications

Metabolic complications of Paget disease are rare today but can occur in an elderly patient who has active, polyostotic (multibone) disease.³³ The accelerated rate of bone remodeling and the increased vascularity of pagetic bone have been reported to lead to high-output heart failure. In theory, treatment should ease this by diminishing blood flow to pagetic bone and restoring bone turnover to more normal levels.³⁴

Hypercalcemia can occur when patients with Paget disease are immobilized for any reason, and there is probably a higher incidence of renal stones in patients with Paget disease.^35,36

Malignant complications

Osteosarcoma rarely arises in pagetic bone. Yet Paget disease may account for a significant number of cases of this cancer in the elderly.³⁷ In these cases, osteosarcoma is presumed to be driven by a second genetic mutation, has a genetic signature distinct from that in osteosarcomas occurring in youth, and is quite resistant to treatment.³⁸ In Scandinavia and Japan, where Paget disease is rare, the second peak of osteosarcoma that occurs with aging seems muted as well.^39,40 These cancers present with pain, soft-tissue swelling, and variable elevations in serum alkaline phosphatase. Investigations to date suggest that pagetic lesions and osteosarcomas arising in pagetic bone are probably both driven to some extent by stromal cells overexpressing RANK ligand and may not represent defects intrinsic to the osteoclast.⁴¹

Giant-cell tumors of bone are also rare but can arise in pagetic bone. A cluster of cases was reported in Avellino and other towns of southern Italy.⁴² Again, the lesions occur in older individuals and in different sites than those seen in the benign giant-cell tumors recorded in patients without Paget disease.

Metastases from lymphomas, prostate cancer, and breast cancer certainly occur in bone, but rarely in pagetic sites.⁴³ A recent case study noted that patients with prostate cancer who also had Paget disease had a later onset of metastasis to bone than patients without coincident Paget disease.⁴⁴

A THOUGHTFUL ASSESSMENT

Evaluating a patient with Paget disease requires a thoughtful assessment of its musculoskeletal consequences in an aging skeleton. Pain in Paget disease is often multifactorial. In the elderly, end-stage degenerative disease of the spine, hip, and knees, mechanical instability, compression fractures of the spine, and neuropathies may compound the clinical picture. Therefore, a thorough evaluation is required to plan effective therapy.

Alkaline phosphatase and other markers

A screening serum alkaline phosphatase level is usually sufficient to measure bone turnover. Produced by osteoblasts, alkaline phosphatase is a marker of bone formation, but an imperfect one. Often it is elevated in active Paget disease—but not always.⁴⁵ Many patients have normal serum alkaline phosphatase levels, particularly if they have monostotic (single-bone) disease. It is unclear why, in a disorder marked by accelerated bone remodeling, the biochemical markers are inconsistent measures of bone turnover.

Research into biochemical markers of Paget disease has had two aims: to identify the single best marker for baseline assessment of pagetic bone activity and to find out whether this measurement responds to therapy.^46,47 Measures of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and the procollagen type I peptides, and measures of bone resorption including the pyridinolines, hydroxyproline, and cross-linked collagens, have been analyzed as markers of bone remodeling and show no real advantage over the serum alkaline phosphatase level as reflections of bone turnover. As alkaline phosphatase measurement is inexpensive, available, and reliable, it should be used preferentially, with gamma-glutamyl transpeptidate or 5′ nucleotidase confirming the source as either liver or bone. Readers are directed to a recent review in which the utility of these markers is explored in more detail.⁴⁸

Imaging studies

Bone scans can give us an idea of the extent, location, and general activity of the disease (Figure 3). Uptake is avid in affected bones, beginning in the subchondral region and spreading throughout the bone. Bone scans can be particularly useful in defining sites of active disease when the serum alkaline phosphatase level is normal.

Plain radiography of the affected bones outlines the anatomy of the problem and gives some insight into the cause of pain (Figure 3).

Computed tomography or magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy (Figure  4), but these studies are expensive and generally are not needed.

Radiographic features. Paget disease is presumed to be a disease of the osteoclast, and the earliest lesion is described as lytic. In my own experience, it is unusual to see a purely lytic lesion, although sometimes the disease presents in the skull in this way—osteoporosis circumscripta—or in the femur or tibia with an advancing edge of pure osteolysis.

More often, one sees evidence of both resorption by osteoclasts and formation by osteoblasts, reflecting the coupling of these two processes in this disease. Radiographic findings on plain films are usually definitive, showing enlargement of the affected bone, deformity, coarsened trabeculae, and thickened cortices with tunneling (Figure 5).⁴⁹ In weightbearing bones, pseudofractures may stud the convex surface. These incongruities of bone may persist for years, heralding fracture only when there is focal pain (Figure 6).⁵⁰

Biopsy is infrequently needed

If these diagnostic findings are not present, then biopsy is indicated. In the United Sates and Canada, where Paget disease is fairly common, biopsy is infrequently needed and is usually reserved for situations in which the differential diagnosis includes cancer, as when the cortex cannot be clearly visualized, the lesions are atypical in pattern or location, or there is a single sclerotic vertebral body on imaging.⁵¹

The other indication for biopsy is a “new” pagetic lesion. For reasons unknown, the pattern of skeletal involvement in Paget disease tends to be stable throughout the patient’s lifetime. This is another reason why a baseline bone scan is useful.

TREATMENT WITH BISPHOSPHONATES

Treatment of Paget disease today relies for the most part on the new generation of nitrogen-containing bisphosphonates. As a class, these are antiresorptive agents that inhibit osteoclasts; in this way they slow bone remodeling and enhance the deposition of normal lamellar bone. Their clinical efficacy in Paget disease, coupled with the observation that the earliest lesion in Paget disease is lytic, underscores the principle that Paget disease is a disorder of the osteoclast.

Oral bisphosphonates

Etidronate, approved in 1977, was the first bisphosphonate licensed to treat Paget disease, and it remains available for this indication in the United States. Used in 6-month regimens, it lowers the serum alkaline phosphatase level in some patients, but it has a narrow therapeutic margin. Drug-induced osteomalacia and worsening lytic lesions and fractures in weight-bearing bones are some of the complications.⁵² When the nitrogen-containing bisphosphonates were developed, they proved to be more potent antiresorptive agents that pose less risk of mineralization defects at prescribed doses.

Alendronate, approved in 1995, is an oral nitrogen-containing bisphosphonate that is effective in treating Paget disease.⁵³ Alendronate is now available in the United States only through special programs (eg, the CVS ProCare Program); the paperwork required to secure this drug is onerous, so the drug is used infrequently. Studies in Paget disease showed that it normalizes the serum alkaline phosphatase level, improves the radiographic appearance, and eases pain in many patients.⁵⁴ The dosage is 40 mg daily for 6 months.

Risedronate, approved in 1998, is another oral nitrogen-containing bisphosphonate and is comparable to alendronate in efficacy.⁵⁵ The dosage is 30 mg daily for 2 months.

Tiludronate is another oral bisphosphonate with a different mechanism of action from the nitrogen-containing bisphosphonates.⁵⁶ It is safe, often effective, but less potent than the newer agents.

The oral bisphosphonates are well tolerated, with few side effects other than gastrointestinal distress. As a class, they are poorly absorbed and so must be taken fasting with a full glass of water on rising, after which the patient should remain upright without food or drink for 30 to 60 minutes. This is a nuisance for elderly patients already on multiple medications and thus makes intravenous agents appealing.

Intravenous bisphosphonates

Pamidronate was approved in 1994. It is quite effective in many patients with Paget disease. There is no consensus around the world on dosing, with regimens ranging from 30 mg to 90 mg or more intravenously in divided doses given over 2 to 4 hours from once a day to once a week. In the United States, 30 mg is given over 4 hours on 3 consecutive days. Resistance to pamidronate has been described; the mechanism is unknown.

Zoledronic acid is a nitrogen-containing bisphosphonate. It is given as a single infusion over 15 minutes, and re-treatment may not be necessary for years. A randomized clinical trial in 2005 demonstrated the efficacy of zoledronic acid 5 mg by infusion compared with oral risedronate in the treatment of Paget disease.⁵⁷ In observational extension studies lasting as long as 6.5 years, zoledronic acid has been shown to be superior to risedronate in terms of the proportion of patients experiencing a sustained clinical remission.⁵⁸

While there are many bisphosphonates on the market, an infusion of 5 mg of zoledronic acid seems optimal in most patients who do not have a contraindication or an aversion to intravenous therapy. It tends to normalize the serum alkaline phosphatase level quickly and to leave more patients in sustained biochemical remission than do older bisphosphonates, as noted above. It also tends to be more effective in normalizing the serum alkaline phosphatase level when a patient has used other bisphosphonates in the past or has become resistant to them.

Bisphosphonates reduce bone turnover but do not correct deformities

In randomized clinical trials, bisphosphonates have been shown to restore bone remodeling to more normal levels, to ease pain from pagetic bone, to lower the serum alkaline phosphatase level, and to heal radiographic lesions, but these drugs have not been proven to prevent progression of deformity or to restore the structural integrity of bone (Figure 6).

The Paget’s Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM), in 1,324 people with Paget disease in the United Kingdom, showed no difference in the incidence of fracture, orthopedic surgery, quality of life, or hearing thresholds over 2 to 5 years in patients treated with bisphosphonates vs those treated symptomatically, despite a significant difference in serum alkaline phosphatase in the two groups (P < .001).⁵⁹

In the observational extension study of zoledronic acid described above,⁵⁸ three of four fractures occurred in the group treated with zoledronic acid, echoing the findings of the PRISM study.

Adverse effects of bisphosphonates

The more potent the bisphosphonate is as an antiresorptive agent, the more it suppresses normal bone remodeling, which can lead to osteonecrosis of the jaw and to atypical femoral fractures.^60,61 These complications are unusual in patients with Paget disease because the treatment is intermittent. Sometimes a single dose of zoledronic acid or one course of risedronate or alendronate will last for years.

All the nitrogen-containing bisphosphonates, particularly zoledronic acid, may provoke flulike symptoms of fever, arthralgias, and bone pain. This effect is self-limited, resolves in days, and does not tend to recur. Bone pain may be more sustained, but this also passes, and within weeks the antiresorptive process has abated and pagetic bone pain will ease. Atrial fibrillation is not an anticipated complication of treatment with a bisphosphonate.⁶² The risk of esophageal cancer is not confirmed at this time.⁶³ Other rare complications of the bisphosphonates include iritis, acute renal failure, and allergy.

Bisphosphonates are not approved for use in patients with creatinine clearance less than 30 mL/min, or in pregnancy.

Other treatments

Calcitonin, an older agent, can still be useful in easing the pain of Paget disease, healing bone lesions, and reducing the metabolic activity of pagetic bone in patients who cannot receive bisphosphonates. It is given by injection in doses of 50 to 100 IU daily or every other day. Although unlikely to effect a sustained clinical remission, calcitonin remains a safe, well-tolerated, and well-studied medication in Paget disease and is approved for this indication.^64,65

Denosumab has not been formally studied in Paget disease, but a recent case report indicated it was effective.⁶⁶

A conservative strategy

Guidelines for treating Paget disease have been written at various times in many countries, including Italy (2007),⁶⁷ the United Kingdom (2004),⁶⁸ Japan (2006),⁶⁹ and Canada (2007).⁷⁰ Recommendations differ, in part because it is hard to ascertain whether long-term outcomes are improved by treatment, and in part because the prevalence of Paget disease is decreasing and its severity is lessening.^11,12 Some guidelines are outdated, since they do not include the newer bisphosphonates.

If the natural history of untreated Paget disease involves the gradual evolution over more than 20 years of bowing deformities in the lower limbs, rigidity and overgrowth of the spine, and softening and enlargement of the skull, as described by Sir James Paget, then treatment should be initiated in hopes that it will modify the outcome. We have no lens to better focus this question on the effect of treatment on the natural history of the disease. We have the PRISM study, designed before zoledronic acid was approved and only 2 to 5 years in duration. And we have the epidemiologic data demonstrating that most patients have no symptoms during their lifetime.

We see the crippling bone disease described by Sir James Paget so infrequently today in the United States that we forget the profound morbidity that may attend the skeletal changes of Paget disease that were common in the early 20th century. Once the bones of the skull are overgrown, the limbs are bowed, and the degenerative joint disease is present, no medication can reverse these changes. Then, the integrity of the bone is lost, and the vulnerability to fracture, early osteoarthritis, nerve compression syndromes, and hearing loss persist. Understanding these consequences prompts the recommendation of early treatment in patients with Paget disease, in hopes of mitigating disease progression.

Patients with active Paget disease, documented either by an elevated serum alkaline phosphatase or by a bone scan, should be treated with a bisphosphonate if the disease is found in sites where remodeling of bone may lead to complications. Such sites include the skull, spine, and long bones of the lower extremity. Paget disease of bone in the pelvis tends to give little trouble (Figure 2) unless it is proximal to a joint, when pain and early arthritis may result. Treatment is safe and, I think, prudent to undertake in any person over age 55 with active disease. To prevent hypocalcemia during treatment, all patients should be repleted with vitamin D and maintained on calcium 1,200 mg daily through diet or supplements with meals.

Throughout the evaluation and treatment, it is important to remember that pain may not emanate from pagetic bone. If medication for Paget disease proves ineffective in the first few months, analgesics, bracing, walking aids, and operative management⁷¹ are adjunctive therapies to improve the functional status of these patients.

It is a remarkable clinical observation that treatment of Paget disease may rapidly reverse neurologic syndromes, resolve the erythema or warmth overlying active pagetic bone, and diminish the risk of bleeding with surgery. This response to therapy suggests that there is prompt inhibition and apoptosis of the osteoclasts, accompanied by diminished vascularity of bone. Whatever the mechanism, it is worth treating patients who have spinal stenosis, arthritis, and nerve compression syndromes with calcitonin or bisphosphonates before surgical intervention, whenever possible.^34,72

Paget disease of bone is a focal disorder of the aging skeleton that can be asymptomatic or can present with pain, bowing deformities, fractures, or nonspecific rheumatic complaints. Physicians often discover it in asymptomatic patients when serum alkaline phosphatase levels are elevated or as an incidental finding on radiography. Despite evidence of germline mutations and polymorphisms that predispose to Paget disease, the environmental determinants that permit disease expression in older people remain unknown.

