From the outset, HM has been about efficiency. And there was nothing wrong with that, for value is quality divided by cost. But in our story, we found that mere efficiency was not enough: The lowering of the denominator (cost) had to be met with an escalation of the numerator (quality) to ensure value.

And see us as being born in the right place at the right time. For with the national focus turning to the need for quality and patient safety, hospital medicine was in the right place and the right time to heed the call to action: appropriately stepping up to enact efforts to make the slope of the line (on a chart of quality vs. cost) “STEEEPER” … finding systems innovations to make care Safe, Timely, Efficient, Effective, Equitable, and Patient-centered.

Of course, the story continued with the Affordable Care Act and healthcare reform, greatly accelerating our evolution as change agents. And now we find ourselves fully invested in a “change the system” mentality, perfectly positioned to meaningfully change healthcare for millions of people. But threats loom—specifically, the “R” in the STEEEPER mnemonic: the risks to quality in the face of healthcare reform.

So in the next chapter of our story, I present to you our challenge: how to overcome the threats to quality in the context of healthcare reform. The first three are presented here; in subsequent articles, I will address the remainder. Overcoming all threats will hinge on mastering the four truisms of cultural change:

1. Systems drive function;
2. Every system is perfectly designed to produce the outcomes that it does;
3. This is not an issue of people needing to try harder; and
4. The “no blame” culture begins with a paradigm shift from the “person at fault” to the “system at fault.”

Threat 1: Failure to Fund Quality

SHM elected to merge its annual State of Hospital Medicine survey with the MGMA. Though not without risk, this has resulted in the anticipated benefits. The MGMA collaboration brings greater leverage in working with the C-suite, which is pre-programmed to react to MGMA surveys. From the most recent MGMA survey comes good news: The financial compensation for hospitalists has increased. A sobering insight, however, is that this increase in compensation has been met with a corresponding increase in work intensity—RVUs. Further, the link between RVUs and compensation appears to be tightening, quantifying what has long been of concern: The time devoted to the nonclinical “value added” duties of the hospitalist is shrinking.

The threat to the culture of quality is captured in the single question: How many RVUs is a quality-improvement (QI) project worth? I’m not sure we have that answer. But without an answer, it is difficult to believe that meaningful QI can be expected without time to do so. And again, as the gap between compensation and RVUs narrows, one is left wondering if there will soon be a day where there is no value-added time remaining to perform QI at all.

Fortunately, the Affordable Care Act might provide some movement in the right direction via value-based purchasing. Linking quality outcomes to financial reimbursement is a big step forward in the hospitalist’s quest to leverage the C-suite in trading RVUs for devoted QI time. Although we still are left asking the question of how many RVUs a QI project is worth, value-based purchasing at least sets the stage for the conversation. But in the interim, it is still upon hospitalists to design these QI projects, and to learn the skills necessary to see the design to its fruition.

 

Threat 2: Quality Stops at Core Measures

It is hard to argue that fulfilling “core measures” is a bad thing. Nonetheless, the core measures were not meant to be quality; instead, they were meant as surrogate measures of quality. The presumption of the core-measures initiative is that the system would exist without direct attention to the core measures, operating as it ordinarily would with generic attention to meeting all standards of quality for all diseases. And at some point in time, the core measures would be assessed to give an overall assessment of the system’s quality.

What has evolved, however, is a concerted attention to meeting the core measures, with little regard to the overall culture of quality.

Let’s say you were tasked with improving the public school system in your state. As a measure of the improvement, you choose five of the 1,000 schools as “core measure” schools. The state board of education is told that the performance of these five sample schools will be assessed at the end of the year, and financial support for the system as a whole will hinge on their performance. The intended result is that attention would be paid to improving the performance of every school in the system, and this improvement would be reflected in the performance of the five sample schools. The board of education could take the route of improving all schools, but the more pragmatic route would be to funnel all resources into these five schools, to the detriment of resources for the other 995 schools. The performance of the core measure schools would dramatically improve, and funding would be secured. But ask yourself: Did the performance of the school system as a whole actually improve?

Such is the risk of the core measures in healthcare. The original intent of the core measures was to instill a culture of QI for all points of care. And this has been a valuable contribution to changing the consciousness of the healthcare system. The presumption was that the core measures would be “seeds,” and that by emphasizing these select measures, the QI culture eventually would spread to all aspects of patient care. But this plan hinged on the presumption that that there is an unlimited amount of mental energy and resources to be devoted to all tasks within healthcare. The reality is that there is a fixed amount of intellectual energy and resources to be devoted to the various aspects of healthcare. One wonders if the overemphasis on meeting the core measures might actually have taken the wind out of the sails for QI in other non-core-measure patient care.

The implications are twofold. By definition, a core measure has to be applicable to all healthcare systems, and with a fixed amount of mental energy and resources, there is a real risk that what portion is reserved for QI finds its way only to the core indicators, especially if they are overemphasized in the system. The second implication is captured in our experience with time to antibiotics. With meeting the core indicator as the priority, many systems instituted the “work-around”: Give antibiotics to every patient presenting to the ED, and you will be sure to have met the four-hour window in the core indicator. The result was an exponential increase in inappropriate antibiotic administration and radiographic tests, all because meeting the indicator became more important than the overall goal.

As stewards of the hospital system, it is upon us to ensure that the original intent of core measures remains secure: The core measures seed a culture of quality, but do not become ends in and of themselves. QI apart from the core measures must remain an equal priority, and it is the hospitalist who will be central in ensuring this comes to fruition.

 

Threat 3: Misplaced Incentives

There is an interesting anecdote in Steven Levitt and Stephen Dubner’s book Freakonomics.¹ The story begins with a daycare center struggling with a problem: Some parents are showing up late to pick up their children at the end of the day, and this is costing the center in the way of overtime charges for the staff. To solve the problem, the center elects to institute a financial disincentive: Those showing up late to pick up their children will pay a modest financial penalty.

Fast-forward to months after the policy was put in place. The result? An exponential increase in the number of parents showing up late to pick up their children.

How do you explain worsening performance in spite of a financial disincentive? The answer resides in understanding human behavior. According to the authors, there are three primary motivations in life: financial, social, and moral. As ugly as it sounds, the decisions people make in life are driven by one of these three motivations. There is nothing wrong with providing incentives for behavior; incentives work.

But the danger arises when incentives are mismatched to behaviors. For example, if a financial outcome is the goal, then financial incentives make sense. If a social outcome (people should play better as a team) is the goal, the social incentives make sense (public recognition). But when the incentives get misaligned with their respective goals, trouble results.

What went wrong with the daycare’s plan is simple—most of the parents were motivated to pick up their children on time out of moral (“I gave my word”) or social (“I don’t want to be talked about by other parents”) incentives. But once a financial incentive was offered, the daycare center had essentially given the parents a way out in absolving their social and moral obligations. The parents had essentially cost-adjusted their behavior.

If you think this couldn’t happen to the healthcare system, let me ask you this. As a hospitalist, I see all of my patients early in the morning, because I see it as part of my obligation to the hospital team to discharge patients by 11 a.m. (social motivation).

But what if the CEO released this directive: “You will see all of your patients early in the morning, or you will take a $1,000 a year pay cut.” Is it possible that I might cost-adjust the $1,000 in exchange for sleeping in a little later and not having to deal with the morning traffic? I don’t know.

When it comes to financial incentives, there is a valley in the U-shaped curve. When the financial incentive is trivial, it is disregarded and the social/moral motivations of behavior persist (the kids are picked up on time; I persist in seeing patients early in the morning). When the financial incentive is huge, the financial incentive trumps all social/moral motivations, ensuring compliance with the goal behavior (every kid is picked up on time to avoid a penalty; I see all patients early in the day to avoid a larger penalty).

But in between is the risk zone: When the person feels they are paying an appropriate penance for not complying with the goal behavior, the financial disincentive absolves any social/moral guilt.

Healthcare reform is about incentives—and there is nothing wrong with that. But as the stewards of the inpatient healthcare system, it is upon us as hospitalists to ensure that the incentives remain matched to their intended goals, and that the untoward consequences of the incentives do not adversely affect the quality and safety of a patient’s care.

 

It is safe to say that the Affordable Care Act of 2010 moves us closer to a true environment of quality and patient safety. But it is equally safe to say that meaningful change will require more than what the law can provide. As stewards of the inpatient system, we have a responsibility to ensure that the healthcare system, particularly in how it responds to incentives, evolves to remain patient-centered, effective, and safe.

The next chapter in our story—the hospitalists’ story—will be one of accountability and responsibility. While there are things the government can do, the majority of what needs to be done will come directly from us. TH

Dr. Wiese is president of SHM.

Reference

1. Levitt SD, Dubner SJ. Freakonomics: A Rogue Economist Explores the Hidden Side of Everything. New York City: William Morrow; 2005.

From the outset, HM has been about efficiency. And there was nothing wrong with that, for value is quality divided by cost. But in our story, we found that mere efficiency was not enough: The lowering of the denominator (cost) had to be met with an escalation of the numerator (quality) to ensure value.

And see us as being born in the right place at the right time. For with the national focus turning to the need for quality and patient safety, hospital medicine was in the right place and the right time to heed the call to action: appropriately stepping up to enact efforts to make the slope of the line (on a chart of quality vs. cost) “STEEEPER” … finding systems innovations to make care Safe, Timely, Efficient, Effective, Equitable, and Patient-centered.

Of course, the story continued with the Affordable Care Act and healthcare reform, greatly accelerating our evolution as change agents. And now we find ourselves fully invested in a “change the system” mentality, perfectly positioned to meaningfully change healthcare for millions of people. But threats loom—specifically, the “R” in the STEEEPER mnemonic: the risks to quality in the face of healthcare reform.

So in the next chapter of our story, I present to you our challenge: how to overcome the threats to quality in the context of healthcare reform. The first three are presented here; in subsequent articles, I will address the remainder. Overcoming all threats will hinge on mastering the four truisms of cultural change:

1. Systems drive function;
2. Every system is perfectly designed to produce the outcomes that it does;
3. This is not an issue of people needing to try harder; and
4. The “no blame” culture begins with a paradigm shift from the “person at fault” to the “system at fault.”

Threat 1: Failure to Fund Quality

SHM elected to merge its annual State of Hospital Medicine survey with the MGMA. Though not without risk, this has resulted in the anticipated benefits. The MGMA collaboration brings greater leverage in working with the C-suite, which is pre-programmed to react to MGMA surveys. From the most recent MGMA survey comes good news: The financial compensation for hospitalists has increased. A sobering insight, however, is that this increase in compensation has been met with a corresponding increase in work intensity—RVUs. Further, the link between RVUs and compensation appears to be tightening, quantifying what has long been of concern: The time devoted to the nonclinical “value added” duties of the hospitalist is shrinking.

The threat to the culture of quality is captured in the single question: How many RVUs is a quality-improvement (QI) project worth? I’m not sure we have that answer. But without an answer, it is difficult to believe that meaningful QI can be expected without time to do so. And again, as the gap between compensation and RVUs narrows, one is left wondering if there will soon be a day where there is no value-added time remaining to perform QI at all.

Fortunately, the Affordable Care Act might provide some movement in the right direction via value-based purchasing. Linking quality outcomes to financial reimbursement is a big step forward in the hospitalist’s quest to leverage the C-suite in trading RVUs for devoted QI time. Although we still are left asking the question of how many RVUs a QI project is worth, value-based purchasing at least sets the stage for the conversation. But in the interim, it is still upon hospitalists to design these QI projects, and to learn the skills necessary to see the design to its fruition.

 

Threat 2: Quality Stops at Core Measures

It is hard to argue that fulfilling “core measures” is a bad thing. Nonetheless, the core measures were not meant to be quality; instead, they were meant as surrogate measures of quality. The presumption of the core-measures initiative is that the system would exist without direct attention to the core measures, operating as it ordinarily would with generic attention to meeting all standards of quality for all diseases. And at some point in time, the core measures would be assessed to give an overall assessment of the system’s quality.

What has evolved, however, is a concerted attention to meeting the core measures, with little regard to the overall culture of quality.