A STRIKING GEOGRAPHIC DISTRIBUTION

Researchers have been studying the determinants and distribution of Paget disease ever since Sir James Paget first described it in 1877.¹

Paget disease has a predilection for the axial skeleton, particularly the lumbosacral spine and pelvis, as well as the skull, femur, and tibia.² Knowing this, investigators have used screening plain films of the abdomen (kidney-ureter-bladder views) to estimate its prevalence in different populations, as these images capture the lumbosacral spine, pelvis, and proximal femurs. Other means of assessing prevalence have included autopsy series, questionnaires, and screens for biochemical markers of bone turnover, such as elevated serum alkaline phosphatase from bone.^3–6

Using these methods, Paget disease has been estimated to occur in 1% to 3% of people over age 55, and in as many as 8% of people over age 80 in certain countries.⁷

This disease has a striking geographic distribution, being frequent in Europe, Canada, the United States, Australia, New Zealand, and cities of South America, but rare in Scandinavia and Japan. It seems to be equally rare in other countries of the Far East and in India, Russia, and Africa, although its prevalence in these areas has not been thoroughly investigated.⁸

That it is an ancient disease has been corroborated by excavations in churchyards in Great Britain.^9,10 It may be familial or sporadic, but its expression is delayed until late middle age in most persons, and it does not occur in children. For reasons unclear, the prevalence seems to be decreasing in many countries.^11–13

GENETICS IS NOT THE WHOLE STORY

The variable prevalence of Paget disease in different geographic regions and its sometimes-familial expression suggest a genetic predisposition, environmental factor, or both.

Mutations in SQSTM1

In 2002, scientists investigating a cohort of French Canadian families found a mutation in the SQSTM1 gene that was present in almost 50% of people with familial Paget disease and in 16% of those with sporadic Paget disease.¹⁴ Hocking and his colleagues in the United Kingdom subsequently found the same mutation in 19% of cases of familial Paget disease and in 9% of sporadic cases.¹⁵

Further, investigators noted that the mutation was often present on a conserved haplotype, consistent with a stable genetic change occurring in the affected population.¹⁶ This observation of a “founder effect” dovetailed with the epidemiology of Paget disease,¹⁷ but only with this SQSTM1 mutation.

Throughout Europe, Australia, and the United States, comparable rates of the SQSTM1 mutation were reported in or around the ubiquitin-associated domain. Several specific mutations exist, the most common one being P392L, ie, a prolineto-leucine substitution at amino acid 392. Scientists have tried to correlate severity of disease with genotype, but the findings have been inconsistent.^18–21

Investigations into the mechanism of disease have pointed to the role of p62, the product of SQSTM1, in signaling osteoclast activation via nuclear factor kappa B. Since this initial discovery, polymorphisms in the genes affecting osteoclast maturation, activation, and fusion pathways have been shown to predispose to Paget disease. Examples:

• TNFRSF11A, which codes for receptor activator of nuclear factor kappa B, or RANK
• TNFRSF11B, which codes for osteoprotegerin, or OPG
• CSF1, which codes for macrophage colony-stimulating factor 1, and
• OPTN, which codes for optineurin, a member of the nuclear factor kappa B-modulating protein family.

Clinicians interested in these details can read an excellent review of the pathogenesis of Paget disease.²²

Other possible factors

Although there is good evidence that measles and canine distemper virus can infect osteoclasts and modify their phenotype, there is no good evidence that these infections by themselves cause Paget disease.^23–25 It is, however, tempting to think of these RNA paramyxoviruses as precipitating factors; conceivably, an infectious agent might seed the ends of long bones, accounting for the fixed distribution of Paget disease and its late expression.

Epidemiologic studies from around the world have failed to identify conclusively any environmental exposure that predisposes to Paget disease, although a rural setting, trauma, infection, and milk ingestion have all been proposed.^26–28 It is also possible that as bone ages and the marrow becomes less cellular and more fatty, these changes may permit the disease to develop.

The greatest risk factor for Paget disease is perhaps aging, followed by ancestry and a known family history of it. That genetics is not the whole story is evident by reports of people with SQSTM1 mutations who show no clinical evidence of Paget disease in their old age, and patients with Paget disease who have no SQSTM1 mutation.^20,29

CLINICAL PRESENTATION

Most patients with Paget disease have no symptoms and come to medical attention because of an elevated serum alkaline phosphatase level or characteristic findings on radiographs ordered for other indications.¹¹ Paget disease is the second most common disorder of aging bone after osteoporosis. Yet unlike osteoporosis, which presents as a systemic fragility of bone, the clinical manifestations of Paget disease depend on which bones are affected and how enlarged or misshapen they have become.

Common complications

As a consequence of this abnormal bone remodeling and overgrowth, many patients present with bone pain. Bone deformity, headache, and hearing loss may also occur (Figure 1), as well as fractures and nerve compression syndromes (eg, spinal stenosis, sciatica, cauda equina syndrome).

It is important to remember that “pagetic” bone may not be the source of pain, and that functional impairment caused by degenerative changes at affected sites is common (Figure  2).^30,31

In a study from the New England Registry for Paget’s Disease,³² most patients knew fairly well which bones were affected and what complications resulted from this when deformity, fracture, or total joint replacement had occurred.³² Although Paget disease did affect their quality of life as measured by physical functioning on the Short Form-12 assessment, these impairments did not seem to affect their outlook, which was as good as or better than that in other people their age.

Metabolic complications

Metabolic complications of Paget disease are rare today but can occur in an elderly patient who has active, polyostotic (multibone) disease.³³ The accelerated rate of bone remodeling and the increased vascularity of pagetic bone have been reported to lead to high-output heart failure. In theory, treatment should ease this by diminishing blood flow to pagetic bone and restoring bone turnover to more normal levels.³⁴

Hypercalcemia can occur when patients with Paget disease are immobilized for any reason, and there is probably a higher incidence of renal stones in patients with Paget disease.^35,36

Malignant complications

Osteosarcoma rarely arises in pagetic bone. Yet Paget disease may account for a significant number of cases of this cancer in the elderly.³⁷ In these cases, osteosarcoma is presumed to be driven by a second genetic mutation, has a genetic signature distinct from that in osteosarcomas occurring in youth, and is quite resistant to treatment.³⁸ In Scandinavia and Japan, where Paget disease is rare, the second peak of osteosarcoma that occurs with aging seems muted as well.^39,40 These cancers present with pain, soft-tissue swelling, and variable elevations in serum alkaline phosphatase. Investigations to date suggest that pagetic lesions and osteosarcomas arising in pagetic bone are probably both driven to some extent by stromal cells overexpressing RANK ligand and may not represent defects intrinsic to the osteoclast.⁴¹

Giant-cell tumors of bone are also rare but can arise in pagetic bone. A cluster of cases was reported in Avellino and other towns of southern Italy.⁴² Again, the lesions occur in older individuals and in different sites than those seen in the benign giant-cell tumors recorded in patients without Paget disease.

Metastases from lymphomas, prostate cancer, and breast cancer certainly occur in bone, but rarely in pagetic sites.⁴³ A recent case study noted that patients with prostate cancer who also had Paget disease had a later onset of metastasis to bone than patients without coincident Paget disease.⁴⁴

A THOUGHTFUL ASSESSMENT

Evaluating a patient with Paget disease requires a thoughtful assessment of its musculoskeletal consequences in an aging skeleton. Pain in Paget disease is often multifactorial. In the elderly, end-stage degenerative disease of the spine, hip, and knees, mechanical instability, compression fractures of the spine, and neuropathies may compound the clinical picture. Therefore, a thorough evaluation is required to plan effective therapy.

Alkaline phosphatase and other markers

A screening serum alkaline phosphatase level is usually sufficient to measure bone turnover. Produced by osteoblasts, alkaline phosphatase is a marker of bone formation, but an imperfect one. Often it is elevated in active Paget disease—but not always.⁴⁵ Many patients have normal serum alkaline phosphatase levels, particularly if they have monostotic (single-bone) disease. It is unclear why, in a disorder marked by accelerated bone remodeling, the biochemical markers are inconsistent measures of bone turnover.

Research into biochemical markers of Paget disease has had two aims: to identify the single best marker for baseline assessment of pagetic bone activity and to find out whether this measurement responds to therapy.^46,47 Measures of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and the procollagen type I peptides, and measures of bone resorption including the pyridinolines, hydroxyproline, and cross-linked collagens, have been analyzed as markers of bone remodeling and show no real advantage over the serum alkaline phosphatase level as reflections of bone turnover. As alkaline phosphatase measurement is inexpensive, available, and reliable, it should be used preferentially, with gamma-glutamyl transpeptidate or 5′ nucleotidase confirming the source as either liver or bone. Readers are directed to a recent review in which the utility of these markers is explored in more detail.⁴⁸

Imaging studies

Bone scans can give us an idea of the extent, location, and general activity of the disease (Figure 3). Uptake is avid in affected bones, beginning in the subchondral region and spreading throughout the bone. Bone scans can be particularly useful in defining sites of active disease when the serum alkaline phosphatase level is normal.

Plain radiography of the affected bones outlines the anatomy of the problem and gives some insight into the cause of pain (Figure 3).

Computed tomography or magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy (Figure  4), but these studies are expensive and generally are not needed.

Radiographic features. Paget disease is presumed to be a disease of the osteoclast, and the earliest lesion is described as lytic. In my own experience, it is unusual to see a purely lytic lesion, although sometimes the disease presents in the skull in this way—osteoporosis circumscripta—or in the femur or tibia with an advancing edge of pure osteolysis.

More often, one sees evidence of both resorption by osteoclasts and formation by osteoblasts, reflecting the coupling of these two processes in this disease. Radiographic findings on plain films are usually definitive, showing enlargement of the affected bone, deformity, coarsened trabeculae, and thickened cortices with tunneling (Figure 5).⁴⁹ In weightbearing bones, pseudofractures may stud the convex surface. These incongruities of bone may persist for years, heralding fracture only when there is focal pain (Figure 6).⁵⁰

Biopsy is infrequently needed

If these diagnostic findings are not present, then biopsy is indicated. In the United Sates and Canada, where Paget disease is fairly common, biopsy is infrequently needed and is usually reserved for situations in which the differential diagnosis includes cancer, as when the cortex cannot be clearly visualized, the lesions are atypical in pattern or location, or there is a single sclerotic vertebral body on imaging.⁵¹

The other indication for biopsy is a “new” pagetic lesion. For reasons unknown, the pattern of skeletal involvement in Paget disease tends to be stable throughout the patient’s lifetime. This is another reason why a baseline bone scan is useful.

TREATMENT WITH BISPHOSPHONATES

Treatment of Paget disease today relies for the most part on the new generation of nitrogen-containing bisphosphonates. As a class, these are antiresorptive agents that inhibit osteoclasts; in this way they slow bone remodeling and enhance the deposition of normal lamellar bone. Their clinical efficacy in Paget disease, coupled with the observation that the earliest lesion in Paget disease is lytic, underscores the principle that Paget disease is a disorder of the osteoclast.

Oral bisphosphonates

Etidronate, approved in 1977, was the first bisphosphonate licensed to treat Paget disease, and it remains available for this indication in the United States. Used in 6-month regimens, it lowers the serum alkaline phosphatase level in some patients, but it has a narrow therapeutic margin. Drug-induced osteomalacia and worsening lytic lesions and fractures in weight-bearing bones are some of the complications.⁵² When the nitrogen-containing bisphosphonates were developed, they proved to be more potent antiresorptive agents that pose less risk of mineralization defects at prescribed doses.

Alendronate, approved in 1995, is an oral nitrogen-containing bisphosphonate that is effective in treating Paget disease.⁵³ Alendronate is now available in the United States only through special programs (eg, the CVS ProCare Program); the paperwork required to secure this drug is onerous, so the drug is used infrequently. Studies in Paget disease showed that it normalizes the serum alkaline phosphatase level, improves the radiographic appearance, and eases pain in many patients.⁵⁴ The dosage is 40 mg daily for 6 months.

Risedronate, approved in 1998, is another oral nitrogen-containing bisphosphonate and is comparable to alendronate in efficacy.⁵⁵ The dosage is 30 mg daily for 2 months.

Tiludronate is another oral bisphosphonate with a different mechanism of action from the nitrogen-containing bisphosphonates.⁵⁶ It is safe, often effective, but less potent than the newer agents.

The oral bisphosphonates are well tolerated, with few side effects other than gastrointestinal distress. As a class, they are poorly absorbed and so must be taken fasting with a full glass of water on rising, after which the patient should remain upright without food or drink for 30 to 60 minutes. This is a nuisance for elderly patients already on multiple medications and thus makes intravenous agents appealing.

Intravenous bisphosphonates

Pamidronate was approved in 1994. It is quite effective in many patients with Paget disease. There is no consensus around the world on dosing, with regimens ranging from 30 mg to 90 mg or more intravenously in divided doses given over 2 to 4 hours from once a day to once a week. In the United States, 30 mg is given over 4 hours on 3 consecutive days. Resistance to pamidronate has been described; the mechanism is unknown.

Zoledronic acid is a nitrogen-containing bisphosphonate. It is given as a single infusion over 15 minutes, and re-treatment may not be necessary for years. A randomized clinical trial in 2005 demonstrated the efficacy of zoledronic acid 5 mg by infusion compared with oral risedronate in the treatment of Paget disease.⁵⁷ In observational extension studies lasting as long as 6.5 years, zoledronic acid has been shown to be superior to risedronate in terms of the proportion of patients experiencing a sustained clinical remission.⁵⁸

While there are many bisphosphonates on the market, an infusion of 5 mg of zoledronic acid seems optimal in most patients who do not have a contraindication or an aversion to intravenous therapy. It tends to normalize the serum alkaline phosphatase level quickly and to leave more patients in sustained biochemical remission than do older bisphosphonates, as noted above. It also tends to be more effective in normalizing the serum alkaline phosphatase level when a patient has used other bisphosphonates in the past or has become resistant to them.

Bisphosphonates reduce bone turnover but do not correct deformities

In randomized clinical trials, bisphosphonates have been shown to restore bone remodeling to more normal levels, to ease pain from pagetic bone, to lower the serum alkaline phosphatase level, and to heal radiographic lesions, but these drugs have not been proven to prevent progression of deformity or to restore the structural integrity of bone (Figure 6).

The Paget’s Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM), in 1,324 people with Paget disease in the United Kingdom, showed no difference in the incidence of fracture, orthopedic surgery, quality of life, or hearing thresholds over 2 to 5 years in patients treated with bisphosphonates vs those treated symptomatically, despite a significant difference in serum alkaline phosphatase in the two groups (P < .001).⁵⁹

In the observational extension study of zoledronic acid described above,⁵⁸ three of four fractures occurred in the group treated with zoledronic acid, echoing the findings of the PRISM study.

Adverse effects of bisphosphonates

The more potent the bisphosphonate is as an antiresorptive agent, the more it suppresses normal bone remodeling, which can lead to osteonecrosis of the jaw and to atypical femoral fractures.^60,61 These complications are unusual in patients with Paget disease because the treatment is intermittent. Sometimes a single dose of zoledronic acid or one course of risedronate or alendronate will last for years.