Let’s say you were tasked with improving the public school system in your state. As a measure of the improvement, you choose five of the 1,000 schools as “core measure” schools. The state board of education is told that the performance of these five sample schools will be assessed at the end of the year, and financial support for the system as a whole will hinge on their performance. The intended result is that attention would be paid to improving the performance of every school in the system, and this improvement would be reflected in the performance of the five sample schools. The board of education could take the route of improving all schools, but the more pragmatic route would be to funnel all resources into these five schools, to the detriment of resources for the other 995 schools. The performance of the core measure schools would dramatically improve, and funding would be secured. But ask yourself: Did the performance of the school system as a whole actually improve?

Such is the risk of the core measures in healthcare. The original intent of the core measures was to instill a culture of QI for all points of care. And this has been a valuable contribution to changing the consciousness of the healthcare system. The presumption was that the core measures would be “seeds,” and that by emphasizing these select measures, the QI culture eventually would spread to all aspects of patient care. But this plan hinged on the presumption that that there is an unlimited amount of mental energy and resources to be devoted to all tasks within healthcare. The reality is that there is a fixed amount of intellectual energy and resources to be devoted to the various aspects of healthcare. One wonders if the overemphasis on meeting the core measures might actually have taken the wind out of the sails for QI in other non-core-measure patient care.

The implications are twofold. By definition, a core measure has to be applicable to all healthcare systems, and with a fixed amount of mental energy and resources, there is a real risk that what portion is reserved for QI finds its way only to the core indicators, especially if they are overemphasized in the system. The second implication is captured in our experience with time to antibiotics. With meeting the core indicator as the priority, many systems instituted the “work-around”: Give antibiotics to every patient presenting to the ED, and you will be sure to have met the four-hour window in the core indicator. The result was an exponential increase in inappropriate antibiotic administration and radiographic tests, all because meeting the indicator became more important than the overall goal.

As stewards of the hospital system, it is upon us to ensure that the original intent of core measures remains secure: The core measures seed a culture of quality, but do not become ends in and of themselves. QI apart from the core measures must remain an equal priority, and it is the hospitalist who will be central in ensuring this comes to fruition.

 

Threat 3: Misplaced Incentives

There is an interesting anecdote in Steven Levitt and Stephen Dubner’s book Freakonomics.¹ The story begins with a daycare center struggling with a problem: Some parents are showing up late to pick up their children at the end of the day, and this is costing the center in the way of overtime charges for the staff. To solve the problem, the center elects to institute a financial disincentive: Those showing up late to pick up their children will pay a modest financial penalty.

Fast-forward to months after the policy was put in place. The result? An exponential increase in the number of parents showing up late to pick up their children.

How do you explain worsening performance in spite of a financial disincentive? The answer resides in understanding human behavior. According to the authors, there are three primary motivations in life: financial, social, and moral. As ugly as it sounds, the decisions people make in life are driven by one of these three motivations. There is nothing wrong with providing incentives for behavior; incentives work.

But the danger arises when incentives are mismatched to behaviors. For example, if a financial outcome is the goal, then financial incentives make sense. If a social outcome (people should play better as a team) is the goal, the social incentives make sense (public recognition). But when the incentives get misaligned with their respective goals, trouble results.

What went wrong with the daycare’s plan is simple—most of the parents were motivated to pick up their children on time out of moral (“I gave my word”) or social (“I don’t want to be talked about by other parents”) incentives. But once a financial incentive was offered, the daycare center had essentially given the parents a way out in absolving their social and moral obligations. The parents had essentially cost-adjusted their behavior.

If you think this couldn’t happen to the healthcare system, let me ask you this. As a hospitalist, I see all of my patients early in the morning, because I see it as part of my obligation to the hospital team to discharge patients by 11 a.m. (social motivation).

But what if the CEO released this directive: “You will see all of your patients early in the morning, or you will take a $1,000 a year pay cut.” Is it possible that I might cost-adjust the $1,000 in exchange for sleeping in a little later and not having to deal with the morning traffic? I don’t know.

When it comes to financial incentives, there is a valley in the U-shaped curve. When the financial incentive is trivial, it is disregarded and the social/moral motivations of behavior persist (the kids are picked up on time; I persist in seeing patients early in the morning). When the financial incentive is huge, the financial incentive trumps all social/moral motivations, ensuring compliance with the goal behavior (every kid is picked up on time to avoid a penalty; I see all patients early in the day to avoid a larger penalty).

But in between is the risk zone: When the person feels they are paying an appropriate penance for not complying with the goal behavior, the financial disincentive absolves any social/moral guilt.

Healthcare reform is about incentives—and there is nothing wrong with that. But as the stewards of the inpatient healthcare system, it is upon us as hospitalists to ensure that the incentives remain matched to their intended goals, and that the untoward consequences of the incentives do not adversely affect the quality and safety of a patient’s care.

 

It is safe to say that the Affordable Care Act of 2010 moves us closer to a true environment of quality and patient safety. But it is equally safe to say that meaningful change will require more than what the law can provide. As stewards of the inpatient system, we have a responsibility to ensure that the healthcare system, particularly in how it responds to incentives, evolves to remain patient-centered, effective, and safe.

The next chapter in our story—the hospitalists’ story—will be one of accountability and responsibility. While there are things the government can do, the majority of what needs to be done will come directly from us. TH

Dr. Wiese is president of SHM.

Reference

1. Levitt SD, Dubner SJ. Freakonomics: A Rogue Economist Explores the Hidden Side of Everything. New York City: William Morrow; 2005.

From the outset, HM has been about efficiency. And there was nothing wrong with that, for value is quality divided by cost. But in our story, we found that mere efficiency was not enough: The lowering of the denominator (cost) had to be met with an escalation of the numerator (quality) to ensure value.

And see us as being born in the right place at the right time. For with the national focus turning to the need for quality and patient safety, hospital medicine was in the right place and the right time to heed the call to action: appropriately stepping up to enact efforts to make the slope of the line (on a chart of quality vs. cost) “STEEEPER” … finding systems innovations to make care Safe, Timely, Efficient, Effective, Equitable, and Patient-centered.

Of course, the story continued with the Affordable Care Act and healthcare reform, greatly accelerating our evolution as change agents. And now we find ourselves fully invested in a “change the system” mentality, perfectly positioned to meaningfully change healthcare for millions of people. But threats loom—specifically, the “R” in the STEEEPER mnemonic: the risks to quality in the face of healthcare reform.

So in the next chapter of our story, I present to you our challenge: how to overcome the threats to quality in the context of healthcare reform. The first three are presented here; in subsequent articles, I will address the remainder. Overcoming all threats will hinge on mastering the four truisms of cultural change:

1. Systems drive function;
2. Every system is perfectly designed to produce the outcomes that it does;
3. This is not an issue of people needing to try harder; and
4. The “no blame” culture begins with a paradigm shift from the “person at fault” to the “system at fault.”

Threat 1: Failure to Fund Quality

SHM elected to merge its annual State of Hospital Medicine survey with the MGMA. Though not without risk, this has resulted in the anticipated benefits. The MGMA collaboration brings greater leverage in working with the C-suite, which is pre-programmed to react to MGMA surveys. From the most recent MGMA survey comes good news: The financial compensation for hospitalists has increased. A sobering insight, however, is that this increase in compensation has been met with a corresponding increase in work intensity—RVUs. Further, the link between RVUs and compensation appears to be tightening, quantifying what has long been of concern: The time devoted to the nonclinical “value added” duties of the hospitalist is shrinking.

The threat to the culture of quality is captured in the single question: How many RVUs is a quality-improvement (QI) project worth? I’m not sure we have that answer. But without an answer, it is difficult to believe that meaningful QI can be expected without time to do so. And again, as the gap between compensation and RVUs narrows, one is left wondering if there will soon be a day where there is no value-added time remaining to perform QI at all.

Fortunately, the Affordable Care Act might provide some movement in the right direction via value-based purchasing. Linking quality outcomes to financial reimbursement is a big step forward in the hospitalist’s quest to leverage the C-suite in trading RVUs for devoted QI time. Although we still are left asking the question of how many RVUs a QI project is worth, value-based purchasing at least sets the stage for the conversation. But in the interim, it is still upon hospitalists to design these QI projects, and to learn the skills necessary to see the design to its fruition.

 

Threat 2: Quality Stops at Core Measures

It is hard to argue that fulfilling “core measures” is a bad thing. Nonetheless, the core measures were not meant to be quality; instead, they were meant as surrogate measures of quality. The presumption of the core-measures initiative is that the system would exist without direct attention to the core measures, operating as it ordinarily would with generic attention to meeting all standards of quality for all diseases. And at some point in time, the core measures would be assessed to give an overall assessment of the system’s quality.

What has evolved, however, is a concerted attention to meeting the core measures, with little regard to the overall culture of quality.

Let’s say you were tasked with improving the public school system in your state. As a measure of the improvement, you choose five of the 1,000 schools as “core measure” schools. The state board of education is told that the performance of these five sample schools will be assessed at the end of the year, and financial support for the system as a whole will hinge on their performance. The intended result is that attention would be paid to improving the performance of every school in the system, and this improvement would be reflected in the performance of the five sample schools. The board of education could take the route of improving all schools, but the more pragmatic route would be to funnel all resources into these five schools, to the detriment of resources for the other 995 schools. The performance of the core measure schools would dramatically improve, and funding would be secured. But ask yourself: Did the performance of the school system as a whole actually improve?

Such is the risk of the core measures in healthcare. The original intent of the core measures was to instill a culture of QI for all points of care. And this has been a valuable contribution to changing the consciousness of the healthcare system. The presumption was that the core measures would be “seeds,” and that by emphasizing these select measures, the QI culture eventually would spread to all aspects of patient care. But this plan hinged on the presumption that that there is an unlimited amount of mental energy and resources to be devoted to all tasks within healthcare. The reality is that there is a fixed amount of intellectual energy and resources to be devoted to the various aspects of healthcare. One wonders if the overemphasis on meeting the core measures might actually have taken the wind out of the sails for QI in other non-core-measure patient care.

The implications are twofold. By definition, a core measure has to be applicable to all healthcare systems, and with a fixed amount of mental energy and resources, there is a real risk that what portion is reserved for QI finds its way only to the core indicators, especially if they are overemphasized in the system. The second implication is captured in our experience with time to antibiotics. With meeting the core indicator as the priority, many systems instituted the “work-around”: Give antibiotics to every patient presenting to the ED, and you will be sure to have met the four-hour window in the core indicator. The result was an exponential increase in inappropriate antibiotic administration and radiographic tests, all because meeting the indicator became more important than the overall goal.

As stewards of the hospital system, it is upon us to ensure that the original intent of core measures remains secure: The core measures seed a culture of quality, but do not become ends in and of themselves. QI apart from the core measures must remain an equal priority, and it is the hospitalist who will be central in ensuring this comes to fruition.

 

Threat 3: Misplaced Incentives

There is an interesting anecdote in Steven Levitt and Stephen Dubner’s book Freakonomics.¹ The story begins with a daycare center struggling with a problem: Some parents are showing up late to pick up their children at the end of the day, and this is costing the center in the way of overtime charges for the staff. To solve the problem, the center elects to institute a financial disincentive: Those showing up late to pick up their children will pay a modest financial penalty.

Fast-forward to months after the policy was put in place. The result? An exponential increase in the number of parents showing up late to pick up their children.

How do you explain worsening performance in spite of a financial disincentive? The answer resides in understanding human behavior. According to the authors, there are three primary motivations in life: financial, social, and moral. As ugly as it sounds, the decisions people make in life are driven by one of these three motivations. There is nothing wrong with providing incentives for behavior; incentives work.

But the danger arises when incentives are mismatched to behaviors. For example, if a financial outcome is the goal, then financial incentives make sense. If a social outcome (people should play better as a team) is the goal, the social incentives make sense (public recognition). But when the incentives get misaligned with their respective goals, trouble results.

What went wrong with the daycare’s plan is simple—most of the parents were motivated to pick up their children on time out of moral (“I gave my word”) or social (“I don’t want to be talked about by other parents”) incentives. But once a financial incentive was offered, the daycare center had essentially given the parents a way out in absolving their social and moral obligations. The parents had essentially cost-adjusted their behavior.

If you think this couldn’t happen to the healthcare system, let me ask you this. As a hospitalist, I see all of my patients early in the morning, because I see it as part of my obligation to the hospital team to discharge patients by 11 a.m. (social motivation).