All the nitrogen-containing bisphosphonates, particularly zoledronic acid, may provoke flulike symptoms of fever, arthralgias, and bone pain. This effect is self-limited, resolves in days, and does not tend to recur. Bone pain may be more sustained, but this also passes, and within weeks the antiresorptive process has abated and pagetic bone pain will ease. Atrial fibrillation is not an anticipated complication of treatment with a bisphosphonate.⁶² The risk of esophageal cancer is not confirmed at this time.⁶³ Other rare complications of the bisphosphonates include iritis, acute renal failure, and allergy.

Bisphosphonates are not approved for use in patients with creatinine clearance less than 30 mL/min, or in pregnancy.

Other treatments

Calcitonin, an older agent, can still be useful in easing the pain of Paget disease, healing bone lesions, and reducing the metabolic activity of pagetic bone in patients who cannot receive bisphosphonates. It is given by injection in doses of 50 to 100 IU daily or every other day. Although unlikely to effect a sustained clinical remission, calcitonin remains a safe, well-tolerated, and well-studied medication in Paget disease and is approved for this indication.^64,65

Denosumab has not been formally studied in Paget disease, but a recent case report indicated it was effective.⁶⁶

A conservative strategy

Guidelines for treating Paget disease have been written at various times in many countries, including Italy (2007),⁶⁷ the United Kingdom (2004),⁶⁸ Japan (2006),⁶⁹ and Canada (2007).⁷⁰ Recommendations differ, in part because it is hard to ascertain whether long-term outcomes are improved by treatment, and in part because the prevalence of Paget disease is decreasing and its severity is lessening.^11,12 Some guidelines are outdated, since they do not include the newer bisphosphonates.

If the natural history of untreated Paget disease involves the gradual evolution over more than 20 years of bowing deformities in the lower limbs, rigidity and overgrowth of the spine, and softening and enlargement of the skull, as described by Sir James Paget, then treatment should be initiated in hopes that it will modify the outcome. We have no lens to better focus this question on the effect of treatment on the natural history of the disease. We have the PRISM study, designed before zoledronic acid was approved and only 2 to 5 years in duration. And we have the epidemiologic data demonstrating that most patients have no symptoms during their lifetime.

We see the crippling bone disease described by Sir James Paget so infrequently today in the United States that we forget the profound morbidity that may attend the skeletal changes of Paget disease that were common in the early 20th century. Once the bones of the skull are overgrown, the limbs are bowed, and the degenerative joint disease is present, no medication can reverse these changes. Then, the integrity of the bone is lost, and the vulnerability to fracture, early osteoarthritis, nerve compression syndromes, and hearing loss persist. Understanding these consequences prompts the recommendation of early treatment in patients with Paget disease, in hopes of mitigating disease progression.

Patients with active Paget disease, documented either by an elevated serum alkaline phosphatase or by a bone scan, should be treated with a bisphosphonate if the disease is found in sites where remodeling of bone may lead to complications. Such sites include the skull, spine, and long bones of the lower extremity. Paget disease of bone in the pelvis tends to give little trouble (Figure 2) unless it is proximal to a joint, when pain and early arthritis may result. Treatment is safe and, I think, prudent to undertake in any person over age 55 with active disease. To prevent hypocalcemia during treatment, all patients should be repleted with vitamin D and maintained on calcium 1,200 mg daily through diet or supplements with meals.

Throughout the evaluation and treatment, it is important to remember that pain may not emanate from pagetic bone. If medication for Paget disease proves ineffective in the first few months, analgesics, bracing, walking aids, and operative management⁷¹ are adjunctive therapies to improve the functional status of these patients.

It is a remarkable clinical observation that treatment of Paget disease may rapidly reverse neurologic syndromes, resolve the erythema or warmth overlying active pagetic bone, and diminish the risk of bleeding with surgery. This response to therapy suggests that there is prompt inhibition and apoptosis of the osteoclasts, accompanied by diminished vascularity of bone. Whatever the mechanism, it is worth treating patients who have spinal stenosis, arthritis, and nerve compression syndromes with calcitonin or bisphosphonates before surgical intervention, whenever possible.^34,72

Paget disease of bone is a focal disorder of the aging skeleton that can be asymptomatic or can present with pain, bowing deformities, fractures, or nonspecific rheumatic complaints. Physicians often discover it in asymptomatic patients when serum alkaline phosphatase levels are elevated or as an incidental finding on radiography. Despite evidence of germline mutations and polymorphisms that predispose to Paget disease, the environmental determinants that permit disease expression in older people remain unknown.

A STRIKING GEOGRAPHIC DISTRIBUTION

Researchers have been studying the determinants and distribution of Paget disease ever since Sir James Paget first described it in 1877.¹

Paget disease has a predilection for the axial skeleton, particularly the lumbosacral spine and pelvis, as well as the skull, femur, and tibia.² Knowing this, investigators have used screening plain films of the abdomen (kidney-ureter-bladder views) to estimate its prevalence in different populations, as these images capture the lumbosacral spine, pelvis, and proximal femurs. Other means of assessing prevalence have included autopsy series, questionnaires, and screens for biochemical markers of bone turnover, such as elevated serum alkaline phosphatase from bone.^3–6

Using these methods, Paget disease has been estimated to occur in 1% to 3% of people over age 55, and in as many as 8% of people over age 80 in certain countries.⁷

This disease has a striking geographic distribution, being frequent in Europe, Canada, the United States, Australia, New Zealand, and cities of South America, but rare in Scandinavia and Japan. It seems to be equally rare in other countries of the Far East and in India, Russia, and Africa, although its prevalence in these areas has not been thoroughly investigated.⁸

That it is an ancient disease has been corroborated by excavations in churchyards in Great Britain.^9,10 It may be familial or sporadic, but its expression is delayed until late middle age in most persons, and it does not occur in children. For reasons unclear, the prevalence seems to be decreasing in many countries.^11–13

GENETICS IS NOT THE WHOLE STORY

The variable prevalence of Paget disease in different geographic regions and its sometimes-familial expression suggest a genetic predisposition, environmental factor, or both.

Mutations in SQSTM1

In 2002, scientists investigating a cohort of French Canadian families found a mutation in the SQSTM1 gene that was present in almost 50% of people with familial Paget disease and in 16% of those with sporadic Paget disease.¹⁴ Hocking and his colleagues in the United Kingdom subsequently found the same mutation in 19% of cases of familial Paget disease and in 9% of sporadic cases.¹⁵

Further, investigators noted that the mutation was often present on a conserved haplotype, consistent with a stable genetic change occurring in the affected population.¹⁶ This observation of a “founder effect” dovetailed with the epidemiology of Paget disease,¹⁷ but only with this SQSTM1 mutation.

Throughout Europe, Australia, and the United States, comparable rates of the SQSTM1 mutation were reported in or around the ubiquitin-associated domain. Several specific mutations exist, the most common one being P392L, ie, a prolineto-leucine substitution at amino acid 392. Scientists have tried to correlate severity of disease with genotype, but the findings have been inconsistent.^18–21

Investigations into the mechanism of disease have pointed to the role of p62, the product of SQSTM1, in signaling osteoclast activation via nuclear factor kappa B. Since this initial discovery, polymorphisms in the genes affecting osteoclast maturation, activation, and fusion pathways have been shown to predispose to Paget disease. Examples:

• TNFRSF11A, which codes for receptor activator of nuclear factor kappa B, or RANK
• TNFRSF11B, which codes for osteoprotegerin, or OPG
• CSF1, which codes for macrophage colony-stimulating factor 1, and
• OPTN, which codes for optineurin, a member of the nuclear factor kappa B-modulating protein family.

Clinicians interested in these details can read an excellent review of the pathogenesis of Paget disease.²²

Other possible factors

Although there is good evidence that measles and canine distemper virus can infect osteoclasts and modify their phenotype, there is no good evidence that these infections by themselves cause Paget disease.^23–25 It is, however, tempting to think of these RNA paramyxoviruses as precipitating factors; conceivably, an infectious agent might seed the ends of long bones, accounting for the fixed distribution of Paget disease and its late expression.

Epidemiologic studies from around the world have failed to identify conclusively any environmental exposure that predisposes to Paget disease, although a rural setting, trauma, infection, and milk ingestion have all been proposed.^26–28 It is also possible that as bone ages and the marrow becomes less cellular and more fatty, these changes may permit the disease to develop.

The greatest risk factor for Paget disease is perhaps aging, followed by ancestry and a known family history of it. That genetics is not the whole story is evident by reports of people with SQSTM1 mutations who show no clinical evidence of Paget disease in their old age, and patients with Paget disease who have no SQSTM1 mutation.^20,29

CLINICAL PRESENTATION

Most patients with Paget disease have no symptoms and come to medical attention because of an elevated serum alkaline phosphatase level or characteristic findings on radiographs ordered for other indications.¹¹ Paget disease is the second most common disorder of aging bone after osteoporosis. Yet unlike osteoporosis, which presents as a systemic fragility of bone, the clinical manifestations of Paget disease depend on which bones are affected and how enlarged or misshapen they have become.

Common complications

As a consequence of this abnormal bone remodeling and overgrowth, many patients present with bone pain. Bone deformity, headache, and hearing loss may also occur (Figure 1), as well as fractures and nerve compression syndromes (eg, spinal stenosis, sciatica, cauda equina syndrome).

It is important to remember that “pagetic” bone may not be the source of pain, and that functional impairment caused by degenerative changes at affected sites is common (Figure  2).^30,31

In a study from the New England Registry for Paget’s Disease,³² most patients knew fairly well which bones were affected and what complications resulted from this when deformity, fracture, or total joint replacement had occurred.³² Although Paget disease did affect their quality of life as measured by physical functioning on the Short Form-12 assessment, these impairments did not seem to affect their outlook, which was as good as or better than that in other people their age.

Metabolic complications

Metabolic complications of Paget disease are rare today but can occur in an elderly patient who has active, polyostotic (multibone) disease.³³ The accelerated rate of bone remodeling and the increased vascularity of pagetic bone have been reported to lead to high-output heart failure. In theory, treatment should ease this by diminishing blood flow to pagetic bone and restoring bone turnover to more normal levels.³⁴

Hypercalcemia can occur when patients with Paget disease are immobilized for any reason, and there is probably a higher incidence of renal stones in patients with Paget disease.^35,36

Malignant complications

Osteosarcoma rarely arises in pagetic bone. Yet Paget disease may account for a significant number of cases of this cancer in the elderly.³⁷ In these cases, osteosarcoma is presumed to be driven by a second genetic mutation, has a genetic signature distinct from that in osteosarcomas occurring in youth, and is quite resistant to treatment.³⁸ In Scandinavia and Japan, where Paget disease is rare, the second peak of osteosarcoma that occurs with aging seems muted as well.^39,40 These cancers present with pain, soft-tissue swelling, and variable elevations in serum alkaline phosphatase. Investigations to date suggest that pagetic lesions and osteosarcomas arising in pagetic bone are probably both driven to some extent by stromal cells overexpressing RANK ligand and may not represent defects intrinsic to the osteoclast.⁴¹

Giant-cell tumors of bone are also rare but can arise in pagetic bone. A cluster of cases was reported in Avellino and other towns of southern Italy.⁴² Again, the lesions occur in older individuals and in different sites than those seen in the benign giant-cell tumors recorded in patients without Paget disease.

Metastases from lymphomas, prostate cancer, and breast cancer certainly occur in bone, but rarely in pagetic sites.⁴³ A recent case study noted that patients with prostate cancer who also had Paget disease had a later onset of metastasis to bone than patients without coincident Paget disease.⁴⁴

A THOUGHTFUL ASSESSMENT

Evaluating a patient with Paget disease requires a thoughtful assessment of its musculoskeletal consequences in an aging skeleton. Pain in Paget disease is often multifactorial. In the elderly, end-stage degenerative disease of the spine, hip, and knees, mechanical instability, compression fractures of the spine, and neuropathies may compound the clinical picture. Therefore, a thorough evaluation is required to plan effective therapy.

Alkaline phosphatase and other markers

A screening serum alkaline phosphatase level is usually sufficient to measure bone turnover. Produced by osteoblasts, alkaline phosphatase is a marker of bone formation, but an imperfect one. Often it is elevated in active Paget disease—but not always.⁴⁵ Many patients have normal serum alkaline phosphatase levels, particularly if they have monostotic (single-bone) disease. It is unclear why, in a disorder marked by accelerated bone remodeling, the biochemical markers are inconsistent measures of bone turnover.

Research into biochemical markers of Paget disease has had two aims: to identify the single best marker for baseline assessment of pagetic bone activity and to find out whether this measurement responds to therapy.^46,47 Measures of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and the procollagen type I peptides, and measures of bone resorption including the pyridinolines, hydroxyproline, and cross-linked collagens, have been analyzed as markers of bone remodeling and show no real advantage over the serum alkaline phosphatase level as reflections of bone turnover. As alkaline phosphatase measurement is inexpensive, available, and reliable, it should be used preferentially, with gamma-glutamyl transpeptidate or 5′ nucleotidase confirming the source as either liver or bone. Readers are directed to a recent review in which the utility of these markers is explored in more detail.⁴⁸

Imaging studies

Bone scans can give us an idea of the extent, location, and general activity of the disease (Figure 3). Uptake is avid in affected bones, beginning in the subchondral region and spreading throughout the bone. Bone scans can be particularly useful in defining sites of active disease when the serum alkaline phosphatase level is normal.

Plain radiography of the affected bones outlines the anatomy of the problem and gives some insight into the cause of pain (Figure 3).

Computed tomography or magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy (Figure  4), but these studies are expensive and generally are not needed.

Radiographic features. Paget disease is presumed to be a disease of the osteoclast, and the earliest lesion is described as lytic. In my own experience, it is unusual to see a purely lytic lesion, although sometimes the disease presents in the skull in this way—osteoporosis circumscripta—or in the femur or tibia with an advancing edge of pure osteolysis.

More often, one sees evidence of both resorption by osteoclasts and formation by osteoblasts, reflecting the coupling of these two processes in this disease. Radiographic findings on plain films are usually definitive, showing enlargement of the affected bone, deformity, coarsened trabeculae, and thickened cortices with tunneling (Figure 5).⁴⁹ In weightbearing bones, pseudofractures may stud the convex surface. These incongruities of bone may persist for years, heralding fracture only when there is focal pain (Figure 6).⁵⁰

Biopsy is infrequently needed

If these diagnostic findings are not present, then biopsy is indicated. In the United Sates and Canada, where Paget disease is fairly common, biopsy is infrequently needed and is usually reserved for situations in which the differential diagnosis includes cancer, as when the cortex cannot be clearly visualized, the lesions are atypical in pattern or location, or there is a single sclerotic vertebral body on imaging.⁵¹

The other indication for biopsy is a “new” pagetic lesion. For reasons unknown, the pattern of skeletal involvement in Paget disease tends to be stable throughout the patient’s lifetime. This is another reason why a baseline bone scan is useful.

TREATMENT WITH BISPHOSPHONATES

Treatment of Paget disease today relies for the most part on the new generation of nitrogen-containing bisphosphonates. As a class, these are antiresorptive agents that inhibit osteoclasts; in this way they slow bone remodeling and enhance the deposition of normal lamellar bone. Their clinical efficacy in Paget disease, coupled with the observation that the earliest lesion in Paget disease is lytic, underscores the principle that Paget disease is a disorder of the osteoclast.

Oral bisphosphonates

Etidronate, approved in 1977, was the first bisphosphonate licensed to treat Paget disease, and it remains available for this indication in the United States. Used in 6-month regimens, it lowers the serum alkaline phosphatase level in some patients, but it has a narrow therapeutic margin. Drug-induced osteomalacia and worsening lytic lesions and fractures in weight-bearing bones are some of the complications.⁵² When the nitrogen-containing bisphosphonates were developed, they proved to be more potent antiresorptive agents that pose less risk of mineralization defects at prescribed doses.

Alendronate, approved in 1995, is an oral nitrogen-containing bisphosphonate that is effective in treating Paget disease.⁵³ Alendronate is now available in the United States only through special programs (eg, the CVS ProCare Program); the paperwork required to secure this drug is onerous, so the drug is used infrequently. Studies in Paget disease showed that it normalizes the serum alkaline phosphatase level, improves the radiographic appearance, and eases pain in many patients.⁵⁴ The dosage is 40 mg daily for 6 months.

Risedronate, approved in 1998, is another oral nitrogen-containing bisphosphonate and is comparable to alendronate in efficacy.⁵⁵ The dosage is 30 mg daily for 2 months.

Tiludronate is another oral bisphosphonate with a different mechanism of action from the nitrogen-containing bisphosphonates.⁵⁶ It is safe, often effective, but less potent than the newer agents.

The oral bisphosphonates are well tolerated, with few side effects other than gastrointestinal distress. As a class, they are poorly absorbed and so must be taken fasting with a full glass of water on rising, after which the patient should remain upright without food or drink for 30 to 60 minutes. This is a nuisance for elderly patients already on multiple medications and thus makes intravenous agents appealing.

Intravenous bisphosphonates

Pamidronate was approved in 1994. It is quite effective in many patients with Paget disease. There is no consensus around the world on dosing, with regimens ranging from 30 mg to 90 mg or more intravenously in divided doses given over 2 to 4 hours from once a day to once a week. In the United States, 30 mg is given over 4 hours on 3 consecutive days. Resistance to pamidronate has been described; the mechanism is unknown.

Zoledronic acid is a nitrogen-containing bisphosphonate. It is given as a single infusion over 15 minutes, and re-treatment may not be necessary for years. A randomized clinical trial in 2005 demonstrated the efficacy of zoledronic acid 5 mg by infusion compared with oral risedronate in the treatment of Paget disease.⁵⁷ In observational extension studies lasting as long as 6.5 years, zoledronic acid has been shown to be superior to risedronate in terms of the proportion of patients experiencing a sustained clinical remission.⁵⁸

While there are many bisphosphonates on the market, an infusion of 5 mg of zoledronic acid seems optimal in most patients who do not have a contraindication or an aversion to intravenous therapy. It tends to normalize the serum alkaline phosphatase level quickly and to leave more patients in sustained biochemical remission than do older bisphosphonates, as noted above. It also tends to be more effective in normalizing the serum alkaline phosphatase level when a patient has used other bisphosphonates in the past or has become resistant to them.

Bisphosphonates reduce bone turnover but do not correct deformities

In randomized clinical trials, bisphosphonates have been shown to restore bone remodeling to more normal levels, to ease pain from pagetic bone, to lower the serum alkaline phosphatase level, and to heal radiographic lesions, but these drugs have not been proven to prevent progression of deformity or to restore the structural integrity of bone (Figure 6).

The Paget’s Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM), in 1,324 people with Paget disease in the United Kingdom, showed no difference in the incidence of fracture, orthopedic surgery, quality of life, or hearing thresholds over 2 to 5 years in patients treated with bisphosphonates vs those treated symptomatically, despite a significant difference in serum alkaline phosphatase in the two groups (P < .001).⁵⁹

In the observational extension study of zoledronic acid described above,⁵⁸ three of four fractures occurred in the group treated with zoledronic acid, echoing the findings of the PRISM study.

Adverse effects of bisphosphonates

The more potent the bisphosphonate is as an antiresorptive agent, the more it suppresses normal bone remodeling, which can lead to osteonecrosis of the jaw and to atypical femoral fractures.^60,61 These complications are unusual in patients with Paget disease because the treatment is intermittent. Sometimes a single dose of zoledronic acid or one course of risedronate or alendronate will last for years.

All the nitrogen-containing bisphosphonates, particularly zoledronic acid, may provoke flulike symptoms of fever, arthralgias, and bone pain. This effect is self-limited, resolves in days, and does not tend to recur. Bone pain may be more sustained, but this also passes, and within weeks the antiresorptive process has abated and pagetic bone pain will ease. Atrial fibrillation is not an anticipated complication of treatment with a bisphosphonate.⁶² The risk of esophageal cancer is not confirmed at this time.⁶³ Other rare complications of the bisphosphonates include iritis, acute renal failure, and allergy.

Bisphosphonates are not approved for use in patients with creatinine clearance less than 30 mL/min, or in pregnancy.

Other treatments

Calcitonin, an older agent, can still be useful in easing the pain of Paget disease, healing bone lesions, and reducing the metabolic activity of pagetic bone in patients who cannot receive bisphosphonates. It is given by injection in doses of 50 to 100 IU daily or every other day. Although unlikely to effect a sustained clinical remission, calcitonin remains a safe, well-tolerated, and well-studied medication in Paget disease and is approved for this indication.^64,65

Denosumab has not been formally studied in Paget disease, but a recent case report indicated it was effective.⁶⁶

A conservative strategy

Guidelines for treating Paget disease have been written at various times in many countries, including Italy (2007),⁶⁷ the United Kingdom (2004),⁶⁸ Japan (2006),⁶⁹ and Canada (2007).⁷⁰ Recommendations differ, in part because it is hard to ascertain whether long-term outcomes are improved by treatment, and in part because the prevalence of Paget disease is decreasing and its severity is lessening.^11,12 Some guidelines are outdated, since they do not include the newer bisphosphonates.

If the natural history of untreated Paget disease involves the gradual evolution over more than 20 years of bowing deformities in the lower limbs, rigidity and overgrowth of the spine, and softening and enlargement of the skull, as described by Sir James Paget, then treatment should be initiated in hopes that it will modify the outcome. We have no lens to better focus this question on the effect of treatment on the natural history of the disease. We have the PRISM study, designed before zoledronic acid was approved and only 2 to 5 years in duration. And we have the epidemiologic data demonstrating that most patients have no symptoms during their lifetime.

We see the crippling bone disease described by Sir James Paget so infrequently today in the United States that we forget the profound morbidity that may attend the skeletal changes of Paget disease that were common in the early 20th century. Once the bones of the skull are overgrown, the limbs are bowed, and the degenerative joint disease is present, no medication can reverse these changes. Then, the integrity of the bone is lost, and the vulnerability to fracture, early osteoarthritis, nerve compression syndromes, and hearing loss persist. Understanding these consequences prompts the recommendation of early treatment in patients with Paget disease, in hopes of mitigating disease progression.

Patients with active Paget disease, documented either by an elevated serum alkaline phosphatase or by a bone scan, should be treated with a bisphosphonate if the disease is found in sites where remodeling of bone may lead to complications. Such sites include the skull, spine, and long bones of the lower extremity. Paget disease of bone in the pelvis tends to give little trouble (Figure 2) unless it is proximal to a joint, when pain and early arthritis may result. Treatment is safe and, I think, prudent to undertake in any person over age 55 with active disease. To prevent hypocalcemia during treatment, all patients should be repleted with vitamin D and maintained on calcium 1,200 mg daily through diet or supplements with meals.

Throughout the evaluation and treatment, it is important to remember that pain may not emanate from pagetic bone. If medication for Paget disease proves ineffective in the first few months, analgesics, bracing, walking aids, and operative management⁷¹ are adjunctive therapies to improve the functional status of these patients.

It is a remarkable clinical observation that treatment of Paget disease may rapidly reverse neurologic syndromes, resolve the erythema or warmth overlying active pagetic bone, and diminish the risk of bleeding with surgery. This response to therapy suggests that there is prompt inhibition and apoptosis of the osteoclasts, accompanied by diminished vascularity of bone. Whatever the mechanism, it is worth treating patients who have spinal stenosis, arthritis, and nerve compression syndromes with calcitonin or bisphosphonates before surgical intervention, whenever possible.^34,72

In the past several years, three new oral anticoagulants—dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)—have been approved for use in the United States. These long-awaited agents are appealing because they are easy to use, do not require laboratory monitoring, and have demonstrated equivalence, or in some cases, superiority to warfarin in preventing stroke or systemic embolism in at-risk populations.^1–4 However, unlike warfarin, they have no specific reversal agents. How then should one manage spontaneous bleeding problems and those due to drug overdose, and how can we quickly reverse anticoagulation if emergency surgery is needed?

For these reasons, physicians and patients have been wary of these agents. However, with a systematic approach based on an understanding of the properties of these drugs, the appropriate use and interpretation of coagulation tests, and awareness of available therapeutic strategies, physicians can more confidently provide care for patients who require urgent reversal of anticoagulant effects.

Here, we review the available literature and suggest practical strategies for management based on an understanding of the pharmacokinetic and pharmacodynamic effects of these drugs and our current knowledge of the coagulation tests.

NEED FOR ANTICOAGULANTS

Anticoagulants are important in preventing systemic embolization in patients with atrial fibrillation and preventing pulmonary embolism in patients with venous thromboembolism.

And the numbers are staggering. The estimated prevalence of atrial fibrillation in the United States was 3.03 million in 2005 and is projected to increase to 7.56 million by 2050.⁵ Ischemic stroke is the most serious complication of atrial fibrillation, which accounts for 23.5% of strokes in patients ages 80 through 89 according to Framingham data.⁶ Venous thromboembolism accounts for 900,000 incident or recurrent fatal and nonfatal events in the United States yearly.⁷

HOW THE NEW AGENTS BLOCK COAGULATION

Thrombin (factor IIa), a serine protease, is central to the process of clot formation during hemostasis. It activates factors V, VIII, and XI (thus generating more thrombin), catalyzes the conversion of fibrinogen to fibrin, and stimulates platelet aggregation. Its role in the final steps of the coagulation cascade has made it a target for new direct thrombin inhibitors such as dabigatran.

Factor Xa is a serine protease that plays a central role in the coagulation cascade. It is a desirable target for anticoagulation because it is the convergence point for the extrinsic and the intrinsic coagulation pathways. It converts prothrombin to thrombin. Rivaroxaban and apixaban are direct factor Xa inhibitors (Figure 1).

Dabigatran, a direct thrombin inhibitor

Dabigatran etexilate is a synthetic, orally available prodrug that is rapidly absorbed and converted by esterases to its active form, dabigatran, a potent direct inhibitor of both free thrombin and clot-bound thrombin.⁸

Plasma levels of dabigatran peak within 2 hours of administration, and its half-life is 14 to 17 hours.⁹ Dabigatran is eliminated mainly via the kidneys, with more that 80% of the drug excreted unchanged in the urine (Table 1).

Rivaroxaban, a factor Xa inhibitor

Rivaroxaban is a potent, selective, direct factor Xa inhibitor.

Plasma levels of rivaroxaban peak 2 to 3 hours after administration, and it is cleared with a terminal half-life of 7 to 11 hours.^10,11

Rivaroxaban is eliminated by the kidneys and in the feces. The kidneys eliminate one-third of the active drug unchanged and another one-third as inactive metabolites. The remaining one-third is metabolized by the liver and then excreted in the feces. Rivaroxaban has a predictable and dose-dependent pharmacodynamic and pharmacokinetic profile that is not affected by age, sex, or body weight (Table 1).¹²

Apixaban, an oral factor Xa inhibitor

Apixaban is a selective, direct oral factor Xa inhibitor.

Plasma levels of apixaban peak about 3 hours after administration, and its terminal half-life is 8 to 14 hours.¹³ Apixaban is eliminated by oxidative metabolism, by the kidney, and in the feces. It has predictable pharmacodynamic and pharmacokinetic profiles and has the least renal dependence of the three agents (Table 1).

THE NEW ORAL ANTICOAGULANTS AND BLOOD COAGULATION ASSAYS

Assessment of the anticoagulant activity of the new oral anticoagulants is not necessary in routine clinical practice, but it may be useful in planning intervention in patients with major bleeding, those with drug overdose, or those who need emergency surgery.

The activated partial thromboplastin time

The activated partial thromboplastin time (aPTT) is a measure of the activity of the intrinsic pathway of the coagulation cascade.

Dabigatran. There is a curvilinear relationship between the aPTT and the plasma concentration of dabigatran and other direct thrombin inhibitors, although the aPTT prolongation appears to vary with different reagents and coagulometers.^9,14,15 However, Stangier et al⁹ found a linear relationship between the aPTT and the square root of the dabigatran plasma concentration.

Rivaroxaban prolongs the aPTT in a dose-dependent manner, but there is no standard for calibration of this assay. Hence, the aPTT is not recommended for monitoring rivaroxaban in clinical practice.

Apixaban may also prolong the aPTT, but there are limited data on its reactivity with different reagents.

The prothrombin time and international normalized ratio

The prothrombin time and international normalized ratio (INR) are measures of the extrinsic pathway of the coagulation cascade.

Dabigatran. The INR has a linear response to the dabigatran concentration, but it is insensitive.⁹ Hence, it is not suitable for monitoring the anticoagulant effects of direct thrombin inhibitors.

Rivaroxaban. The prothrombin time correlates strongly with the plasma concentration of rivaroxaban in healthy trial participants¹¹ and in patients undergoing total hip arthroplasty or total knee arthroplasty.¹⁶ Samama et al¹⁷ noted that, unlike with vitamin K antagonists, the INR cannot be used to monitor patients on rivaroxaban because the prothrombin time results varied with different reagents. They used a standard calibration curve to express the prothrombin time results in plasma concentrations of rivaroxaban rather than in seconds or the INR.

Apixaban increases the INR in a dose-dependent manner.¹⁸ Its effect on different reagents remains unknown.

The thrombin time

The thrombin time reflects the activity of thrombin in the plasma. The amount of thrombin and the concentration of thrombin inhibitors in the plasma sample determine the time to clot formation.