But what if the CEO released this directive: “You will see all of your patients early in the morning, or you will take a $1,000 a year pay cut.” Is it possible that I might cost-adjust the $1,000 in exchange for sleeping in a little later and not having to deal with the morning traffic? I don’t know.

When it comes to financial incentives, there is a valley in the U-shaped curve. When the financial incentive is trivial, it is disregarded and the social/moral motivations of behavior persist (the kids are picked up on time; I persist in seeing patients early in the morning). When the financial incentive is huge, the financial incentive trumps all social/moral motivations, ensuring compliance with the goal behavior (every kid is picked up on time to avoid a penalty; I see all patients early in the day to avoid a larger penalty).

But in between is the risk zone: When the person feels they are paying an appropriate penance for not complying with the goal behavior, the financial disincentive absolves any social/moral guilt.

Healthcare reform is about incentives—and there is nothing wrong with that. But as the stewards of the inpatient healthcare system, it is upon us as hospitalists to ensure that the incentives remain matched to their intended goals, and that the untoward consequences of the incentives do not adversely affect the quality and safety of a patient’s care.

 

It is safe to say that the Affordable Care Act of 2010 moves us closer to a true environment of quality and patient safety. But it is equally safe to say that meaningful change will require more than what the law can provide. As stewards of the inpatient system, we have a responsibility to ensure that the healthcare system, particularly in how it responds to incentives, evolves to remain patient-centered, effective, and safe.

The next chapter in our story—the hospitalists’ story—will be one of accountability and responsibility. While there are things the government can do, the majority of what needs to be done will come directly from us. TH

Dr. Wiese is president of SHM.

Reference

1. Levitt SD, Dubner SJ. Freakonomics: A Rogue Economist Explores the Hidden Side of Everything. New York City: William Morrow; 2005.

Several months ago, my toilet broke. You should also know that I’m not particularly handy. So when I first realized that the toilet bowl seemed to fill constantly, I got a little stressed out.

How much was it going cost to call in a plumber on the weekend?

What kind of a water bill was I going to have?

Was this a serious problem?

I took a quick peek in the tank, but that just made me more confused. I was paralyzed by a lack of know-how.

Normally, I would have just Googled a local plumber. But that day, I decided to do something different. Maybe it was because it was the fantasy football offseason. Maybe it was because my wife had started to ask my father-in-law to change light bulbs around the house. Or, maybe, I wanted to learn to actually fix the problem. A few hours later, after an Internet lesson in toilet physiology, a $4.12 trip to Home Depot, and a wet pair of hands, I had replaced my first toilet flapper.

This wasn’t the rebuilding of a car engine, but it was a clear DIY step toward self-improvement. Easily the most memorable moment here was my sense of accomplishment.

I felt empowered.

One Part Science, One Part Art

It’s taken me a while to realize this, but I’ve begun to take advantage of improvement opportunities at work as well. No, I haven’t been moonlighting as a plumber for my hospital. I’ve just been fortunate to be part of a trifecta of rewarding quality-improvement (QI) projects over the past year. Before I’d gotten my hands dirty with these, my understanding of QI was fairly naive. I’d heard about Plan-Do-Study-Act many times. I had listened to a talk at a national conference. And I had kept up with the general medical literature on the subject.

But none of those activities had truly prepared me for experience of actually doing the work on my own.

By taking on a project, an ambitious attempt to reduce continuous pulse oximetry use, I experienced a crash course in both the science and the art of process improvement. I was forced to overcome my “I don’t know how” inertia. And with expert guidance in the form of a clinical safety and effectiveness class, I learned the importance of run charts (science) and a well-crafted multidisciplinary team (art) in changing established but inefficient behavior.

Our rates of continuous pulse oximetry usage dropped by 50%, and cost savings were $12,000 per year on one unit. These results made my prior attempts at change—years of complaining about ingrained nursing culture—look infantile. (OK, maybe it was ineffective, but who hasn’t complained about the overuse of continuous monitoring?)

I haven’t met a pediatric hospitalist who wouldn’t understand the symbolic importance of this success. But I know of many hospitalists who have not yet participated in meaningful QI project. Imagine calling a plumber who grasped the flush and fill mechanism of a toilet but had never touched real porcelain. Here’s an even better analogy: What if doctors could get licensed without having touched real patients?

If pediatric hospitalists are to transform the care delivery of hospitalized children, and quality learning only comes through hands-on training, then we need some more hands in the pot.

Discharge Improvement

On the heels of my first project, I was fortunate enough to augment my education through another effort—this time with a cohort of fellow pediatric hospitalists. This was a national collaborative to improve discharge handoffs, and I will admit that, at the outset, I was as puzzled as the first time I pulled the lid off the tank of the toilet. There were just too many permutations on PCP communication at the participating institutions, and some felt our aim of timely discharge handoffs was unattainable.

 

What carried me through, however, was the collective and infectious DIY—no, QIY (Quality Improve-it-Yourself) attitude of the group. We were all learning, and regular participation in the collaborative essentially guaranteed improvement. We achieved our aim of 90% communication with PCPs within two days of discharge. The secret was simple: The more you do, the more you learn.

Pediatric hospitalists can transform care delivery through a focus on safe and quality care, but the tools to accomplish this must come through post-residency, on-the-job learning. This QI know-how must efficiently spread among our ranks through practical and project-based educational efforts. It’s “see one, do one, teach one,” but we’re not talking about lumbar punctures anymore.

This is a journey in which we all take on the responsibility of rolling up our sleeves and simply learn by doing. And here is where the third leg of my as-yet-unfinished QI course unfolds.

Through my involvement with the Value in Inpatient Pediatrics (VIP) Network, I’ve gained a newfound vision for what the future might hold. VIP has evolved from a benchmarking project focused on bronchiolitis to an improvement network that will incorporate projects similar to the discharge handoff collaborative above.

In the process, a model for how to rapidly spread QI learning has emerged. The capacity lies in the network’s rapidly growing connectivity. The power comes from the individuals: motivated, card-carrying pediatric hospitalists from a wide array of sites. Collaborative learning harbors the potential to exponentially increase the pace at which we improve.

The future of our quality care is bright. I see an open network of improvement doers and learners. I see collaboration on quality and safety initiatives in all manner of hospitals and communities. I see that this will all be built upon a foundation of hard work and a QIY attitude.

You, too, will play a role.

Just don’t be afraid to get your hands a little dirty. TH

Dr. Shen is medical director of hospital medicine at Dell Children’s Medical Center in Austin, Texas. He is pediatric editor of The Hospitalist.

Several months ago, my toilet broke. You should also know that I’m not particularly handy. So when I first realized that the toilet bowl seemed to fill constantly, I got a little stressed out.

How much was it going cost to call in a plumber on the weekend?

What kind of a water bill was I going to have?

Was this a serious problem?

I took a quick peek in the tank, but that just made me more confused. I was paralyzed by a lack of know-how.

Normally, I would have just Googled a local plumber. But that day, I decided to do something different. Maybe it was because it was the fantasy football offseason. Maybe it was because my wife had started to ask my father-in-law to change light bulbs around the house. Or, maybe, I wanted to learn to actually fix the problem. A few hours later, after an Internet lesson in toilet physiology, a $4.12 trip to Home Depot, and a wet pair of hands, I had replaced my first toilet flapper.

This wasn’t the rebuilding of a car engine, but it was a clear DIY step toward self-improvement. Easily the most memorable moment here was my sense of accomplishment.

I felt empowered.

One Part Science, One Part Art

It’s taken me a while to realize this, but I’ve begun to take advantage of improvement opportunities at work as well. No, I haven’t been moonlighting as a plumber for my hospital. I’ve just been fortunate to be part of a trifecta of rewarding quality-improvement (QI) projects over the past year. Before I’d gotten my hands dirty with these, my understanding of QI was fairly naive. I’d heard about Plan-Do-Study-Act many times. I had listened to a talk at a national conference. And I had kept up with the general medical literature on the subject.

But none of those activities had truly prepared me for experience of actually doing the work on my own.

By taking on a project, an ambitious attempt to reduce continuous pulse oximetry use, I experienced a crash course in both the science and the art of process improvement. I was forced to overcome my “I don’t know how” inertia. And with expert guidance in the form of a clinical safety and effectiveness class, I learned the importance of run charts (science) and a well-crafted multidisciplinary team (art) in changing established but inefficient behavior.

Our rates of continuous pulse oximetry usage dropped by 50%, and cost savings were $12,000 per year on one unit. These results made my prior attempts at change—years of complaining about ingrained nursing culture—look infantile. (OK, maybe it was ineffective, but who hasn’t complained about the overuse of continuous monitoring?)

I haven’t met a pediatric hospitalist who wouldn’t understand the symbolic importance of this success. But I know of many hospitalists who have not yet participated in meaningful QI project. Imagine calling a plumber who grasped the flush and fill mechanism of a toilet but had never touched real porcelain. Here’s an even better analogy: What if doctors could get licensed without having touched real patients?

If pediatric hospitalists are to transform the care delivery of hospitalized children, and quality learning only comes through hands-on training, then we need some more hands in the pot.

Discharge Improvement

On the heels of my first project, I was fortunate enough to augment my education through another effort—this time with a cohort of fellow pediatric hospitalists. This was a national collaborative to improve discharge handoffs, and I will admit that, at the outset, I was as puzzled as the first time I pulled the lid off the tank of the toilet. There were just too many permutations on PCP communication at the participating institutions, and some felt our aim of timely discharge handoffs was unattainable.

 

What carried me through, however, was the collective and infectious DIY—no, QIY (Quality Improve-it-Yourself) attitude of the group. We were all learning, and regular participation in the collaborative essentially guaranteed improvement. We achieved our aim of 90% communication with PCPs within two days of discharge. The secret was simple: The more you do, the more you learn.

Pediatric hospitalists can transform care delivery through a focus on safe and quality care, but the tools to accomplish this must come through post-residency, on-the-job learning. This QI know-how must efficiently spread among our ranks through practical and project-based educational efforts. It’s “see one, do one, teach one,” but we’re not talking about lumbar punctures anymore.

This is a journey in which we all take on the responsibility of rolling up our sleeves and simply learn by doing. And here is where the third leg of my as-yet-unfinished QI course unfolds.

Through my involvement with the Value in Inpatient Pediatrics (VIP) Network, I’ve gained a newfound vision for what the future might hold. VIP has evolved from a benchmarking project focused on bronchiolitis to an improvement network that will incorporate projects similar to the discharge handoff collaborative above.

In the process, a model for how to rapidly spread QI learning has emerged. The capacity lies in the network’s rapidly growing connectivity. The power comes from the individuals: motivated, card-carrying pediatric hospitalists from a wide array of sites. Collaborative learning harbors the potential to exponentially increase the pace at which we improve.

The future of our quality care is bright. I see an open network of improvement doers and learners. I see collaboration on quality and safety initiatives in all manner of hospitals and communities. I see that this will all be built upon a foundation of hard work and a QIY attitude.

You, too, will play a role.

Just don’t be afraid to get your hands a little dirty. TH

Dr. Shen is medical director of hospital medicine at Dell Children’s Medical Center in Austin, Texas. He is pediatric editor of The Hospitalist.

Several months ago, my toilet broke. You should also know that I’m not particularly handy. So when I first realized that the toilet bowl seemed to fill constantly, I got a little stressed out.

How much was it going cost to call in a plumber on the weekend?

What kind of a water bill was I going to have?

Was this a serious problem?

I took a quick peek in the tank, but that just made me more confused. I was paralyzed by a lack of know-how.

Normally, I would have just Googled a local plumber. But that day, I decided to do something different. Maybe it was because it was the fantasy football offseason. Maybe it was because my wife had started to ask my father-in-law to change light bulbs around the house. Or, maybe, I wanted to learn to actually fix the problem. A few hours later, after an Internet lesson in toilet physiology, a $4.12 trip to Home Depot, and a wet pair of hands, I had replaced my first toilet flapper.

This wasn’t the rebuilding of a car engine, but it was a clear DIY step toward self-improvement. Easily the most memorable moment here was my sense of accomplishment.

I felt empowered.

One Part Science, One Part Art

It’s taken me a while to realize this, but I’ve begun to take advantage of improvement opportunities at work as well. No, I haven’t been moonlighting as a plumber for my hospital. I’ve just been fortunate to be part of a trifecta of rewarding quality-improvement (QI) projects over the past year. Before I’d gotten my hands dirty with these, my understanding of QI was fairly naive. I’d heard about Plan-Do-Study-Act many times. I had listened to a talk at a national conference. And I had kept up with the general medical literature on the subject.