Dabigatran. The thrombin time displays a linear dose-response to dabigatran, but only over the range of therapeutic concentrations. At a dabigatran concentration greater than 600 ng/mL, the test often exceeds the maximum measurement time of coagulometers.⁹ Hence, this test is too sensitive for emergency monitoring, especially in cases of drug overdose. However, it is well suited for determining if any dabigatran is present.

Rivaroxaban and apixaban have no effect on the thrombin time.

The Hemoclot direct thrombin inhibitor assay and dabigatran

The Hemoclot direct thrombin inhibitor assay (Hyphen BioMed, France) is a sensitive diluted thrombin time assay that can be used for quantitative measurement of dabigatran activity in plasma. This test is based on inhibition of a constant amount of highly purified human alpha-thrombin by adding it to diluted test plasma (1:8 to 1:20) mixed with normal pooled human plasma.^19,20

Stangier et al¹⁹ found that the Hemoclot assay was suitable for calculating a wide range of dabigatran concentrations up to 4,000 nmol/L (1,886 ng/mL). Although this finding has not been confirmed in larger studies, this test may provide a rapid and accurate assessment of dabigatran’s anticoagulant activity in cases of emergency surgery or overdose.

The ecarin clotting time and dabigatran

The ecarin clotting time is a measure of the activity of direct thrombin inhibitors, but not the factor Xa inhibitors.

Ecarin is a highly purified metalloprotease isolated from the venom of a snake, Echis carinatus, and it generates meizothrombin from prothrombin.²¹ Meizothrombin facilitates clot formation by converting fibrinogen to fibrin and, like thrombin, it can be inactivated by direct thrombin inhibitors, thereby prolonging the clotting time.

The limitations of the ecarin clotting time include dependence on the plasma levels of fibrinogen and prothrombin.

The ecarin chromogenic assay and dabigatran

The ecarin chromogenic assay is an improvement on the principle of the ecarin clotting time that can be used to measure the activity of direct thrombin inhibitors.²² In this test, ecarin is added to a plasma sample to generate meizothrombin, and the amidolytic activity of meizothrombin towards a chromogenic substrate is then determined.

Results of the ecarin chromogenic assay are not influenced by the levels of fibrinogen or prothrombin. Another advantage is that this assay can be used in automated and manual analyzers, thus enabling its use at the bedside. However, to our knowledge, it is not being regularly used to monitor direct thrombin inhibitors in the clinical setting, and there is no standard calibration of the ecarin clotting time method.

Assays of factor Xa activity

A variety of assays to monitor the anticoagulant activity of factor Xa inhibitors have been proposed.^23–25 All measure inhibition of the activity of factor Xa using methods similar to those used in monitoring heparin levels. All require calibrators with a known concentration of the Xa inhibitor; many are easily adapted for laboratories currently providing measurement of factor Xa inhibition from heparin.²³ These assays have been suggested as a better indicator of plasma concentration of factor Xa inhibitor drugs than the prothrombin time.²⁵

CONTROLLING BLEEDING IN PATIENTS ON THE NEW ORAL ANTICOAGULANTS

Bleeding is an anticipated adverse event in patients taking anticoagulants. It is associated with significant morbidity and risk of death.^26,27

Many physicians still have limited experience with using the new oral anticoagulants and managing the attendant bleeding risks. Hence, we recommend that every health institution have a treatment policy or algorithm to guide all clinical staff in the management of such emergencies.

Prevention of bleeding

Management of bleeding from these agents should begin with preventing bleeding in the first place.

The physician should adhere to the recommended dosages of these medications. Studies have shown that the plasma concentration of these drugs and the risk of bleeding increase with increasing dosage.^1,28,29

In addition, these medications should be used for the shortest time for which anticoagulation is required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding.^30,31

Most patients who need anticoagulation have comorbidities such as heart failure, renal failure, diabetes mellitus, and hypertension. Although the kidneys play a major role in the excretion of dabigatran and, to some extent, rivaroxaban and apixaban, patients with severe renal impairment were excluded from the major trials of all three drugs.^1–3 Hence, to avoid excessive drug accumulation and bleeding, these medications should not be used in such patients pending further studies. Further, patients taking these medications should be closely followed to detect new clinical situations, such as acute renal failure, that will necessitate their discontinuation or dose adjustment.

If a patient taking a new oral anticoagulant needs to undergo elective surgery, it is important to temporarily discontinue the drug, assess the risk of bleeding, and test for renal impairment.

Renal impairment is particularly relevant in the case of dabigatran, since more than 80% of the unchanged drug is cleared by the kidneys. Decreasing the dose, prolonging the dosing interval, or both have been suggested as means to reduce the risk of bleeding in patients with renal impairment who are taking dabigatran.^32,33 Patients with normal renal function undergoing low-risk surgery should discontinue dabigatran at least 24 hours before the surgery. If the creatinine clearance is 31 to 50 mL/min, inclusively, the last dose should be at least 48 hours before the procedure for low-risk surgery, and 4 days before a procedure that poses a high risk of bleeding.^32–34 Some experts have given the same recommendations for rivaroxaban and apixaban (Table 2).³⁴

The aPTT and prothrombin time are readily available tests, but they cannot determine the residual anticoagulant effects of dabigatran, rivaroxaban, or apixaban. However, in many (but not all) cases, a normal aPTT suggests that the hemostatic function is not impaired by dabigatran, and a normal prothrombin time or an absence of anti-factor Xa activity would similarly exclude hemostatic dysfunction caused by rivaroxaban or apixaban. These tests are potentially useful as adjuncts before surgical procedures that require complete hemostasis.

Furthermore, a normal thrombin time rules out the presence of a significant amount of dabigatran. Therefore, a normal thrombin time might be particularly useful in a patient undergoing a high-risk intervention such as epidural cannulation or neurosurgery and who is normally receiving dabigatran.

Managing overdose and bleeding complications

Assessing the severity of bleeding is the key to managing bleeding complications (Table 3).

Minor bleeding such as epistaxis and ecchymosis can be managed symptomatically (eg, with nasal packing), perhaps with short-term withdrawal of the anticoagulant. Moderate bleeding such as upper or lower gastrointestinal bleeding can be managed by withdrawal of the anticoagulant, clinical monitoring, blood transfusion if needed, and treatment directed at the etiology.

Major and life-threatening bleeding (eg, intracerebral hemorrhage) requires aggressive treatment in the intensive care unit, withdrawal of the anticoagulant, mechanical compression of the bleeding site if accessible, fluid replacement and blood transfusion as appropriate, and interventional procedures. Nonspecific reversal agents might be considered in patients with major or life-threatening bleeding.

The half-life of dabigatran after multiple doses is approximately 14 to 17 hours and is not dose-dependent.⁹ Hence, if there is no active bleeding after a dabigatran overdose, stopping the drug may be sufficient. Since the pharmacodynamic effect of dabigatran declines in parallel to its plasma concentration, urgent but not emergency surgery may need to be delayed for only about 12 hours from the last dose of dabigatran.

The 2011 American College of Cardiology Foundation/American Heart Association guidelines recommend that patients with severe hemorrhage resulting from dabigatran should receive supportive therapy, including transfusion of fresh-frozen plasma, transfusion of packed red blood cells, or surgical intervention if appropriate.³⁵ However, transfusion of fresh-frozen plasma is debatable because there is no evidence to support its use in this situation. While fresh-frozen plasma may be useful in cases of coagulation factor depletion, it does not effectively reverse inhibition of coagulation factors.³⁶

Off-label use of nonspecific hemostatic agents

To date, no specific agent has been demonstrated to reverse excessive bleeding in patients taking the new oral anticoagulants. However, in view of their procoagulant capabilities, nonspecific hemostatic agents have been suggested for use in reversal of major bleeding resulting from these drugs.^37–39 Examples are:

Recombinant factor VIIa (NovoSeven) initiates thrombin generation by activating factor X.

Four-factor prothrombin complex concentrate (Beriplex, recently approved in the United States) contains relatively large amounts of four nonactive vitamin K-dependent procoagulant factors (factors II, VII, IX, and X) that stimulate thrombin formation.

Three-factor prothrombin complex concentrate (Bebulin VH and Profilnine SD) contains low amounts of nonactive factor VII relative to factors II, IX, and X. In some centers a four-factor equivalent is produced by transfusion of a three-factor product with the addition of small amounts of recombinant factor VIIa or fresh-frozen plasma to replace the missing factor VII.⁴⁰

Activated prothrombin complex concentrate (FEIBA NF) contains activated factor VII and factors II, IX, and X, mainly in nonactivated form.³⁶ Therefore, it combines the effect of both recombinant factor VIIa and four-factor prothrombin complex concentrate.³⁷

Studies of nonspecific hemostatic agents

In a study of rats infused with high doses of dabigatran, van Ryn et al³⁸ observed that activated prothrombin complex concentrate at a dose of 50 or 100 U/kg and recombinant factor VIIa at a dose of 0.1 or 0.5 mg/kg reduced the rat-tail bleeding time in a dose-dependent manner but not the blood loss, compared with controls, even with a higher dose of recombinant factor VIIa (1 mg/kg). Recombinant factor VIIa also reversed the prolonged aPTT induced by dabigatran, whereas activated prothrombin complex concentrate did not. They suggested that recombinant factor VIIa and activated prothrombin complex concentrate may be potential antidotes for dabigatran-induced severe bleeding in humans.

In an ex vivo study of healthy people who took a single dose of dabigatran 150 mg or rivaroxaban 20 mg, Marlu et al³⁷ found that activated prothrombin complex concentrate and four-factor prothrombin complex concentrate could be reasonable antidotes to these drugs.

Dabigatran-associated bleeding after cardiac surgery in humans has been successfully managed with hemodialysis and recombinant factor VIIa, although the efficacy of the latter cannot be individually assessed in the study.⁴¹

In a randomized placebo-controlled trial aimed at reversing rivaroxaban and dabigatran in healthy participants, Eerenberg et al³⁹ showed that four-factor prothrombin complex concentrate at a dose of 50 IU/kg reversed prolongation of the prothrombin time and decreased the endogenous thrombin potential in those who received rivaroxaban, but it failed to reverse the aPTT, the endogenous thrombin potential, and thrombin time in those who received dabigatran.

However, Marlu et al reported that four-factor prothrombin complex concentrate at three doses (12.5 U/kg, 25 U/kg, and 50 U/kg)—or better still, activated prothrombin complex concentrate (40–80 U/kg)—could be a useful antidote to dabigatran.³⁷

It is important to note that the healthy participants in the Eerenberg et al study³⁹ took dabigatran 150 mg twice daily and rivaroxaban 20 mg daily for 2.5 days, whereas those in the Marlu et al study³⁷ took the same dose of each medication, but only once.

The three-factor prothrombin complex concentrate products have been shown to be less effective than four-factor ones in reversing supratherapeutic INRs in patients with warfarin overdose, but whether this will be true with the new oral anticoagulants remains unknown. Furthermore, the four-factor concentrates effectively reversed warfarin-induced coagulopathy and bleeding in patients,⁴² but to our knowledge, the same is yet to be demonstrated in bleeding related to the newer agents.

Other measures

Gastric lavage or the administration of activated charcoal (or in some cases both) may reduce drug absorption if done within 2 or 3 hours of drug ingestion (Table 1). Because it is lipophilic, more than 99.9% of dabigatran etexilate was adsorbed by activated charcoal from water prepared to simulate gastric fluid in an in vitro experiment by van Ryn et al.⁴³ This has not been tested in patients, and no similar study has been done for rivaroxaban or apixaban. However, use of charcoal in cases of recent ingestion, particularly with intentional overdose of these agents, seems reasonable.

Hemodialysis may reverse the anticoagulant effects of dabigatran overdose or severe bleeding because only about 35% of dabigatran is bound to plasma proteins (Table 1). In a single-center study, 50 mg of dabigatran etexilate was given orally to six patients with end-stage renal disease before dialysis, and the mean fraction of the drug removed by the dialyzer was 62% at 2 hours and 68% at 4 hours.³² This study suggests that hemodialysis may be useful to accelerate the removal of the drug in cases of life-threatening bleeding.

Rivaroxaban and apixaban are not dialyzable: the plasma protein binding of rivaroxaban is 95% and that of apixaban is 87%.

FUTURE DIRECTIONS

Because the new oral anticoagulants, unlike warfarin, have a wide therapeutic window, routine anticoagulant monitoring is not needed and might be misleading. However, there are times when monitoring might be useful; at such times, a validated, widely available, easily understood test would be good to have—but we don’t have it—at least not yet.

Therapeutic ranges for the aPTT have been established empirically for heparin in various indications.⁴⁴ Additional study is needed to determine if an appropriate aPTT range can be determined for the new oral anticoagulants, particularly dabigatran.

Similarly, as with low-molecular-weight heparins, anti-factor Xa activity monitoring may become a more available validated means of testing for exposure to rivaroxaban and apixaban. More promising, using concepts derived from the development of the INR for warfarin monitoring,⁴⁵ Tripodi et al⁴⁶ have derived normalized INR-like assays to report rivaroxaban levels. A standardized schema for reporting results is being developed.⁴⁶ Studies are required to determine if and how this assay may be useful. Initial trials in this regard are encouraging.⁴⁷

Finally, the thrombotic risk associated with the use of nonspecific prohemostatic agents is unknown.^37,48 Additional studies are required to standardize their dosages, frequency of administration, and duration of action, as well as to quantify their complications in bleeding patients.

In the past several years, three new oral anticoagulants—dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)—have been approved for use in the United States. These long-awaited agents are appealing because they are easy to use, do not require laboratory monitoring, and have demonstrated equivalence, or in some cases, superiority to warfarin in preventing stroke or systemic embolism in at-risk populations.^1–4 However, unlike warfarin, they have no specific reversal agents. How then should one manage spontaneous bleeding problems and those due to drug overdose, and how can we quickly reverse anticoagulation if emergency surgery is needed?

For these reasons, physicians and patients have been wary of these agents. However, with a systematic approach based on an understanding of the properties of these drugs, the appropriate use and interpretation of coagulation tests, and awareness of available therapeutic strategies, physicians can more confidently provide care for patients who require urgent reversal of anticoagulant effects.

Here, we review the available literature and suggest practical strategies for management based on an understanding of the pharmacokinetic and pharmacodynamic effects of these drugs and our current knowledge of the coagulation tests.

NEED FOR ANTICOAGULANTS

Anticoagulants are important in preventing systemic embolization in patients with atrial fibrillation and preventing pulmonary embolism in patients with venous thromboembolism.

And the numbers are staggering. The estimated prevalence of atrial fibrillation in the United States was 3.03 million in 2005 and is projected to increase to 7.56 million by 2050.⁵ Ischemic stroke is the most serious complication of atrial fibrillation, which accounts for 23.5% of strokes in patients ages 80 through 89 according to Framingham data.⁶ Venous thromboembolism accounts for 900,000 incident or recurrent fatal and nonfatal events in the United States yearly.⁷

HOW THE NEW AGENTS BLOCK COAGULATION

Thrombin (factor IIa), a serine protease, is central to the process of clot formation during hemostasis. It activates factors V, VIII, and XI (thus generating more thrombin), catalyzes the conversion of fibrinogen to fibrin, and stimulates platelet aggregation. Its role in the final steps of the coagulation cascade has made it a target for new direct thrombin inhibitors such as dabigatran.

Factor Xa is a serine protease that plays a central role in the coagulation cascade. It is a desirable target for anticoagulation because it is the convergence point for the extrinsic and the intrinsic coagulation pathways. It converts prothrombin to thrombin. Rivaroxaban and apixaban are direct factor Xa inhibitors (Figure 1).

Dabigatran, a direct thrombin inhibitor

Dabigatran etexilate is a synthetic, orally available prodrug that is rapidly absorbed and converted by esterases to its active form, dabigatran, a potent direct inhibitor of both free thrombin and clot-bound thrombin.⁸

Plasma levels of dabigatran peak within 2 hours of administration, and its half-life is 14 to 17 hours.⁹ Dabigatran is eliminated mainly via the kidneys, with more that 80% of the drug excreted unchanged in the urine (Table 1).

Rivaroxaban, a factor Xa inhibitor

Rivaroxaban is a potent, selective, direct factor Xa inhibitor.

Plasma levels of rivaroxaban peak 2 to 3 hours after administration, and it is cleared with a terminal half-life of 7 to 11 hours.^10,11

Rivaroxaban is eliminated by the kidneys and in the feces. The kidneys eliminate one-third of the active drug unchanged and another one-third as inactive metabolites. The remaining one-third is metabolized by the liver and then excreted in the feces. Rivaroxaban has a predictable and dose-dependent pharmacodynamic and pharmacokinetic profile that is not affected by age, sex, or body weight (Table 1).¹²

Apixaban, an oral factor Xa inhibitor

Apixaban is a selective, direct oral factor Xa inhibitor.

Plasma levels of apixaban peak about 3 hours after administration, and its terminal half-life is 8 to 14 hours.¹³ Apixaban is eliminated by oxidative metabolism, by the kidney, and in the feces. It has predictable pharmacodynamic and pharmacokinetic profiles and has the least renal dependence of the three agents (Table 1).

THE NEW ORAL ANTICOAGULANTS AND BLOOD COAGULATION ASSAYS

Assessment of the anticoagulant activity of the new oral anticoagulants is not necessary in routine clinical practice, but it may be useful in planning intervention in patients with major bleeding, those with drug overdose, or those who need emergency surgery.

The activated partial thromboplastin time

The activated partial thromboplastin time (aPTT) is a measure of the activity of the intrinsic pathway of the coagulation cascade.

Dabigatran. There is a curvilinear relationship between the aPTT and the plasma concentration of dabigatran and other direct thrombin inhibitors, although the aPTT prolongation appears to vary with different reagents and coagulometers.^9,14,15 However, Stangier et al⁹ found a linear relationship between the aPTT and the square root of the dabigatran plasma concentration.

Rivaroxaban prolongs the aPTT in a dose-dependent manner, but there is no standard for calibration of this assay. Hence, the aPTT is not recommended for monitoring rivaroxaban in clinical practice.

Apixaban may also prolong the aPTT, but there are limited data on its reactivity with different reagents.

The prothrombin time and international normalized ratio

The prothrombin time and international normalized ratio (INR) are measures of the extrinsic pathway of the coagulation cascade.

Dabigatran. The INR has a linear response to the dabigatran concentration, but it is insensitive.⁹ Hence, it is not suitable for monitoring the anticoagulant effects of direct thrombin inhibitors.

Rivaroxaban. The prothrombin time correlates strongly with the plasma concentration of rivaroxaban in healthy trial participants¹¹ and in patients undergoing total hip arthroplasty or total knee arthroplasty.¹⁶ Samama et al¹⁷ noted that, unlike with vitamin K antagonists, the INR cannot be used to monitor patients on rivaroxaban because the prothrombin time results varied with different reagents. They used a standard calibration curve to express the prothrombin time results in plasma concentrations of rivaroxaban rather than in seconds or the INR.

Apixaban increases the INR in a dose-dependent manner.¹⁸ Its effect on different reagents remains unknown.

The thrombin time

The thrombin time reflects the activity of thrombin in the plasma. The amount of thrombin and the concentration of thrombin inhibitors in the plasma sample determine the time to clot formation.

Dabigatran. The thrombin time displays a linear dose-response to dabigatran, but only over the range of therapeutic concentrations. At a dabigatran concentration greater than 600 ng/mL, the test often exceeds the maximum measurement time of coagulometers.⁹ Hence, this test is too sensitive for emergency monitoring, especially in cases of drug overdose. However, it is well suited for determining if any dabigatran is present.

Rivaroxaban and apixaban have no effect on the thrombin time.

The Hemoclot direct thrombin inhibitor assay and dabigatran

The Hemoclot direct thrombin inhibitor assay (Hyphen BioMed, France) is a sensitive diluted thrombin time assay that can be used for quantitative measurement of dabigatran activity in plasma. This test is based on inhibition of a constant amount of highly purified human alpha-thrombin by adding it to diluted test plasma (1:8 to 1:20) mixed with normal pooled human plasma.^19,20

Stangier et al¹⁹ found that the Hemoclot assay was suitable for calculating a wide range of dabigatran concentrations up to 4,000 nmol/L (1,886 ng/mL). Although this finding has not been confirmed in larger studies, this test may provide a rapid and accurate assessment of dabigatran’s anticoagulant activity in cases of emergency surgery or overdose.

The ecarin clotting time and dabigatran

The ecarin clotting time is a measure of the activity of direct thrombin inhibitors, but not the factor Xa inhibitors.

Ecarin is a highly purified metalloprotease isolated from the venom of a snake, Echis carinatus, and it generates meizothrombin from prothrombin.²¹ Meizothrombin facilitates clot formation by converting fibrinogen to fibrin and, like thrombin, it can be inactivated by direct thrombin inhibitors, thereby prolonging the clotting time.

The limitations of the ecarin clotting time include dependence on the plasma levels of fibrinogen and prothrombin.

The ecarin chromogenic assay and dabigatran

The ecarin chromogenic assay is an improvement on the principle of the ecarin clotting time that can be used to measure the activity of direct thrombin inhibitors.²² In this test, ecarin is added to a plasma sample to generate meizothrombin, and the amidolytic activity of meizothrombin towards a chromogenic substrate is then determined.

Results of the ecarin chromogenic assay are not influenced by the levels of fibrinogen or prothrombin. Another advantage is that this assay can be used in automated and manual analyzers, thus enabling its use at the bedside. However, to our knowledge, it is not being regularly used to monitor direct thrombin inhibitors in the clinical setting, and there is no standard calibration of the ecarin clotting time method.

Assays of factor Xa activity

A variety of assays to monitor the anticoagulant activity of factor Xa inhibitors have been proposed.^23–25 All measure inhibition of the activity of factor Xa using methods similar to those used in monitoring heparin levels. All require calibrators with a known concentration of the Xa inhibitor; many are easily adapted for laboratories currently providing measurement of factor Xa inhibition from heparin.²³ These assays have been suggested as a better indicator of plasma concentration of factor Xa inhibitor drugs than the prothrombin time.²⁵

CONTROLLING BLEEDING IN PATIENTS ON THE NEW ORAL ANTICOAGULANTS

Bleeding is an anticipated adverse event in patients taking anticoagulants. It is associated with significant morbidity and risk of death.^26,27

Many physicians still have limited experience with using the new oral anticoagulants and managing the attendant bleeding risks. Hence, we recommend that every health institution have a treatment policy or algorithm to guide all clinical staff in the management of such emergencies.

Prevention of bleeding

Management of bleeding from these agents should begin with preventing bleeding in the first place.

The physician should adhere to the recommended dosages of these medications. Studies have shown that the plasma concentration of these drugs and the risk of bleeding increase with increasing dosage.^1,28,29

In addition, these medications should be used for the shortest time for which anticoagulation is required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding.^30,31

Most patients who need anticoagulation have comorbidities such as heart failure, renal failure, diabetes mellitus, and hypertension. Although the kidneys play a major role in the excretion of dabigatran and, to some extent, rivaroxaban and apixaban, patients with severe renal impairment were excluded from the major trials of all three drugs.^1–3 Hence, to avoid excessive drug accumulation and bleeding, these medications should not be used in such patients pending further studies. Further, patients taking these medications should be closely followed to detect new clinical situations, such as acute renal failure, that will necessitate their discontinuation or dose adjustment.

If a patient taking a new oral anticoagulant needs to undergo elective surgery, it is important to temporarily discontinue the drug, assess the risk of bleeding, and test for renal impairment.

Renal impairment is particularly relevant in the case of dabigatran, since more than 80% of the unchanged drug is cleared by the kidneys. Decreasing the dose, prolonging the dosing interval, or both have been suggested as means to reduce the risk of bleeding in patients with renal impairment who are taking dabigatran.^32,33 Patients with normal renal function undergoing low-risk surgery should discontinue dabigatran at least 24 hours before the surgery. If the creatinine clearance is 31 to 50 mL/min, inclusively, the last dose should be at least 48 hours before the procedure for low-risk surgery, and 4 days before a procedure that poses a high risk of bleeding.^32–34 Some experts have given the same recommendations for rivaroxaban and apixaban (Table 2).³⁴

The aPTT and prothrombin time are readily available tests, but they cannot determine the residual anticoagulant effects of dabigatran, rivaroxaban, or apixaban. However, in many (but not all) cases, a normal aPTT suggests that the hemostatic function is not impaired by dabigatran, and a normal prothrombin time or an absence of anti-factor Xa activity would similarly exclude hemostatic dysfunction caused by rivaroxaban or apixaban. These tests are potentially useful as adjuncts before surgical procedures that require complete hemostasis.

Furthermore, a normal thrombin time rules out the presence of a significant amount of dabigatran. Therefore, a normal thrombin time might be particularly useful in a patient undergoing a high-risk intervention such as epidural cannulation or neurosurgery and who is normally receiving dabigatran.

Managing overdose and bleeding complications

Assessing the severity of bleeding is the key to managing bleeding complications (Table 3).

Minor bleeding such as epistaxis and ecchymosis can be managed symptomatically (eg, with nasal packing), perhaps with short-term withdrawal of the anticoagulant. Moderate bleeding such as upper or lower gastrointestinal bleeding can be managed by withdrawal of the anticoagulant, clinical monitoring, blood transfusion if needed, and treatment directed at the etiology.

Major and life-threatening bleeding (eg, intracerebral hemorrhage) requires aggressive treatment in the intensive care unit, withdrawal of the anticoagulant, mechanical compression of the bleeding site if accessible, fluid replacement and blood transfusion as appropriate, and interventional procedures. Nonspecific reversal agents might be considered in patients with major or life-threatening bleeding.

The half-life of dabigatran after multiple doses is approximately 14 to 17 hours and is not dose-dependent.⁹ Hence, if there is no active bleeding after a dabigatran overdose, stopping the drug may be sufficient. Since the pharmacodynamic effect of dabigatran declines in parallel to its plasma concentration, urgent but not emergency surgery may need to be delayed for only about 12 hours from the last dose of dabigatran.

The 2011 American College of Cardiology Foundation/American Heart Association guidelines recommend that patients with severe hemorrhage resulting from dabigatran should receive supportive therapy, including transfusion of fresh-frozen plasma, transfusion of packed red blood cells, or surgical intervention if appropriate.³⁵ However, transfusion of fresh-frozen plasma is debatable because there is no evidence to support its use in this situation. While fresh-frozen plasma may be useful in cases of coagulation factor depletion, it does not effectively reverse inhibition of coagulation factors.³⁶

Off-label use of nonspecific hemostatic agents

To date, no specific agent has been demonstrated to reverse excessive bleeding in patients taking the new oral anticoagulants. However, in view of their procoagulant capabilities, nonspecific hemostatic agents have been suggested for use in reversal of major bleeding resulting from these drugs.^37–39 Examples are:

Recombinant factor VIIa (NovoSeven) initiates thrombin generation by activating factor X.

Four-factor prothrombin complex concentrate (Beriplex, recently approved in the United States) contains relatively large amounts of four nonactive vitamin K-dependent procoagulant factors (factors II, VII, IX, and X) that stimulate thrombin formation.

Three-factor prothrombin complex concentrate (Bebulin VH and Profilnine SD) contains low amounts of nonactive factor VII relative to factors II, IX, and X. In some centers a four-factor equivalent is produced by transfusion of a three-factor product with the addition of small amounts of recombinant factor VIIa or fresh-frozen plasma to replace the missing factor VII.⁴⁰

Activated prothrombin complex concentrate (FEIBA NF) contains activated factor VII and factors II, IX, and X, mainly in nonactivated form.³⁶ Therefore, it combines the effect of both recombinant factor VIIa and four-factor prothrombin complex concentrate.³⁷

Studies of nonspecific hemostatic agents

In a study of rats infused with high doses of dabigatran, van Ryn et al³⁸ observed that activated prothrombin complex concentrate at a dose of 50 or 100 U/kg and recombinant factor VIIa at a dose of 0.1 or 0.5 mg/kg reduced the rat-tail bleeding time in a dose-dependent manner but not the blood loss, compared with controls, even with a higher dose of recombinant factor VIIa (1 mg/kg). Recombinant factor VIIa also reversed the prolonged aPTT induced by dabigatran, whereas activated prothrombin complex concentrate did not. They suggested that recombinant factor VIIa and activated prothrombin complex concentrate may be potential antidotes for dabigatran-induced severe bleeding in humans.

In an ex vivo study of healthy people who took a single dose of dabigatran 150 mg or rivaroxaban 20 mg, Marlu et al³⁷ found that activated prothrombin complex concentrate and four-factor prothrombin complex concentrate could be reasonable antidotes to these drugs.

Dabigatran-associated bleeding after cardiac surgery in humans has been successfully managed with hemodialysis and recombinant factor VIIa, although the efficacy of the latter cannot be individually assessed in the study.⁴¹

In a randomized placebo-controlled trial aimed at reversing rivaroxaban and dabigatran in healthy participants, Eerenberg et al³⁹ showed that four-factor prothrombin complex concentrate at a dose of 50 IU/kg reversed prolongation of the prothrombin time and decreased the endogenous thrombin potential in those who received rivaroxaban, but it failed to reverse the aPTT, the endogenous thrombin potential, and thrombin time in those who received dabigatran.