But none of those activities had truly prepared me for experience of actually doing the work on my own.

By taking on a project, an ambitious attempt to reduce continuous pulse oximetry use, I experienced a crash course in both the science and the art of process improvement. I was forced to overcome my “I don’t know how” inertia. And with expert guidance in the form of a clinical safety and effectiveness class, I learned the importance of run charts (science) and a well-crafted multidisciplinary team (art) in changing established but inefficient behavior.

Our rates of continuous pulse oximetry usage dropped by 50%, and cost savings were $12,000 per year on one unit. These results made my prior attempts at change—years of complaining about ingrained nursing culture—look infantile. (OK, maybe it was ineffective, but who hasn’t complained about the overuse of continuous monitoring?)

I haven’t met a pediatric hospitalist who wouldn’t understand the symbolic importance of this success. But I know of many hospitalists who have not yet participated in meaningful QI project. Imagine calling a plumber who grasped the flush and fill mechanism of a toilet but had never touched real porcelain. Here’s an even better analogy: What if doctors could get licensed without having touched real patients?

If pediatric hospitalists are to transform the care delivery of hospitalized children, and quality learning only comes through hands-on training, then we need some more hands in the pot.

Discharge Improvement

On the heels of my first project, I was fortunate enough to augment my education through another effort—this time with a cohort of fellow pediatric hospitalists. This was a national collaborative to improve discharge handoffs, and I will admit that, at the outset, I was as puzzled as the first time I pulled the lid off the tank of the toilet. There were just too many permutations on PCP communication at the participating institutions, and some felt our aim of timely discharge handoffs was unattainable.

 

What carried me through, however, was the collective and infectious DIY—no, QIY (Quality Improve-it-Yourself) attitude of the group. We were all learning, and regular participation in the collaborative essentially guaranteed improvement. We achieved our aim of 90% communication with PCPs within two days of discharge. The secret was simple: The more you do, the more you learn.

Pediatric hospitalists can transform care delivery through a focus on safe and quality care, but the tools to accomplish this must come through post-residency, on-the-job learning. This QI know-how must efficiently spread among our ranks through practical and project-based educational efforts. It’s “see one, do one, teach one,” but we’re not talking about lumbar punctures anymore.

This is a journey in which we all take on the responsibility of rolling up our sleeves and simply learn by doing. And here is where the third leg of my as-yet-unfinished QI course unfolds.

Through my involvement with the Value in Inpatient Pediatrics (VIP) Network, I’ve gained a newfound vision for what the future might hold. VIP has evolved from a benchmarking project focused on bronchiolitis to an improvement network that will incorporate projects similar to the discharge handoff collaborative above.

In the process, a model for how to rapidly spread QI learning has emerged. The capacity lies in the network’s rapidly growing connectivity. The power comes from the individuals: motivated, card-carrying pediatric hospitalists from a wide array of sites. Collaborative learning harbors the potential to exponentially increase the pace at which we improve.

The future of our quality care is bright. I see an open network of improvement doers and learners. I see collaboration on quality and safety initiatives in all manner of hospitals and communities. I see that this will all be built upon a foundation of hard work and a QIY attitude.

You, too, will play a role.

Just don’t be afraid to get your hands a little dirty. TH

Dr. Shen is medical director of hospital medicine at Dell Children’s Medical Center in Austin, Texas. He is pediatric editor of The Hospitalist.

Despite never advancing his musical tastes beyond the arena bands of the 1970s and ’80s (think Def Leppard), Mark Williams, MD, FACP, FHM, editor-in-chief of the Journal of Hospital Medicine, has done a great job in securing informative and meaningful research and opinion for the journal. Did you see read the July/August 2010 issue of JHM? It is a great example of content uniquely relevant to hospitalists: several original research articles documenting how hospitalists spend their time. Anyone thinking about the best way to organize and operate a hospitalist practice should read through these studies, along with one published by Kevin O’Leary, MD, and colleagues in the March/April 2006 issue.¹ But as a service, I’ll provide a CliffsNotes version of them, along with some comments here.

Time-Motion Studies

What all the studies demonstrate is that academic hospitalists spend only about 15% to 20% of their time in direct patient care, generally defined as time spent taking a patient’s history and examination, meeting with families, etc. Indirect patient care, such as time spent reviewing records, documenting, and communicating with consultants and other patient care staff, consumes about 60% to 70% of their time. The remainder of time is spent in transit (around 7% of each day) and in personal activities.

Remember, all these studies reported on academic hospitalists in large academic medical centers. As noted in the discussion sections, the results in nonteaching community hospitals might be different. My guess is that community hospitalists spend about the same portion of time in the broad categories above, but the individual activities within each category might differ. So I’m willing to believe that these studies tell us something about the majority of hospitalists who practice outside of academia.

90 Minutes of Doctoring?

While the JHM studies assess hospitalist time in a number of different categories, I think it makes the most sense to divide our time into just two categories: “real doctoring” and other. We’ll probably never see a study that divides hospitalists’ time that way, as there would be endless debate about what is and isn’t real doctoring. But it is worth thinking about your work this way.

A lot of what the studies generally defined as indirect patient care is still “real doctoring.” Things like reviewing old records are critically important and typically can’t be done adequately by a nonclinician. But the 10 minutes you spent to get the CD of outside X-rays to show up on your computer, and rearranging the faxed pages so they’re all oriented the same way and in order, are not a good use of your time; a clerical person could do it.

I periodically have an experience that makes me think I spend too much time on patients’ social issues (e.g. long conversations about why Medicare won’t pay for a patient’s skilled nursing facility stay) and too little on “real doctoring.” One such experience is when I have a patient with an unusual pulmonary infiltrate and the radiologist is able to generate a much more comprehensive differential diagnosis than I can. This is embarrassing. Maybe the radiologist is just smarter than I am, but I think it could be because, compared to me, he spends more of his time every day thinking about “real medicine,” such as pulmonary diseases, and less time dealing with nonclinical issues.

 

Even though we’re paid for a full day’s work, I suspect many hospitalists might spend only about 90 minutes a day immersed in thought about “real medicine,” while doctors in most other specialties probably spend a lot more. If I’m right, then it shouldn’t be a surprise that after practicing for many years, the radiologist who spends several hours a day exercising his fund of medical knowledge probably has more command of some clinical things than a hospitalist who does so only 90 minutes a day. Actively practicing as a hospitalist might not be as effective a method of maintaining proficiency as it is in other specialties. More than many other specialties, we need to rely on self-study and continuing education courses to prevent erosion of our knowledge base.

I’ve just made up this 90-minute figure. I have no idea how accurate it might be, and, the JHM studies don’t offer a lot of insight either. Clearly, it varies a lot by individual doctor and practice setting. How much of your day do you think you spend on “real doctoring” vs. other activities?

What really matters is whether we’ve ended up with too much work that isn’t “real doctoring.” Sure, all of the work needs to be done, but the system isn’t served best when paying a doctor to do work a less expensive person could do.

Max “Doctoring” Time

I think most hospitalists, including me, are stuck spending too much time on activities that don’t add value. For example, while complete and informative documentation is essential, most of us probably spend too much time on it, in part because we’re trying to immunize against lawsuits and ensure our documentation matches the relevant coding regulations.

I think hospitalists have a communication burden that is higher than that of most other specialties. The JHM article by Tipping and colleagues notes that a time-motion study of ED doctors (Ann Emerg Med. 1998:31(1):87-91) found that they spent 13% of their time communicating with other providers and staff, compared with their finding that hospitalists spent 26% of their time communicating.² Only a portion of this communication is real doctoring. Discussing patient management with a surgeon is, but spending 20 minutes figuring out which surgeon is on call and how to reach her isn’t.

Tipping’s study also found that when patient census was above average, hospitalists spent less time communicating and documenting in the electronic record, even though the total time spent working on those days increased. Of course, it is possible that when the patient census is below average, we just work more slowly and let work fill the time available, and the reduced time spent documenting and communicating when busy simply reflects working more efficiently. But I suspect that when our patient census climbs above a certain point, or we’re made less efficient by things like implementing a new technology, we compensate in part by relying on consultants more to do the real doctoring we would otherwise be doing and communicating with them less.

All of us should be thinking about ways to make communication as efficient as possible so that we can spend less time doing it. I’m hopeful that we will figure out new ways to communicate (e-mail, text, IM, etc.) that are quicker and just as effective in certain situations.

Coda

I try to write most of my columns in a way that minimizes the editorializing and maximizes the practical advice. This month is an exception; it’s all editorializing. But I do have some advice for Dr. Williams: Investigate music options other than the arena bands of the 1980s. Try something like Alison Krauss’ live album or Puccini’s opera Gianni Schicchi, which has the beautiful aria O mio babbino caro.

 

Or do what I do: Ask former SHM board member Brad Flansbaum, MD, SFHM, for advice. TH

Dr. Nelson has been a practicing hospitalist since 1988 and is co-founder and past president of SHM. He is a principal in Nelson Flores Hospital Medicine Consultants, a national hospitalist practice management consulting firm (www.nelsonflores.com). He is course co-director and faculty for SHM’s “Best Practices in Managing a Hospital Medicine Program.” This column represents his views and is not intended to reflect an official position of SHM.

References

1. O’Leary KJ, Liebovitz DM, Baker DW. How hospitalists spend their time: insights on efficiency and safety. J Hosp Med. 2006;1(2):88-93.
2. Tipping MD, Forth VE, O’Leary KJ, et al. Where did the day go? A time-motion study of hospitalists. J Hosp Med. 2010;5(6):323-328.

Despite never advancing his musical tastes beyond the arena bands of the 1970s and ’80s (think Def Leppard), Mark Williams, MD, FACP, FHM, editor-in-chief of the Journal of Hospital Medicine, has done a great job in securing informative and meaningful research and opinion for the journal. Did you see read the July/August 2010 issue of JHM? It is a great example of content uniquely relevant to hospitalists: several original research articles documenting how hospitalists spend their time. Anyone thinking about the best way to organize and operate a hospitalist practice should read through these studies, along with one published by Kevin O’Leary, MD, and colleagues in the March/April 2006 issue.¹ But as a service, I’ll provide a CliffsNotes version of them, along with some comments here.

Time-Motion Studies

What all the studies demonstrate is that academic hospitalists spend only about 15% to 20% of their time in direct patient care, generally defined as time spent taking a patient’s history and examination, meeting with families, etc. Indirect patient care, such as time spent reviewing records, documenting, and communicating with consultants and other patient care staff, consumes about 60% to 70% of their time. The remainder of time is spent in transit (around 7% of each day) and in personal activities.

Remember, all these studies reported on academic hospitalists in large academic medical centers. As noted in the discussion sections, the results in nonteaching community hospitals might be different. My guess is that community hospitalists spend about the same portion of time in the broad categories above, but the individual activities within each category might differ. So I’m willing to believe that these studies tell us something about the majority of hospitalists who practice outside of academia.

90 Minutes of Doctoring?

While the JHM studies assess hospitalist time in a number of different categories, I think it makes the most sense to divide our time into just two categories: “real doctoring” and other. We’ll probably never see a study that divides hospitalists’ time that way, as there would be endless debate about what is and isn’t real doctoring. But it is worth thinking about your work this way.

A lot of what the studies generally defined as indirect patient care is still “real doctoring.” Things like reviewing old records are critically important and typically can’t be done adequately by a nonclinician. But the 10 minutes you spent to get the CD of outside X-rays to show up on your computer, and rearranging the faxed pages so they’re all oriented the same way and in order, are not a good use of your time; a clerical person could do it.

I periodically have an experience that makes me think I spend too much time on patients’ social issues (e.g. long conversations about why Medicare won’t pay for a patient’s skilled nursing facility stay) and too little on “real doctoring.” One such experience is when I have a patient with an unusual pulmonary infiltrate and the radiologist is able to generate a much more comprehensive differential diagnosis than I can. This is embarrassing. Maybe the radiologist is just smarter than I am, but I think it could be because, compared to me, he spends more of his time every day thinking about “real medicine,” such as pulmonary diseases, and less time dealing with nonclinical issues.

 

Even though we’re paid for a full day’s work, I suspect many hospitalists might spend only about 90 minutes a day immersed in thought about “real medicine,” while doctors in most other specialties probably spend a lot more. If I’m right, then it shouldn’t be a surprise that after practicing for many years, the radiologist who spends several hours a day exercising his fund of medical knowledge probably has more command of some clinical things than a hospitalist who does so only 90 minutes a day. Actively practicing as a hospitalist might not be as effective a method of maintaining proficiency as it is in other specialties. More than many other specialties, we need to rely on self-study and continuing education courses to prevent erosion of our knowledge base.

I’ve just made up this 90-minute figure. I have no idea how accurate it might be, and, the JHM studies don’t offer a lot of insight either. Clearly, it varies a lot by individual doctor and practice setting. How much of your day do you think you spend on “real doctoring” vs. other activities?

What really matters is whether we’ve ended up with too much work that isn’t “real doctoring.” Sure, all of the work needs to be done, but the system isn’t served best when paying a doctor to do work a less expensive person could do.

Max “Doctoring” Time

I think most hospitalists, including me, are stuck spending too much time on activities that don’t add value. For example, while complete and informative documentation is essential, most of us probably spend too much time on it, in part because we’re trying to immunize against lawsuits and ensure our documentation matches the relevant coding regulations.

I think hospitalists have a communication burden that is higher than that of most other specialties. The JHM article by Tipping and colleagues notes that a time-motion study of ED doctors (Ann Emerg Med. 1998:31(1):87-91) found that they spent 13% of their time communicating with other providers and staff, compared with their finding that hospitalists spent 26% of their time communicating.² Only a portion of this communication is real doctoring. Discussing patient management with a surgeon is, but spending 20 minutes figuring out which surgeon is on call and how to reach her isn’t.

Tipping’s study also found that when patient census was above average, hospitalists spent less time communicating and documenting in the electronic record, even though the total time spent working on those days increased. Of course, it is possible that when the patient census is below average, we just work more slowly and let work fill the time available, and the reduced time spent documenting and communicating when busy simply reflects working more efficiently. But I suspect that when our patient census climbs above a certain point, or we’re made less efficient by things like implementing a new technology, we compensate in part by relying on consultants more to do the real doctoring we would otherwise be doing and communicating with them less.

All of us should be thinking about ways to make communication as efficient as possible so that we can spend less time doing it. I’m hopeful that we will figure out new ways to communicate (e-mail, text, IM, etc.) that are quicker and just as effective in certain situations.

Coda

I try to write most of my columns in a way that minimizes the editorializing and maximizes the practical advice. This month is an exception; it’s all editorializing. But I do have some advice for Dr. Williams: Investigate music options other than the arena bands of the 1980s. Try something like Alison Krauss’ live album or Puccini’s opera Gianni Schicchi, which has the beautiful aria O mio babbino caro.

 

Or do what I do: Ask former SHM board member Brad Flansbaum, MD, SFHM, for advice. TH

Dr. Nelson has been a practicing hospitalist since 1988 and is co-founder and past president of SHM. He is a principal in Nelson Flores Hospital Medicine Consultants, a national hospitalist practice management consulting firm (www.nelsonflores.com). He is course co-director and faculty for SHM’s “Best Practices in Managing a Hospital Medicine Program.” This column represents his views and is not intended to reflect an official position of SHM.

References

1. O’Leary KJ, Liebovitz DM, Baker DW. How hospitalists spend their time: insights on efficiency and safety. J Hosp Med. 2006;1(2):88-93.
2. Tipping MD, Forth VE, O’Leary KJ, et al. Where did the day go? A time-motion study of hospitalists. J Hosp Med. 2010;5(6):323-328.

Despite never advancing his musical tastes beyond the arena bands of the 1970s and ’80s (think Def Leppard), Mark Williams, MD, FACP, FHM, editor-in-chief of the Journal of Hospital Medicine, has done a great job in securing informative and meaningful research and opinion for the journal. Did you see read the July/August 2010 issue of JHM? It is a great example of content uniquely relevant to hospitalists: several original research articles documenting how hospitalists spend their time. Anyone thinking about the best way to organize and operate a hospitalist practice should read through these studies, along with one published by Kevin O’Leary, MD, and colleagues in the March/April 2006 issue.¹ But as a service, I’ll provide a CliffsNotes version of them, along with some comments here.

Time-Motion Studies

What all the studies demonstrate is that academic hospitalists spend only about 15% to 20% of their time in direct patient care, generally defined as time spent taking a patient’s history and examination, meeting with families, etc. Indirect patient care, such as time spent reviewing records, documenting, and communicating with consultants and other patient care staff, consumes about 60% to 70% of their time. The remainder of time is spent in transit (around 7% of each day) and in personal activities.

Remember, all these studies reported on academic hospitalists in large academic medical centers. As noted in the discussion sections, the results in nonteaching community hospitals might be different. My guess is that community hospitalists spend about the same portion of time in the broad categories above, but the individual activities within each category might differ. So I’m willing to believe that these studies tell us something about the majority of hospitalists who practice outside of academia.

90 Minutes of Doctoring?

While the JHM studies assess hospitalist time in a number of different categories, I think it makes the most sense to divide our time into just two categories: “real doctoring” and other. We’ll probably never see a study that divides hospitalists’ time that way, as there would be endless debate about what is and isn’t real doctoring. But it is worth thinking about your work this way.

A lot of what the studies generally defined as indirect patient care is still “real doctoring.” Things like reviewing old records are critically important and typically can’t be done adequately by a nonclinician. But the 10 minutes you spent to get the CD of outside X-rays to show up on your computer, and rearranging the faxed pages so they’re all oriented the same way and in order, are not a good use of your time; a clerical person could do it.

I periodically have an experience that makes me think I spend too much time on patients’ social issues (e.g. long conversations about why Medicare won’t pay for a patient’s skilled nursing facility stay) and too little on “real doctoring.” One such experience is when I have a patient with an unusual pulmonary infiltrate and the radiologist is able to generate a much more comprehensive differential diagnosis than I can. This is embarrassing. Maybe the radiologist is just smarter than I am, but I think it could be because, compared to me, he spends more of his time every day thinking about “real medicine,” such as pulmonary diseases, and less time dealing with nonclinical issues.

 

Even though we’re paid for a full day’s work, I suspect many hospitalists might spend only about 90 minutes a day immersed in thought about “real medicine,” while doctors in most other specialties probably spend a lot more. If I’m right, then it shouldn’t be a surprise that after practicing for many years, the radiologist who spends several hours a day exercising his fund of medical knowledge probably has more command of some clinical things than a hospitalist who does so only 90 minutes a day. Actively practicing as a hospitalist might not be as effective a method of maintaining proficiency as it is in other specialties. More than many other specialties, we need to rely on self-study and continuing education courses to prevent erosion of our knowledge base.

I’ve just made up this 90-minute figure. I have no idea how accurate it might be, and, the JHM studies don’t offer a lot of insight either. Clearly, it varies a lot by individual doctor and practice setting. How much of your day do you think you spend on “real doctoring” vs. other activities?

What really matters is whether we’ve ended up with too much work that isn’t “real doctoring.” Sure, all of the work needs to be done, but the system isn’t served best when paying a doctor to do work a less expensive person could do.

Max “Doctoring” Time

I think most hospitalists, including me, are stuck spending too much time on activities that don’t add value. For example, while complete and informative documentation is essential, most of us probably spend too much time on it, in part because we’re trying to immunize against lawsuits and ensure our documentation matches the relevant coding regulations.

I think hospitalists have a communication burden that is higher than that of most other specialties. The JHM article by Tipping and colleagues notes that a time-motion study of ED doctors (Ann Emerg Med. 1998:31(1):87-91) found that they spent 13% of their time communicating with other providers and staff, compared with their finding that hospitalists spent 26% of their time communicating.² Only a portion of this communication is real doctoring. Discussing patient management with a surgeon is, but spending 20 minutes figuring out which surgeon is on call and how to reach her isn’t.

Tipping’s study also found that when patient census was above average, hospitalists spent less time communicating and documenting in the electronic record, even though the total time spent working on those days increased. Of course, it is possible that when the patient census is below average, we just work more slowly and let work fill the time available, and the reduced time spent documenting and communicating when busy simply reflects working more efficiently. But I suspect that when our patient census climbs above a certain point, or we’re made less efficient by things like implementing a new technology, we compensate in part by relying on consultants more to do the real doctoring we would otherwise be doing and communicating with them less.

All of us should be thinking about ways to make communication as efficient as possible so that we can spend less time doing it. I’m hopeful that we will figure out new ways to communicate (e-mail, text, IM, etc.) that are quicker and just as effective in certain situations.

Coda

I try to write most of my columns in a way that minimizes the editorializing and maximizes the practical advice. This month is an exception; it’s all editorializing. But I do have some advice for Dr. Williams: Investigate music options other than the arena bands of the 1980s. Try something like Alison Krauss’ live album or Puccini’s opera Gianni Schicchi, which has the beautiful aria O mio babbino caro.

 

Or do what I do: Ask former SHM board member Brad Flansbaum, MD, SFHM, for advice. TH

Dr. Nelson has been a practicing hospitalist since 1988 and is co-founder and past president of SHM. He is a principal in Nelson Flores Hospital Medicine Consultants, a national hospitalist practice management consulting firm (www.nelsonflores.com). He is course co-director and faculty for SHM’s “Best Practices in Managing a Hospital Medicine Program.” This column represents his views and is not intended to reflect an official position of SHM.

References

1. O’Leary KJ, Liebovitz DM, Baker DW. How hospitalists spend their time: insights on efficiency and safety. J Hosp Med. 2006;1(2):88-93.
2. Tipping MD, Forth VE, O’Leary KJ, et al. Where did the day go? A time-motion study of hospitalists. J Hosp Med. 2010;5(6):323-328.

If every system is perfectly designed to get the results it gets …

And if 15 million patients are harmed every year from medical care …

And if as many as 98,000 people die every year due to medical errors in hospitals …

Then what does that say about the system we have designed?

A System Designed to Competently Hurt Many

By now you’ve no doubt heard, read, and possibly even uttered the above facts and figures yourself. I think we all have our opinions about the veracity of these numbers, but I don’t think any of us would argue with the sentiment. The U.S. healthcare system comprises the most competent, compassionate, well-meaning, and caring professionals on this planet—who harm, maim, and kill countless people every year.

What a discomforting paradox.

Equity: The Overlooked Quality Domain

Many years back, the Institute of Medicine (IOM) published a list of six “domains” of healthcare quality. You’ve no doubt stumbled across the IOM’s Safe … Timely … Effective … Efficient … Equitable … Patient-Centered mnemonic recipe—STEEEP—for high-quality care.¹ In fact, it’s hard to read a journal, attend a medical presentation, or open a local newspaper without finding reference to these domains. It’s all the rage to talk about wrong-site surgery (safe), access to care (timely), comparative-effectiveness research (effective), lean concepts (efficient), and individualized medicine (patient-centered). However, the sixth domain often seems to get the Jan Brady treatment—minimized, marginalized, and oft-forgotten.

The IOM defines equitable care as that which “does not vary in quality because of personal characteristics such as gender, ethnicity, geographic location, and socioeconomic status.”1 To be sure, there is some hum at the national level about issues of equity, especially around healthcare coverage for all. And this is important. However, what appears lost in the rant surrounding the inherent inequities in our tiered health insurance system is that we have blantant inequalities baked into the everyday machinery of our hospitals. And they affect all, regardless of skin color, gender, or insurance status.

Think for a moment about your hospital. Are the type, level, and access to care equal at all times? Does the level of care change when the streetlights come on? How about on weekends and holidays? Do your operating rooms run on Saturdays and Sundays? Can patients get chemotherapy on the weekends? Does your hospital alter its nursing staff ratios after hours? Can you get an ultrasound at midnight? How about a urology or neurosurgery consult at 2 a.m.? How about getting interventional radiology to place an IVC filter on a holiday?

Now scratch a bit closer to home. Does your hospitalist group downstaff on weekends and holidays, even though the volumes probably warrant more coverage? Are your night providers part of your group, or are they moonlighters? Do your after-hours providers cross-cover and admit a reasonable number of patients, or are they frequently overwhelmed? Do they cover patients or admit for services that they don’t typically care for during the day (e.g. ICU, neurosurgical, subspecialty cardiology or oncology patients)? For the intensely ill patients admitted to U.S. hospitals today, should the type and availability of care differ when it’s delivered at 3 p.m. or 3 a.m., Sunday or Monday?