However, Marlu et al reported that four-factor prothrombin complex concentrate at three doses (12.5 U/kg, 25 U/kg, and 50 U/kg)—or better still, activated prothrombin complex concentrate (40–80 U/kg)—could be a useful antidote to dabigatran.³⁷

It is important to note that the healthy participants in the Eerenberg et al study³⁹ took dabigatran 150 mg twice daily and rivaroxaban 20 mg daily for 2.5 days, whereas those in the Marlu et al study³⁷ took the same dose of each medication, but only once.

The three-factor prothrombin complex concentrate products have been shown to be less effective than four-factor ones in reversing supratherapeutic INRs in patients with warfarin overdose, but whether this will be true with the new oral anticoagulants remains unknown. Furthermore, the four-factor concentrates effectively reversed warfarin-induced coagulopathy and bleeding in patients,⁴² but to our knowledge, the same is yet to be demonstrated in bleeding related to the newer agents.

Other measures

Gastric lavage or the administration of activated charcoal (or in some cases both) may reduce drug absorption if done within 2 or 3 hours of drug ingestion (Table 1). Because it is lipophilic, more than 99.9% of dabigatran etexilate was adsorbed by activated charcoal from water prepared to simulate gastric fluid in an in vitro experiment by van Ryn et al.⁴³ This has not been tested in patients, and no similar study has been done for rivaroxaban or apixaban. However, use of charcoal in cases of recent ingestion, particularly with intentional overdose of these agents, seems reasonable.

Hemodialysis may reverse the anticoagulant effects of dabigatran overdose or severe bleeding because only about 35% of dabigatran is bound to plasma proteins (Table 1). In a single-center study, 50 mg of dabigatran etexilate was given orally to six patients with end-stage renal disease before dialysis, and the mean fraction of the drug removed by the dialyzer was 62% at 2 hours and 68% at 4 hours.³² This study suggests that hemodialysis may be useful to accelerate the removal of the drug in cases of life-threatening bleeding.

Rivaroxaban and apixaban are not dialyzable: the plasma protein binding of rivaroxaban is 95% and that of apixaban is 87%.

FUTURE DIRECTIONS

Because the new oral anticoagulants, unlike warfarin, have a wide therapeutic window, routine anticoagulant monitoring is not needed and might be misleading. However, there are times when monitoring might be useful; at such times, a validated, widely available, easily understood test would be good to have—but we don’t have it—at least not yet.

Therapeutic ranges for the aPTT have been established empirically for heparin in various indications.⁴⁴ Additional study is needed to determine if an appropriate aPTT range can be determined for the new oral anticoagulants, particularly dabigatran.

Similarly, as with low-molecular-weight heparins, anti-factor Xa activity monitoring may become a more available validated means of testing for exposure to rivaroxaban and apixaban. More promising, using concepts derived from the development of the INR for warfarin monitoring,⁴⁵ Tripodi et al⁴⁶ have derived normalized INR-like assays to report rivaroxaban levels. A standardized schema for reporting results is being developed.⁴⁶ Studies are required to determine if and how this assay may be useful. Initial trials in this regard are encouraging.⁴⁷

Finally, the thrombotic risk associated with the use of nonspecific prohemostatic agents is unknown.^37,48 Additional studies are required to standardize their dosages, frequency of administration, and duration of action, as well as to quantify their complications in bleeding patients.

In the past several years, three new oral anticoagulants—dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)—have been approved for use in the United States. These long-awaited agents are appealing because they are easy to use, do not require laboratory monitoring, and have demonstrated equivalence, or in some cases, superiority to warfarin in preventing stroke or systemic embolism in at-risk populations.^1–4 However, unlike warfarin, they have no specific reversal agents. How then should one manage spontaneous bleeding problems and those due to drug overdose, and how can we quickly reverse anticoagulation if emergency surgery is needed?

For these reasons, physicians and patients have been wary of these agents. However, with a systematic approach based on an understanding of the properties of these drugs, the appropriate use and interpretation of coagulation tests, and awareness of available therapeutic strategies, physicians can more confidently provide care for patients who require urgent reversal of anticoagulant effects.

Here, we review the available literature and suggest practical strategies for management based on an understanding of the pharmacokinetic and pharmacodynamic effects of these drugs and our current knowledge of the coagulation tests.

NEED FOR ANTICOAGULANTS

Anticoagulants are important in preventing systemic embolization in patients with atrial fibrillation and preventing pulmonary embolism in patients with venous thromboembolism.

And the numbers are staggering. The estimated prevalence of atrial fibrillation in the United States was 3.03 million in 2005 and is projected to increase to 7.56 million by 2050.⁵ Ischemic stroke is the most serious complication of atrial fibrillation, which accounts for 23.5% of strokes in patients ages 80 through 89 according to Framingham data.⁶ Venous thromboembolism accounts for 900,000 incident or recurrent fatal and nonfatal events in the United States yearly.⁷

HOW THE NEW AGENTS BLOCK COAGULATION

Thrombin (factor IIa), a serine protease, is central to the process of clot formation during hemostasis. It activates factors V, VIII, and XI (thus generating more thrombin), catalyzes the conversion of fibrinogen to fibrin, and stimulates platelet aggregation. Its role in the final steps of the coagulation cascade has made it a target for new direct thrombin inhibitors such as dabigatran.

Factor Xa is a serine protease that plays a central role in the coagulation cascade. It is a desirable target for anticoagulation because it is the convergence point for the extrinsic and the intrinsic coagulation pathways. It converts prothrombin to thrombin. Rivaroxaban and apixaban are direct factor Xa inhibitors (Figure 1).

Dabigatran, a direct thrombin inhibitor

Dabigatran etexilate is a synthetic, orally available prodrug that is rapidly absorbed and converted by esterases to its active form, dabigatran, a potent direct inhibitor of both free thrombin and clot-bound thrombin.⁸

Plasma levels of dabigatran peak within 2 hours of administration, and its half-life is 14 to 17 hours.⁹ Dabigatran is eliminated mainly via the kidneys, with more that 80% of the drug excreted unchanged in the urine (Table 1).

Rivaroxaban, a factor Xa inhibitor

Rivaroxaban is a potent, selective, direct factor Xa inhibitor.

Plasma levels of rivaroxaban peak 2 to 3 hours after administration, and it is cleared with a terminal half-life of 7 to 11 hours.^10,11

Rivaroxaban is eliminated by the kidneys and in the feces. The kidneys eliminate one-third of the active drug unchanged and another one-third as inactive metabolites. The remaining one-third is metabolized by the liver and then excreted in the feces. Rivaroxaban has a predictable and dose-dependent pharmacodynamic and pharmacokinetic profile that is not affected by age, sex, or body weight (Table 1).¹²

Apixaban, an oral factor Xa inhibitor

Apixaban is a selective, direct oral factor Xa inhibitor.

Plasma levels of apixaban peak about 3 hours after administration, and its terminal half-life is 8 to 14 hours.¹³ Apixaban is eliminated by oxidative metabolism, by the kidney, and in the feces. It has predictable pharmacodynamic and pharmacokinetic profiles and has the least renal dependence of the three agents (Table 1).

THE NEW ORAL ANTICOAGULANTS AND BLOOD COAGULATION ASSAYS

Assessment of the anticoagulant activity of the new oral anticoagulants is not necessary in routine clinical practice, but it may be useful in planning intervention in patients with major bleeding, those with drug overdose, or those who need emergency surgery.

The activated partial thromboplastin time

The activated partial thromboplastin time (aPTT) is a measure of the activity of the intrinsic pathway of the coagulation cascade.

Dabigatran. There is a curvilinear relationship between the aPTT and the plasma concentration of dabigatran and other direct thrombin inhibitors, although the aPTT prolongation appears to vary with different reagents and coagulometers.^9,14,15 However, Stangier et al⁹ found a linear relationship between the aPTT and the square root of the dabigatran plasma concentration.

Rivaroxaban prolongs the aPTT in a dose-dependent manner, but there is no standard for calibration of this assay. Hence, the aPTT is not recommended for monitoring rivaroxaban in clinical practice.

Apixaban may also prolong the aPTT, but there are limited data on its reactivity with different reagents.

The prothrombin time and international normalized ratio

The prothrombin time and international normalized ratio (INR) are measures of the extrinsic pathway of the coagulation cascade.

Dabigatran. The INR has a linear response to the dabigatran concentration, but it is insensitive.⁹ Hence, it is not suitable for monitoring the anticoagulant effects of direct thrombin inhibitors.

Rivaroxaban. The prothrombin time correlates strongly with the plasma concentration of rivaroxaban in healthy trial participants¹¹ and in patients undergoing total hip arthroplasty or total knee arthroplasty.¹⁶ Samama et al¹⁷ noted that, unlike with vitamin K antagonists, the INR cannot be used to monitor patients on rivaroxaban because the prothrombin time results varied with different reagents. They used a standard calibration curve to express the prothrombin time results in plasma concentrations of rivaroxaban rather than in seconds or the INR.

Apixaban increases the INR in a dose-dependent manner.¹⁸ Its effect on different reagents remains unknown.

The thrombin time

The thrombin time reflects the activity of thrombin in the plasma. The amount of thrombin and the concentration of thrombin inhibitors in the plasma sample determine the time to clot formation.

Dabigatran. The thrombin time displays a linear dose-response to dabigatran, but only over the range of therapeutic concentrations. At a dabigatran concentration greater than 600 ng/mL, the test often exceeds the maximum measurement time of coagulometers.⁹ Hence, this test is too sensitive for emergency monitoring, especially in cases of drug overdose. However, it is well suited for determining if any dabigatran is present.

Rivaroxaban and apixaban have no effect on the thrombin time.

The Hemoclot direct thrombin inhibitor assay and dabigatran

The Hemoclot direct thrombin inhibitor assay (Hyphen BioMed, France) is a sensitive diluted thrombin time assay that can be used for quantitative measurement of dabigatran activity in plasma. This test is based on inhibition of a constant amount of highly purified human alpha-thrombin by adding it to diluted test plasma (1:8 to 1:20) mixed with normal pooled human plasma.^19,20

Stangier et al¹⁹ found that the Hemoclot assay was suitable for calculating a wide range of dabigatran concentrations up to 4,000 nmol/L (1,886 ng/mL). Although this finding has not been confirmed in larger studies, this test may provide a rapid and accurate assessment of dabigatran’s anticoagulant activity in cases of emergency surgery or overdose.

The ecarin clotting time and dabigatran

The ecarin clotting time is a measure of the activity of direct thrombin inhibitors, but not the factor Xa inhibitors.

Ecarin is a highly purified metalloprotease isolated from the venom of a snake, Echis carinatus, and it generates meizothrombin from prothrombin.²¹ Meizothrombin facilitates clot formation by converting fibrinogen to fibrin and, like thrombin, it can be inactivated by direct thrombin inhibitors, thereby prolonging the clotting time.

The limitations of the ecarin clotting time include dependence on the plasma levels of fibrinogen and prothrombin.

The ecarin chromogenic assay and dabigatran

The ecarin chromogenic assay is an improvement on the principle of the ecarin clotting time that can be used to measure the activity of direct thrombin inhibitors.²² In this test, ecarin is added to a plasma sample to generate meizothrombin, and the amidolytic activity of meizothrombin towards a chromogenic substrate is then determined.

Results of the ecarin chromogenic assay are not influenced by the levels of fibrinogen or prothrombin. Another advantage is that this assay can be used in automated and manual analyzers, thus enabling its use at the bedside. However, to our knowledge, it is not being regularly used to monitor direct thrombin inhibitors in the clinical setting, and there is no standard calibration of the ecarin clotting time method.

Assays of factor Xa activity

A variety of assays to monitor the anticoagulant activity of factor Xa inhibitors have been proposed.^23–25 All measure inhibition of the activity of factor Xa using methods similar to those used in monitoring heparin levels. All require calibrators with a known concentration of the Xa inhibitor; many are easily adapted for laboratories currently providing measurement of factor Xa inhibition from heparin.²³ These assays have been suggested as a better indicator of plasma concentration of factor Xa inhibitor drugs than the prothrombin time.²⁵

CONTROLLING BLEEDING IN PATIENTS ON THE NEW ORAL ANTICOAGULANTS

Bleeding is an anticipated adverse event in patients taking anticoagulants. It is associated with significant morbidity and risk of death.^26,27

Many physicians still have limited experience with using the new oral anticoagulants and managing the attendant bleeding risks. Hence, we recommend that every health institution have a treatment policy or algorithm to guide all clinical staff in the management of such emergencies.

Prevention of bleeding

Management of bleeding from these agents should begin with preventing bleeding in the first place.

The physician should adhere to the recommended dosages of these medications. Studies have shown that the plasma concentration of these drugs and the risk of bleeding increase with increasing dosage.^1,28,29

In addition, these medications should be used for the shortest time for which anticoagulation is required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding.^30,31

Most patients who need anticoagulation have comorbidities such as heart failure, renal failure, diabetes mellitus, and hypertension. Although the kidneys play a major role in the excretion of dabigatran and, to some extent, rivaroxaban and apixaban, patients with severe renal impairment were excluded from the major trials of all three drugs.^1–3 Hence, to avoid excessive drug accumulation and bleeding, these medications should not be used in such patients pending further studies. Further, patients taking these medications should be closely followed to detect new clinical situations, such as acute renal failure, that will necessitate their discontinuation or dose adjustment.

If a patient taking a new oral anticoagulant needs to undergo elective surgery, it is important to temporarily discontinue the drug, assess the risk of bleeding, and test for renal impairment.

Renal impairment is particularly relevant in the case of dabigatran, since more than 80% of the unchanged drug is cleared by the kidneys. Decreasing the dose, prolonging the dosing interval, or both have been suggested as means to reduce the risk of bleeding in patients with renal impairment who are taking dabigatran.^32,33 Patients with normal renal function undergoing low-risk surgery should discontinue dabigatran at least 24 hours before the surgery. If the creatinine clearance is 31 to 50 mL/min, inclusively, the last dose should be at least 48 hours before the procedure for low-risk surgery, and 4 days before a procedure that poses a high risk of bleeding.^32–34 Some experts have given the same recommendations for rivaroxaban and apixaban (Table 2).³⁴

The aPTT and prothrombin time are readily available tests, but they cannot determine the residual anticoagulant effects of dabigatran, rivaroxaban, or apixaban. However, in many (but not all) cases, a normal aPTT suggests that the hemostatic function is not impaired by dabigatran, and a normal prothrombin time or an absence of anti-factor Xa activity would similarly exclude hemostatic dysfunction caused by rivaroxaban or apixaban. These tests are potentially useful as adjuncts before surgical procedures that require complete hemostasis.