Disregarding the macro-inequities in our societal approach to healthcare, can we even ensure equitable care within our own hospital walls 24 hours a day, seven days a week?

 

The Answer: An Unfortunate “No”

For the record, I hate working nights, abhor working weekends, and resent working holidays. But the thing I’d hate even more than working nights, weekends, and holidays would be being a patient admitted during a night, weekend, or holiday. To understand why, I have to look no further than my hospital parking lot. During bankers’ hours, I can barely find a parking spot on the top floor of our multilevel parking structure.

Fast-forward to Saturday, and I have my pick of empty football fields’ worth of spots on all floors. Ditto Sundays, nights, and holidays.

Why is it that nationally, a collectively near-trillion-dollar hospital enterprise finds it acceptable to effectively shutter itself for a quarter to a third of the week? Especially when doing so seems to counter their primary mission of providing safe, timely, effective, efficient, equitable, and patient-centered care.

The Weekend Effect

There are, of course, economic and operational reasons to downshift during off hours—some hospitals don’t have the elective procedures to run operating rooms seven days a week, and very few patients want to have their elective colonoscopy at 11 p.m. or their chemotherapy during Thanksgiving dinner. However, in most cases, the reasons for doing so center on hospital staff and physician satisfaction. Most us of just don’t like working off hours. As a result, studies have shown significantly less access to such high-level care as coronary angiography and percutaneous coronary intervention on weekends.^2,3

And the effects of this “weekend effect” can be devastating.

A recent paper in the New England Journal of Medicine reported that for every 1,000 patients admitted with a myocardial infarction on a weekend, nine more would die than a comparable group admitted during the week.⁴ Their offense? Having the misfortune to get ill on a Saturday morning. The authors concluded that this higher mortality was secondary to a lower rate of invasive cardiac procedures, presumably because they were less available. And the weekend effect isn’t just limited to coronary care. Poorer outcomes, including higher mortality rates, have been reported for weekend admissions to the neonatal ICU and adult ICU, as well as admission for epiglottitis, ruptured abdominal aortic aneurysms, and pulmonary embolism.^5,6,7

So let’s connect the dots: A system designed with inequal access to lifesaving therapies and appropriate staffing results in worse outcomes, more harm, more deaths.

To be clear, 98,000 people don’t die every year because of my disdain for working nights and weekends. This is a much deeper problem that hinges on many unsatisfactory systems working unsatisfactorily in tandem (e.g. see the other five IOM domains of quality care). Furthermore, I don’t mean to suggest that hospitalists necessarily have a lot of say in cardiac catheterization schedules. Yet we do control our own systems of care—how many patients we admit and cover during a shift, how strongly we advocate for timely testing and consultation, how we staff weekends and cover patients at night.

And, more and more, we are in a position to enhance the care delivery systems of the hospital and its providers that surround us. With that comes a responsibility to ensure that these systems are highly functioning and equitable, regardless of the time of day, day of the week.

If we are going to fundamentally enhance the quality of care, then we have to design safer systems of care. It will take time and resources to alter many of our bruised systems of care, but we can begin by at least ensuring equity in how we deliver care at our own institutions. That is, unless we are comfortable with a system perfectly designed to harm. TH

 

Dr. Glasheen is associate professor of medicine at the University of Colorado Denver, where he serves as director of the Hospital Medicine Program and the Hospitalist Training Program, and as associate program director of the Internal Medicine Residency Program.

References

1. Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C.: National Academy Press; 2001.
2. Bell CM, Redelmeier DA. Waiting for urgent procedures on the weekend among emergently hospitalized patients. Am J Med. 2004:117(3):175-181.
3. Magid DJ, Wang Y, Herrin J, et al. Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA. 2005;294(7):803-812.
4. Kostis WJ, Demissie K, Marcella SW, Shao YH, Wilson AC, Moreyra AE. Weekend versus weekday admission and mortality from myocardial infarction. N Eng J Med. 2007;356 (11):1099-1109.
5. Hendry RA. The weekend—a dangerous time to be born? Br J Obstet Gynaecol. 1981;88(12):1200-1203.
6. Barnett MJ, Kaboli PJ, Sirio CA, Rosenthal GE. Day of the week of intensive care admission and patient outcomes: a multisite regional evaluation. Med Care. 2002;40(6):530-539.
7. Bell CM, Redelmeier DA. Mortality among patients admitted to hospitals on weekends as compared with weekdays. N Eng J Med. 2001;345(9):663-668.

If every system is perfectly designed to get the results it gets …

And if 15 million patients are harmed every year from medical care …

And if as many as 98,000 people die every year due to medical errors in hospitals …

Then what does that say about the system we have designed?

A System Designed to Competently Hurt Many

By now you’ve no doubt heard, read, and possibly even uttered the above facts and figures yourself. I think we all have our opinions about the veracity of these numbers, but I don’t think any of us would argue with the sentiment. The U.S. healthcare system comprises the most competent, compassionate, well-meaning, and caring professionals on this planet—who harm, maim, and kill countless people every year.

What a discomforting paradox.

Equity: The Overlooked Quality Domain

Many years back, the Institute of Medicine (IOM) published a list of six “domains” of healthcare quality. You’ve no doubt stumbled across the IOM’s Safe … Timely … Effective … Efficient … Equitable … Patient-Centered mnemonic recipe—STEEEP—for high-quality care.¹ In fact, it’s hard to read a journal, attend a medical presentation, or open a local newspaper without finding reference to these domains. It’s all the rage to talk about wrong-site surgery (safe), access to care (timely), comparative-effectiveness research (effective), lean concepts (efficient), and individualized medicine (patient-centered). However, the sixth domain often seems to get the Jan Brady treatment—minimized, marginalized, and oft-forgotten.

The IOM defines equitable care as that which “does not vary in quality because of personal characteristics such as gender, ethnicity, geographic location, and socioeconomic status.”1 To be sure, there is some hum at the national level about issues of equity, especially around healthcare coverage for all. And this is important. However, what appears lost in the rant surrounding the inherent inequities in our tiered health insurance system is that we have blantant inequalities baked into the everyday machinery of our hospitals. And they affect all, regardless of skin color, gender, or insurance status.

Think for a moment about your hospital. Are the type, level, and access to care equal at all times? Does the level of care change when the streetlights come on? How about on weekends and holidays? Do your operating rooms run on Saturdays and Sundays? Can patients get chemotherapy on the weekends? Does your hospital alter its nursing staff ratios after hours? Can you get an ultrasound at midnight? How about a urology or neurosurgery consult at 2 a.m.? How about getting interventional radiology to place an IVC filter on a holiday?

Now scratch a bit closer to home. Does your hospitalist group downstaff on weekends and holidays, even though the volumes probably warrant more coverage? Are your night providers part of your group, or are they moonlighters? Do your after-hours providers cross-cover and admit a reasonable number of patients, or are they frequently overwhelmed? Do they cover patients or admit for services that they don’t typically care for during the day (e.g. ICU, neurosurgical, subspecialty cardiology or oncology patients)? For the intensely ill patients admitted to U.S. hospitals today, should the type and availability of care differ when it’s delivered at 3 p.m. or 3 a.m., Sunday or Monday?

Disregarding the macro-inequities in our societal approach to healthcare, can we even ensure equitable care within our own hospital walls 24 hours a day, seven days a week?

 

The Answer: An Unfortunate “No”

For the record, I hate working nights, abhor working weekends, and resent working holidays. But the thing I’d hate even more than working nights, weekends, and holidays would be being a patient admitted during a night, weekend, or holiday. To understand why, I have to look no further than my hospital parking lot. During bankers’ hours, I can barely find a parking spot on the top floor of our multilevel parking structure.

Fast-forward to Saturday, and I have my pick of empty football fields’ worth of spots on all floors. Ditto Sundays, nights, and holidays.

Why is it that nationally, a collectively near-trillion-dollar hospital enterprise finds it acceptable to effectively shutter itself for a quarter to a third of the week? Especially when doing so seems to counter their primary mission of providing safe, timely, effective, efficient, equitable, and patient-centered care.

The Weekend Effect

There are, of course, economic and operational reasons to downshift during off hours—some hospitals don’t have the elective procedures to run operating rooms seven days a week, and very few patients want to have their elective colonoscopy at 11 p.m. or their chemotherapy during Thanksgiving dinner. However, in most cases, the reasons for doing so center on hospital staff and physician satisfaction. Most us of just don’t like working off hours. As a result, studies have shown significantly less access to such high-level care as coronary angiography and percutaneous coronary intervention on weekends.^2,3

And the effects of this “weekend effect” can be devastating.

A recent paper in the New England Journal of Medicine reported that for every 1,000 patients admitted with a myocardial infarction on a weekend, nine more would die than a comparable group admitted during the week.⁴ Their offense? Having the misfortune to get ill on a Saturday morning. The authors concluded that this higher mortality was secondary to a lower rate of invasive cardiac procedures, presumably because they were less available. And the weekend effect isn’t just limited to coronary care. Poorer outcomes, including higher mortality rates, have been reported for weekend admissions to the neonatal ICU and adult ICU, as well as admission for epiglottitis, ruptured abdominal aortic aneurysms, and pulmonary embolism.^5,6,7

So let’s connect the dots: A system designed with inequal access to lifesaving therapies and appropriate staffing results in worse outcomes, more harm, more deaths.

To be clear, 98,000 people don’t die every year because of my disdain for working nights and weekends. This is a much deeper problem that hinges on many unsatisfactory systems working unsatisfactorily in tandem (e.g. see the other five IOM domains of quality care). Furthermore, I don’t mean to suggest that hospitalists necessarily have a lot of say in cardiac catheterization schedules. Yet we do control our own systems of care—how many patients we admit and cover during a shift, how strongly we advocate for timely testing and consultation, how we staff weekends and cover patients at night.

And, more and more, we are in a position to enhance the care delivery systems of the hospital and its providers that surround us. With that comes a responsibility to ensure that these systems are highly functioning and equitable, regardless of the time of day, day of the week.

If we are going to fundamentally enhance the quality of care, then we have to design safer systems of care. It will take time and resources to alter many of our bruised systems of care, but we can begin by at least ensuring equity in how we deliver care at our own institutions. That is, unless we are comfortable with a system perfectly designed to harm. TH

 

Dr. Glasheen is associate professor of medicine at the University of Colorado Denver, where he serves as director of the Hospital Medicine Program and the Hospitalist Training Program, and as associate program director of the Internal Medicine Residency Program.

References

1. Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C.: National Academy Press; 2001.
2. Bell CM, Redelmeier DA. Waiting for urgent procedures on the weekend among emergently hospitalized patients. Am J Med. 2004:117(3):175-181.
3. Magid DJ, Wang Y, Herrin J, et al. Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA. 2005;294(7):803-812.
4. Kostis WJ, Demissie K, Marcella SW, Shao YH, Wilson AC, Moreyra AE. Weekend versus weekday admission and mortality from myocardial infarction. N Eng J Med. 2007;356 (11):1099-1109.
5. Hendry RA. The weekend—a dangerous time to be born? Br J Obstet Gynaecol. 1981;88(12):1200-1203.
6. Barnett MJ, Kaboli PJ, Sirio CA, Rosenthal GE. Day of the week of intensive care admission and patient outcomes: a multisite regional evaluation. Med Care. 2002;40(6):530-539.
7. Bell CM, Redelmeier DA. Mortality among patients admitted to hospitals on weekends as compared with weekdays. N Eng J Med. 2001;345(9):663-668.

If every system is perfectly designed to get the results it gets …

And if 15 million patients are harmed every year from medical care …

And if as many as 98,000 people die every year due to medical errors in hospitals …

Then what does that say about the system we have designed?

A System Designed to Competently Hurt Many

By now you’ve no doubt heard, read, and possibly even uttered the above facts and figures yourself. I think we all have our opinions about the veracity of these numbers, but I don’t think any of us would argue with the sentiment. The U.S. healthcare system comprises the most competent, compassionate, well-meaning, and caring professionals on this planet—who harm, maim, and kill countless people every year.

What a discomforting paradox.

Equity: The Overlooked Quality Domain

Many years back, the Institute of Medicine (IOM) published a list of six “domains” of healthcare quality. You’ve no doubt stumbled across the IOM’s Safe … Timely … Effective … Efficient … Equitable … Patient-Centered mnemonic recipe—STEEEP—for high-quality care.¹ In fact, it’s hard to read a journal, attend a medical presentation, or open a local newspaper without finding reference to these domains. It’s all the rage to talk about wrong-site surgery (safe), access to care (timely), comparative-effectiveness research (effective), lean concepts (efficient), and individualized medicine (patient-centered). However, the sixth domain often seems to get the Jan Brady treatment—minimized, marginalized, and oft-forgotten.

The IOM defines equitable care as that which “does not vary in quality because of personal characteristics such as gender, ethnicity, geographic location, and socioeconomic status.”1 To be sure, there is some hum at the national level about issues of equity, especially around healthcare coverage for all. And this is important. However, what appears lost in the rant surrounding the inherent inequities in our tiered health insurance system is that we have blantant inequalities baked into the everyday machinery of our hospitals. And they affect all, regardless of skin color, gender, or insurance status.

Think for a moment about your hospital. Are the type, level, and access to care equal at all times? Does the level of care change when the streetlights come on? How about on weekends and holidays? Do your operating rooms run on Saturdays and Sundays? Can patients get chemotherapy on the weekends? Does your hospital alter its nursing staff ratios after hours? Can you get an ultrasound at midnight? How about a urology or neurosurgery consult at 2 a.m.? How about getting interventional radiology to place an IVC filter on a holiday?

Now scratch a bit closer to home. Does your hospitalist group downstaff on weekends and holidays, even though the volumes probably warrant more coverage? Are your night providers part of your group, or are they moonlighters? Do your after-hours providers cross-cover and admit a reasonable number of patients, or are they frequently overwhelmed? Do they cover patients or admit for services that they don’t typically care for during the day (e.g. ICU, neurosurgical, subspecialty cardiology or oncology patients)? For the intensely ill patients admitted to U.S. hospitals today, should the type and availability of care differ when it’s delivered at 3 p.m. or 3 a.m., Sunday or Monday?

Disregarding the macro-inequities in our societal approach to healthcare, can we even ensure equitable care within our own hospital walls 24 hours a day, seven days a week?

 

The Answer: An Unfortunate “No”

For the record, I hate working nights, abhor working weekends, and resent working holidays. But the thing I’d hate even more than working nights, weekends, and holidays would be being a patient admitted during a night, weekend, or holiday. To understand why, I have to look no further than my hospital parking lot. During bankers’ hours, I can barely find a parking spot on the top floor of our multilevel parking structure.

Fast-forward to Saturday, and I have my pick of empty football fields’ worth of spots on all floors. Ditto Sundays, nights, and holidays.

Why is it that nationally, a collectively near-trillion-dollar hospital enterprise finds it acceptable to effectively shutter itself for a quarter to a third of the week? Especially when doing so seems to counter their primary mission of providing safe, timely, effective, efficient, equitable, and patient-centered care.

The Weekend Effect

There are, of course, economic and operational reasons to downshift during off hours—some hospitals don’t have the elective procedures to run operating rooms seven days a week, and very few patients want to have their elective colonoscopy at 11 p.m. or their chemotherapy during Thanksgiving dinner. However, in most cases, the reasons for doing so center on hospital staff and physician satisfaction. Most us of just don’t like working off hours. As a result, studies have shown significantly less access to such high-level care as coronary angiography and percutaneous coronary intervention on weekends.^2,3

And the effects of this “weekend effect” can be devastating.

A recent paper in the New England Journal of Medicine reported that for every 1,000 patients admitted with a myocardial infarction on a weekend, nine more would die than a comparable group admitted during the week.⁴ Their offense? Having the misfortune to get ill on a Saturday morning. The authors concluded that this higher mortality was secondary to a lower rate of invasive cardiac procedures, presumably because they were less available. And the weekend effect isn’t just limited to coronary care. Poorer outcomes, including higher mortality rates, have been reported for weekend admissions to the neonatal ICU and adult ICU, as well as admission for epiglottitis, ruptured abdominal aortic aneurysms, and pulmonary embolism.^5,6,7

So let’s connect the dots: A system designed with inequal access to lifesaving therapies and appropriate staffing results in worse outcomes, more harm, more deaths.

To be clear, 98,000 people don’t die every year because of my disdain for working nights and weekends. This is a much deeper problem that hinges on many unsatisfactory systems working unsatisfactorily in tandem (e.g. see the other five IOM domains of quality care). Furthermore, I don’t mean to suggest that hospitalists necessarily have a lot of say in cardiac catheterization schedules. Yet we do control our own systems of care—how many patients we admit and cover during a shift, how strongly we advocate for timely testing and consultation, how we staff weekends and cover patients at night.

And, more and more, we are in a position to enhance the care delivery systems of the hospital and its providers that surround us. With that comes a responsibility to ensure that these systems are highly functioning and equitable, regardless of the time of day, day of the week.

If we are going to fundamentally enhance the quality of care, then we have to design safer systems of care. It will take time and resources to alter many of our bruised systems of care, but we can begin by at least ensuring equity in how we deliver care at our own institutions. That is, unless we are comfortable with a system perfectly designed to harm. TH

 

Dr. Glasheen is associate professor of medicine at the University of Colorado Denver, where he serves as director of the Hospital Medicine Program and the Hospitalist Training Program, and as associate program director of the Internal Medicine Residency Program.

References

1. Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C.: National Academy Press; 2001.
2. Bell CM, Redelmeier DA. Waiting for urgent procedures on the weekend among emergently hospitalized patients. Am J Med. 2004:117(3):175-181.
3. Magid DJ, Wang Y, Herrin J, et al. Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA. 2005;294(7):803-812.
4. Kostis WJ, Demissie K, Marcella SW, Shao YH, Wilson AC, Moreyra AE. Weekend versus weekday admission and mortality from myocardial infarction. N Eng J Med. 2007;356 (11):1099-1109.
5. Hendry RA. The weekend—a dangerous time to be born? Br J Obstet Gynaecol. 1981;88(12):1200-1203.
6. Barnett MJ, Kaboli PJ, Sirio CA, Rosenthal GE. Day of the week of intensive care admission and patient outcomes: a multisite regional evaluation. Med Care. 2002;40(6):530-539.
7. Bell CM, Redelmeier DA. Mortality among patients admitted to hospitals on weekends as compared with weekdays. N Eng J Med. 2001;345(9):663-668.

While most physicians say patients who discharge from the hospital against medical advice (AMA) put themselves at great risk, little research has been conducted to prove that theory. So two hospitalists at the Montefiore Medical Center in Bronx, N.Y., put it to the test, and they found that discharge AMA could literally be a matter of life or death.

In their award-winning HM10 research poster (PDF), Will Southern, MD, MS, and Julia Arnsten, MD, MPH, discovered that discharge AMA significantly increases the risk for both mortality and readmission in a general medical inpatient population. Their research equally divided more than 7,100 inpatients into two groups that were identical in every measurable domain, including admission laboratory values, acuity of illness, and medical history; one of the two groups chose discharge AMA.

Results showed that the AMA group was at a 45% increased risk of mortality and readmission within 30 days, whereas the non-AMA group was at approximately half the risk, with only a 27% chance of mortality and readmission.

Acknowledging the possibility that patients intuitively know when they are ready to leave and the fundamental medical, behavioral, and psychiatric differences in patients who discharge AMA, Dr. Southern says, "the real question is, 'If I [the hospitalist] intervene and, by whatever means necessary, try to convince the patients not to leave AMA, are their outcomes improved?' "

According to Dr. Southern, outcomes can be improved through patient communication, engagement, and intervention. "If you're interested in leaving AMA, it's OK, it's your choice," he says, "but your chances of being dead within the next 30 days are about double and your chances of being readmitted are about double."

Dr. Southern says that, although their findings are a useful starting point for further disease-centric study, for the practicing hospitalist with a patient considering discharge AMA, "it's about finding out why someone needs to leave: They need to feed their cat, cash their Social Security check, whatever the reason is."

While most physicians say patients who discharge from the hospital against medical advice (AMA) put themselves at great risk, little research has been conducted to prove that theory. So two hospitalists at the Montefiore Medical Center in Bronx, N.Y., put it to the test, and they found that discharge AMA could literally be a matter of life or death.

In their award-winning HM10 research poster (PDF), Will Southern, MD, MS, and Julia Arnsten, MD, MPH, discovered that discharge AMA significantly increases the risk for both mortality and readmission in a general medical inpatient population. Their research equally divided more than 7,100 inpatients into two groups that were identical in every measurable domain, including admission laboratory values, acuity of illness, and medical history; one of the two groups chose discharge AMA.

Results showed that the AMA group was at a 45% increased risk of mortality and readmission within 30 days, whereas the non-AMA group was at approximately half the risk, with only a 27% chance of mortality and readmission.

Acknowledging the possibility that patients intuitively know when they are ready to leave and the fundamental medical, behavioral, and psychiatric differences in patients who discharge AMA, Dr. Southern says, "the real question is, 'If I [the hospitalist] intervene and, by whatever means necessary, try to convince the patients not to leave AMA, are their outcomes improved?' "

According to Dr. Southern, outcomes can be improved through patient communication, engagement, and intervention. "If you're interested in leaving AMA, it's OK, it's your choice," he says, "but your chances of being dead within the next 30 days are about double and your chances of being readmitted are about double."

Dr. Southern says that, although their findings are a useful starting point for further disease-centric study, for the practicing hospitalist with a patient considering discharge AMA, "it's about finding out why someone needs to leave: They need to feed their cat, cash their Social Security check, whatever the reason is."

While most physicians say patients who discharge from the hospital against medical advice (AMA) put themselves at great risk, little research has been conducted to prove that theory. So two hospitalists at the Montefiore Medical Center in Bronx, N.Y., put it to the test, and they found that discharge AMA could literally be a matter of life or death.

In their award-winning HM10 research poster (PDF), Will Southern, MD, MS, and Julia Arnsten, MD, MPH, discovered that discharge AMA significantly increases the risk for both mortality and readmission in a general medical inpatient population. Their research equally divided more than 7,100 inpatients into two groups that were identical in every measurable domain, including admission laboratory values, acuity of illness, and medical history; one of the two groups chose discharge AMA.

Results showed that the AMA group was at a 45% increased risk of mortality and readmission within 30 days, whereas the non-AMA group was at approximately half the risk, with only a 27% chance of mortality and readmission.

Acknowledging the possibility that patients intuitively know when they are ready to leave and the fundamental medical, behavioral, and psychiatric differences in patients who discharge AMA, Dr. Southern says, "the real question is, 'If I [the hospitalist] intervene and, by whatever means necessary, try to convince the patients not to leave AMA, are their outcomes improved?' "

According to Dr. Southern, outcomes can be improved through patient communication, engagement, and intervention. "If you're interested in leaving AMA, it's OK, it's your choice," he says, "but your chances of being dead within the next 30 days are about double and your chances of being readmitted are about double."

Dr. Southern says that, although their findings are a useful starting point for further disease-centric study, for the practicing hospitalist with a patient considering discharge AMA, "it's about finding out why someone needs to leave: They need to feed their cat, cash their Social Security check, whatever the reason is."

Martin Johns, MD, joined Gifford Medical Center, a 25-bed full access hospital in rural Randolph, Vt., five years ago to launch its HM program. The landmark push toward implementing electronic health records (EHR) now has Dr. Johns and his colleagues scrambling.

Dr. Johns, whose program now has four hospitalists and four physician assistants, recently spoke with The Hospitalist eWire to talk about the technology challenges specifically faced by rural hospitalist programs.

Question: What role did EHR play in your HM group when you began the service?

Answer: Five years ago, I was definitely concerned about that. I came from Geisinger Medical Center (in Danville, Pa.). They had Epic embedded into every aspect of documentation. I was very used to the seamless integration of information in transitions of care. I was somewhat spoiled in that regard, but I also realized a small hospital was going to have different types of systems.

Q: How far has your digital record-keeping in the hospital come to date?