Furthermore, a normal thrombin time rules out the presence of a significant amount of dabigatran. Therefore, a normal thrombin time might be particularly useful in a patient undergoing a high-risk intervention such as epidural cannulation or neurosurgery and who is normally receiving dabigatran.

Managing overdose and bleeding complications

Assessing the severity of bleeding is the key to managing bleeding complications (Table 3).

Minor bleeding such as epistaxis and ecchymosis can be managed symptomatically (eg, with nasal packing), perhaps with short-term withdrawal of the anticoagulant. Moderate bleeding such as upper or lower gastrointestinal bleeding can be managed by withdrawal of the anticoagulant, clinical monitoring, blood transfusion if needed, and treatment directed at the etiology.

Major and life-threatening bleeding (eg, intracerebral hemorrhage) requires aggressive treatment in the intensive care unit, withdrawal of the anticoagulant, mechanical compression of the bleeding site if accessible, fluid replacement and blood transfusion as appropriate, and interventional procedures. Nonspecific reversal agents might be considered in patients with major or life-threatening bleeding.

The half-life of dabigatran after multiple doses is approximately 14 to 17 hours and is not dose-dependent.⁹ Hence, if there is no active bleeding after a dabigatran overdose, stopping the drug may be sufficient. Since the pharmacodynamic effect of dabigatran declines in parallel to its plasma concentration, urgent but not emergency surgery may need to be delayed for only about 12 hours from the last dose of dabigatran.

The 2011 American College of Cardiology Foundation/American Heart Association guidelines recommend that patients with severe hemorrhage resulting from dabigatran should receive supportive therapy, including transfusion of fresh-frozen plasma, transfusion of packed red blood cells, or surgical intervention if appropriate.³⁵ However, transfusion of fresh-frozen plasma is debatable because there is no evidence to support its use in this situation. While fresh-frozen plasma may be useful in cases of coagulation factor depletion, it does not effectively reverse inhibition of coagulation factors.³⁶

Off-label use of nonspecific hemostatic agents

To date, no specific agent has been demonstrated to reverse excessive bleeding in patients taking the new oral anticoagulants. However, in view of their procoagulant capabilities, nonspecific hemostatic agents have been suggested for use in reversal of major bleeding resulting from these drugs.^37–39 Examples are:

Recombinant factor VIIa (NovoSeven) initiates thrombin generation by activating factor X.

Four-factor prothrombin complex concentrate (Beriplex, recently approved in the United States) contains relatively large amounts of four nonactive vitamin K-dependent procoagulant factors (factors II, VII, IX, and X) that stimulate thrombin formation.

Three-factor prothrombin complex concentrate (Bebulin VH and Profilnine SD) contains low amounts of nonactive factor VII relative to factors II, IX, and X. In some centers a four-factor equivalent is produced by transfusion of a three-factor product with the addition of small amounts of recombinant factor VIIa or fresh-frozen plasma to replace the missing factor VII.⁴⁰

Activated prothrombin complex concentrate (FEIBA NF) contains activated factor VII and factors II, IX, and X, mainly in nonactivated form.³⁶ Therefore, it combines the effect of both recombinant factor VIIa and four-factor prothrombin complex concentrate.³⁷

Studies of nonspecific hemostatic agents

In a study of rats infused with high doses of dabigatran, van Ryn et al³⁸ observed that activated prothrombin complex concentrate at a dose of 50 or 100 U/kg and recombinant factor VIIa at a dose of 0.1 or 0.5 mg/kg reduced the rat-tail bleeding time in a dose-dependent manner but not the blood loss, compared with controls, even with a higher dose of recombinant factor VIIa (1 mg/kg). Recombinant factor VIIa also reversed the prolonged aPTT induced by dabigatran, whereas activated prothrombin complex concentrate did not. They suggested that recombinant factor VIIa and activated prothrombin complex concentrate may be potential antidotes for dabigatran-induced severe bleeding in humans.

In an ex vivo study of healthy people who took a single dose of dabigatran 150 mg or rivaroxaban 20 mg, Marlu et al³⁷ found that activated prothrombin complex concentrate and four-factor prothrombin complex concentrate could be reasonable antidotes to these drugs.

Dabigatran-associated bleeding after cardiac surgery in humans has been successfully managed with hemodialysis and recombinant factor VIIa, although the efficacy of the latter cannot be individually assessed in the study.⁴¹

In a randomized placebo-controlled trial aimed at reversing rivaroxaban and dabigatran in healthy participants, Eerenberg et al³⁹ showed that four-factor prothrombin complex concentrate at a dose of 50 IU/kg reversed prolongation of the prothrombin time and decreased the endogenous thrombin potential in those who received rivaroxaban, but it failed to reverse the aPTT, the endogenous thrombin potential, and thrombin time in those who received dabigatran.

However, Marlu et al reported that four-factor prothrombin complex concentrate at three doses (12.5 U/kg, 25 U/kg, and 50 U/kg)—or better still, activated prothrombin complex concentrate (40–80 U/kg)—could be a useful antidote to dabigatran.³⁷

It is important to note that the healthy participants in the Eerenberg et al study³⁹ took dabigatran 150 mg twice daily and rivaroxaban 20 mg daily for 2.5 days, whereas those in the Marlu et al study³⁷ took the same dose of each medication, but only once.

The three-factor prothrombin complex concentrate products have been shown to be less effective than four-factor ones in reversing supratherapeutic INRs in patients with warfarin overdose, but whether this will be true with the new oral anticoagulants remains unknown. Furthermore, the four-factor concentrates effectively reversed warfarin-induced coagulopathy and bleeding in patients,⁴² but to our knowledge, the same is yet to be demonstrated in bleeding related to the newer agents.

Other measures

Gastric lavage or the administration of activated charcoal (or in some cases both) may reduce drug absorption if done within 2 or 3 hours of drug ingestion (Table 1). Because it is lipophilic, more than 99.9% of dabigatran etexilate was adsorbed by activated charcoal from water prepared to simulate gastric fluid in an in vitro experiment by van Ryn et al.⁴³ This has not been tested in patients, and no similar study has been done for rivaroxaban or apixaban. However, use of charcoal in cases of recent ingestion, particularly with intentional overdose of these agents, seems reasonable.

Hemodialysis may reverse the anticoagulant effects of dabigatran overdose or severe bleeding because only about 35% of dabigatran is bound to plasma proteins (Table 1). In a single-center study, 50 mg of dabigatran etexilate was given orally to six patients with end-stage renal disease before dialysis, and the mean fraction of the drug removed by the dialyzer was 62% at 2 hours and 68% at 4 hours.³² This study suggests that hemodialysis may be useful to accelerate the removal of the drug in cases of life-threatening bleeding.

Rivaroxaban and apixaban are not dialyzable: the plasma protein binding of rivaroxaban is 95% and that of apixaban is 87%.

FUTURE DIRECTIONS

Because the new oral anticoagulants, unlike warfarin, have a wide therapeutic window, routine anticoagulant monitoring is not needed and might be misleading. However, there are times when monitoring might be useful; at such times, a validated, widely available, easily understood test would be good to have—but we don’t have it—at least not yet.

Therapeutic ranges for the aPTT have been established empirically for heparin in various indications.⁴⁴ Additional study is needed to determine if an appropriate aPTT range can be determined for the new oral anticoagulants, particularly dabigatran.

Similarly, as with low-molecular-weight heparins, anti-factor Xa activity monitoring may become a more available validated means of testing for exposure to rivaroxaban and apixaban. More promising, using concepts derived from the development of the INR for warfarin monitoring,⁴⁵ Tripodi et al⁴⁶ have derived normalized INR-like assays to report rivaroxaban levels. A standardized schema for reporting results is being developed.⁴⁶ Studies are required to determine if and how this assay may be useful. Initial trials in this regard are encouraging.⁴⁷

Finally, the thrombotic risk associated with the use of nonspecific prohemostatic agents is unknown.^37,48 Additional studies are required to standardize their dosages, frequency of administration, and duration of action, as well as to quantify their complications in bleeding patients.

ANSWER
This ECG shows sinus tachycardia at a rate of 110 beats/min, evidenced by the presence of a P wave for every QRS complex with regular R-R intervals. Left atrial enlargement is evident from the presence of P waves ≥ 110 ms (admittedly difficult to see in this example) and a terminal negativity of the P wave in lead V₁ ≥ 1 mm². A rightward axis is evidenced by the presence of an R-wave axis of 96°; however, it does not meet criteria for a true right-axis deviation 
(≥ 105°). Nonspecific T-wave abnormalities are observed in leads V₅ and V₆. 

The most intriguing aspect of this ECG is observed in lead V₃. Note the abrupt disruption of R-wave progression between leads V₂ and V₄. This was due to incorrect placement of the ECG electrode for V₃, which occurred in the haste to obtain the ECG prior to the CT scan. This illustrates the importance of correct electrode placement for an accurate tracing.

ANSWER
This ECG shows sinus tachycardia at a rate of 110 beats/min, evidenced by the presence of a P wave for every QRS complex with regular R-R intervals. Left atrial enlargement is evident from the presence of P waves ≥ 110 ms (admittedly difficult to see in this example) and a terminal negativity of the P wave in lead V₁ ≥ 1 mm². A rightward axis is evidenced by the presence of an R-wave axis of 96°; however, it does not meet criteria for a true right-axis deviation 
(≥ 105°). Nonspecific T-wave abnormalities are observed in leads V₅ and V₆. 

The most intriguing aspect of this ECG is observed in lead V₃. Note the abrupt disruption of R-wave progression between leads V₂ and V₄. This was due to incorrect placement of the ECG electrode for V₃, which occurred in the haste to obtain the ECG prior to the CT scan. This illustrates the importance of correct electrode placement for an accurate tracing.

ANSWER
This ECG shows sinus tachycardia at a rate of 110 beats/min, evidenced by the presence of a P wave for every QRS complex with regular R-R intervals. Left atrial enlargement is evident from the presence of P waves ≥ 110 ms (admittedly difficult to see in this example) and a terminal negativity of the P wave in lead V₁ ≥ 1 mm². A rightward axis is evidenced by the presence of an R-wave axis of 96°; however, it does not meet criteria for a true right-axis deviation 
(≥ 105°). Nonspecific T-wave abnormalities are observed in leads V₅ and V₆. 

The most intriguing aspect of this ECG is observed in lead V₃. Note the abrupt disruption of R-wave progression between leads V₂ and V₄. This was due to incorrect placement of the ECG electrode for V₃, which occurred in the haste to obtain the ECG prior to the CT scan. This illustrates the importance of correct electrode placement for an accurate tracing.

ANSWER
The correct answer is dilated pore of Winer (choice “b”), a hair structure anomaly discussed below. Sebaceous cysts (choice “a”) often present with a surface punctum, but the depth and appearance of this pore are not consistent with a simple punctum. The same could be said of the other two choices: ice-pick scar secondary to acne (choice “c”) and ingrown hair (choice “d”).

DISCUSSION
Dilated pore of Winer is actually a tumor of the intraepidermal follicle and related infundibulum of the pilosebaceous apparatus, a fact confirmed by immunohistochemical studies. It has no implication for health, but its appearance is occasionally distressing. Unfortunately, this patient has matching dilated pores on either side of his nose.

These scar-like pits are most commonly seen on the face, especially the maxillae. Even though they resemble one another, dilated pore of Winer differs significantly from a simple comedone: The former is considerably deeper, as well as markedly different in structure.

TREATMENT
The only effective treatment for dilated pore of Winer is surgical excision, which is easily accomplished under local anesthesia. A 4- to 5-mm punch biopsy tool is introduced into the skin at the same angle as the course of the pore, then taken down to adipose tissue, which ensures complete removal. Two interrupted skin sutures serve to convert the round punch defect into a linear wound, preferably matching skin tension lines. The tissue thus removed is always sent for pathologic examination to rule out basal cell carcinoma.

But for the vast majority of patients affected by dilated pore of Winer, the best treatment is to leave the lesions alone.

ANSWER
The correct answer is dilated pore of Winer (choice “b”), a hair structure anomaly discussed below. Sebaceous cysts (choice “a”) often present with a surface punctum, but the depth and appearance of this pore are not consistent with a simple punctum. The same could be said of the other two choices: ice-pick scar secondary to acne (choice “c”) and ingrown hair (choice “d”).

DISCUSSION
Dilated pore of Winer is actually a tumor of the intraepidermal follicle and related infundibulum of the pilosebaceous apparatus, a fact confirmed by immunohistochemical studies. It has no implication for health, but its appearance is occasionally distressing. Unfortunately, this patient has matching dilated pores on either side of his nose.

These scar-like pits are most commonly seen on the face, especially the maxillae. Even though they resemble one another, dilated pore of Winer differs significantly from a simple comedone: The former is considerably deeper, as well as markedly different in structure.

TREATMENT
The only effective treatment for dilated pore of Winer is surgical excision, which is easily accomplished under local anesthesia. A 4- to 5-mm punch biopsy tool is introduced into the skin at the same angle as the course of the pore, then taken down to adipose tissue, which ensures complete removal. Two interrupted skin sutures serve to convert the round punch defect into a linear wound, preferably matching skin tension lines. The tissue thus removed is always sent for pathologic examination to rule out basal cell carcinoma.

But for the vast majority of patients affected by dilated pore of Winer, the best treatment is to leave the lesions alone.

ANSWER
The correct answer is dilated pore of Winer (choice “b”), a hair structure anomaly discussed below. Sebaceous cysts (choice “a”) often present with a surface punctum, but the depth and appearance of this pore are not consistent with a simple punctum. The same could be said of the other two choices: ice-pick scar secondary to acne (choice “c”) and ingrown hair (choice “d”).

DISCUSSION
Dilated pore of Winer is actually a tumor of the intraepidermal follicle and related infundibulum of the pilosebaceous apparatus, a fact confirmed by immunohistochemical studies. It has no implication for health, but its appearance is occasionally distressing. Unfortunately, this patient has matching dilated pores on either side of his nose.

These scar-like pits are most commonly seen on the face, especially the maxillae. Even though they resemble one another, dilated pore of Winer differs significantly from a simple comedone: The former is considerably deeper, as well as markedly different in structure.

TREATMENT
The only effective treatment for dilated pore of Winer is surgical excision, which is easily accomplished under local anesthesia. A 4- to 5-mm punch biopsy tool is introduced into the skin at the same angle as the course of the pore, then taken down to adipose tissue, which ensures complete removal. Two interrupted skin sutures serve to convert the round punch defect into a linear wound, preferably matching skin tension lines. The tissue thus removed is always sent for pathologic examination to rule out basal cell carcinoma.

But for the vast majority of patients affected by dilated pore of Winer, the best treatment is to leave the lesions alone.