A: We currently have a data repository more than EHR. CPSI is the system we use. One of the difficulties in us making the decision to move to an EHR is a very interesting problem for all small hospitals. Because they require so much augmentation after installation, small hospitals can't afford to have your large Epic system, for example, to put in place. They can't have 10 IT people in house running the service. What ends up happening is that the hospital purchases an EHR based on outpatient clinic interest and said EHR usually doesn't really speak to your inpatient system.

Q: How can a smaller institution transition into a comprehensive system?

A: The biggest barrier is there's just not a really great all-level-of-care product that would take you through that in a small hospital. It's just too difficult and too expensive for someone to create that product, or at least it appears that way. An all-encompassing solution for a small hospital—the market is not just there.

Q: So where does that leave the rural hospitalist?

A: At a smaller place, it sets up all the variables for a communication breakdown. Mrs. Jones comes in for cataract surgery and she gets morphine and she has a reaction. That's on her hospital chart, but doesn't make its way onto her clinic chart. Those are the breakdowns that can happen and that's really challenging. … With this EHR push, if it's not done correctly, the patient can suffer more than they would with paper records.

Martin Johns, MD, joined Gifford Medical Center, a 25-bed full access hospital in rural Randolph, Vt., five years ago to launch its HM program. The landmark push toward implementing electronic health records (EHR) now has Dr. Johns and his colleagues scrambling.

Dr. Johns, whose program now has four hospitalists and four physician assistants, recently spoke with The Hospitalist eWire to talk about the technology challenges specifically faced by rural hospitalist programs.

Question: What role did EHR play in your HM group when you began the service?

Answer: Five years ago, I was definitely concerned about that. I came from Geisinger Medical Center (in Danville, Pa.). They had Epic embedded into every aspect of documentation. I was very used to the seamless integration of information in transitions of care. I was somewhat spoiled in that regard, but I also realized a small hospital was going to have different types of systems.

Q: How far has your digital record-keeping in the hospital come to date?

A: We currently have a data repository more than EHR. CPSI is the system we use. One of the difficulties in us making the decision to move to an EHR is a very interesting problem for all small hospitals. Because they require so much augmentation after installation, small hospitals can't afford to have your large Epic system, for example, to put in place. They can't have 10 IT people in house running the service. What ends up happening is that the hospital purchases an EHR based on outpatient clinic interest and said EHR usually doesn't really speak to your inpatient system.

Q: How can a smaller institution transition into a comprehensive system?

A: The biggest barrier is there's just not a really great all-level-of-care product that would take you through that in a small hospital. It's just too difficult and too expensive for someone to create that product, or at least it appears that way. An all-encompassing solution for a small hospital—the market is not just there.

Q: So where does that leave the rural hospitalist?

A: At a smaller place, it sets up all the variables for a communication breakdown. Mrs. Jones comes in for cataract surgery and she gets morphine and she has a reaction. That's on her hospital chart, but doesn't make its way onto her clinic chart. Those are the breakdowns that can happen and that's really challenging. … With this EHR push, if it's not done correctly, the patient can suffer more than they would with paper records.

Martin Johns, MD, joined Gifford Medical Center, a 25-bed full access hospital in rural Randolph, Vt., five years ago to launch its HM program. The landmark push toward implementing electronic health records (EHR) now has Dr. Johns and his colleagues scrambling.

Dr. Johns, whose program now has four hospitalists and four physician assistants, recently spoke with The Hospitalist eWire to talk about the technology challenges specifically faced by rural hospitalist programs.

Question: What role did EHR play in your HM group when you began the service?

Answer: Five years ago, I was definitely concerned about that. I came from Geisinger Medical Center (in Danville, Pa.). They had Epic embedded into every aspect of documentation. I was very used to the seamless integration of information in transitions of care. I was somewhat spoiled in that regard, but I also realized a small hospital was going to have different types of systems.

Q: How far has your digital record-keeping in the hospital come to date?

A: We currently have a data repository more than EHR. CPSI is the system we use. One of the difficulties in us making the decision to move to an EHR is a very interesting problem for all small hospitals. Because they require so much augmentation after installation, small hospitals can't afford to have your large Epic system, for example, to put in place. They can't have 10 IT people in house running the service. What ends up happening is that the hospital purchases an EHR based on outpatient clinic interest and said EHR usually doesn't really speak to your inpatient system.

Q: How can a smaller institution transition into a comprehensive system?

A: The biggest barrier is there's just not a really great all-level-of-care product that would take you through that in a small hospital. It's just too difficult and too expensive for someone to create that product, or at least it appears that way. An all-encompassing solution for a small hospital—the market is not just there.

Q: So where does that leave the rural hospitalist?

A: At a smaller place, it sets up all the variables for a communication breakdown. Mrs. Jones comes in for cataract surgery and she gets morphine and she has a reaction. That's on her hospital chart, but doesn't make its way onto her clinic chart. Those are the breakdowns that can happen and that's really challenging. … With this EHR push, if it's not done correctly, the patient can suffer more than they would with paper records.

You have a 54-year-old black patient with gout, diabetes mellitus, hypertension, and chronic kidney disease (CKD). He has an acute gout flare involving his right knee. In the past year he has had four attacks of gout in the ankles and knees, which you treated with intra-articular glucocorticoid injections. He has been on allopurinol (Zyloprim) 200 mg daily, but his last serum urate level was 9.4 mg/dL (reference range 3.0–8.0). His creatinine clearance is 45 mL/minute (reference range 85–125).

In view of his kidney disease, you are concerned about increasing his dose of allopurinol, but also about the need to treat his frequent attacks. How should you manage this patient?

GOUT IS CHALLENGING TO TREAT IN PATIENTS WITH KIDNEY DISEASE

A major challenge in treating patients with gout is to avoid therapeutic interactions with common comorbidities, including hypertension, insulin resistance, coronary artery disease, heart failure, and especially CKD.¹

In this paper, we discuss approaches to and controversies in the management of gout and hyperuricemia in patients with CKD. Unfortunately, the evidence from clinical trials to guide treatment decisions is limited; therefore, decisions must often be based on experience and pathophysiologic principles.

GENERAL GOALS OF GOUT THERAPY

Depending on the patient and the stage of the disease, the goals in treating patients with gout are to:

• Terminate acute attacks as promptly and safely as possible
• Prevent recurrences of acute gout attacks
• Prevent or reverse complications resulting from deposition of monosodium urate in the joints, in the kidneys, or at other sites.

These goals are more difficult to achieve in patients with CKD because of the potential complications from many of the available drugs.

TERMINATING ACUTE GOUT FLARES

In patients with acute gout, treatment is aimed at quickly resolving pain and inflammation.

Several types of drugs can terminate acute gout flares. The choice in most situations is colchicine (Colcrys); a nonsteroidal anti-inflammatory drug (NSAID); a corticosteroid; or corticotropin (ACTH).

However, in patients with CKD, there are concerns about using colchicine or NSAIDs, and corticotropin is very expensive; thus, corticosteroids are often used.

Colchicine’s clearance is reduced in CKD

Colchicine is somewhat effective in treating acute gout attacks and probably more effective in preventing attacks.

Due to concerns about inappropriate dosing and reported deaths,² the intravenous formulation is not available in many countries, including the United States.

After oral administration, colchicine is rapidly absorbed, with a bioavailability of up to 50%. It undergoes metabolism by the liver, and its metabolites are excreted by renal and biliary-intestinal routes. Up to 20% of the active drug is excreted by the kidneys.³

Colchicine’s clearance is significantly reduced in patients with renal or hepatic insufficiency, and the drug may accumulate in cells, with resultant toxicity.⁴ Colchicine-induced toxicity has been observed when the drug was used for acute treatment, as well as for chronic prophylaxis of gout in patients with CKD; thus, alternative agents for treating acute attacks should be considered.^5,6 With prolonged use, reversible colchicine-induced axonal neuropathy, neutropenia, and vacuolar myopathy can develop in patients with CKD.⁷

In a trial in patients with normal renal function, nearly 100% who received an initial dose of 1 mg followed by 0.5 mg every 2 hours developed diarrhea at a median time of 24 hours.⁸ Emesis may also occur.

A lower dose of 1.8 mg (two 0.6-mg pills followed by one pill an hour later) was well tolerated but only moderately effective in treating acute gout, causing at least a 50% reduction in pain at 24 hours in only 38% of patients.⁹ This study does not clarify the dosage to use to completely resolve attacks. Using additional colchicine likely will increase the response rate, but will also increase side effects. Patients with CKD were not included.

Some patients, as shown in the above trial, can abort attacks by taking only one or two colchicine tablets when they feel the first “twinge” of an attack. This approach is likely to be safe in CKD, but it may be of value to only a few patients.

Nonsteroidal anti-inflammatory drugs can worsen chronic kidney disease

NSAIDs in high doses can effectively treat the pain and inflammation of acute gout. Indomethacin (Indocin) 50 mg three times daily has been standard NSAID therapy.

Other nonselective NSAIDs and NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) are effective, but all can cause acute renal toxicity or worsen CKD.¹⁰ Renal side effects include salt and water retention, acute tubular necrosis, acute interstitial nephritis, proteinuria, hypertension, hyperkalemia, and chronic renal injury.¹¹

Even short-term use of high-dose NSAIDs should generally be avoided in patients with preexisting CKD, for whom there is no established safe threshold dose. When NSAIDs (including selective COX-2 inhibitors) are used, renal function should be monitored closely and the duration limited as much as possible.

 

 

Corticosteroids are often used to treat acute attacks

Due to the concerns about NSAIDs or colchicine to treat acute gout attacks in patients with CKD, corticosteroids are often used in this setting.

Intra-articular steroid injections are useful in treating acute gout limited to a single joint or bursa.¹² However, one should first make sure that the joint is not infected: septic arthritis should ideally be excluded by arthrocentesis, particularly in immunosuppressed patients¹³ or those with end-stage renal disease, who are predisposed to bacteremia.

Oral, intramuscular, or intravenous steroids can provide complete relief from acute gout, although high doses (eg, prednisone 30–60 mg/day or the equivalent) are often needed. Common errors resulting in inefficacy include using too low a dose or not treating for a sufficient time before tapering or stopping. Groff and colleagues¹⁴ described 13 patients who received oral or intravenous steroids for acute gout. Nine patients received an initial single dose of prednisone ranging from 20 to 50 mg, with tapering over a mean of 10 days. Twelve of the 13 patients had improvement within 48 hours, and the signs and symptoms of acute gout resolved completely within 7 to 10 days.

We often give prednisone 40 mg daily until a day after the acute attack resolves and then taper over another 7 to 10 days. There are no data to guide steroid dosing in an evidence-based way, but we believe too short a course of therapy may result in return of symptoms.

Corticotropin and other agents: Effective but costly

Corticotropin shares the same indications as systemic corticosteroids, being used to treat flares when NSAIDs, intra-articular steroids, and colchicine are contraindicated. However, corticotropin is far more expensive than generic corticosteroids, costing nearly $2,000 for a single 80-IU dose, which may need to be repeated.

Corticotropin is available for subcutaneous or intramuscular injection. A single intramuscular injection of corticotropin gel (H.P. Acthar, 25–80 IU) may terminate an acute gout attack.¹⁵ However, many patients need another injection after 24 to 72 hours, which would require another visit to the physician. This treatment has been touted by some as being more effective than corticosteroid therapy, possibly because of a unique peripheral mechanism of action in addition to stimulating cortisol release.¹⁶

We rarely use corticotropin, in view of its cost as well as concerns about excessive sodium and water retention due to the release of multiple hormones from the adrenal gland. This may be especially deleterious in patients with CKD or congestive heart failure.¹⁷

Parenteral anti-tumor necrosis factor agents or interleukin 1 antagonists can be dramatically effective but are also expensive.^18,19 For example, anakinra (Kineret) 100 mg costs about $73, and multiple daily doses may be necessary.

Under unique conditions in which they can be safely used (eg, patients with CKD, diabetes mellitus, liver disease), they may be cost-effective if they can shorten the stay of a hospitalized patient with acute gout.

PROPHYLACTIC ANTI-INFLAMMATORY THERAPY FOR PATIENTS WITH GOUT

Between attacks, the goal is to prevent new attacks through prophylactic management, which may include anti-inflammatory and hypouricemic therapy along with dietary instruction (such as avoiding excessive beer, liquor, and fructose ingestion).

Colchicine can be used as prophylaxis, with caution and monitoring

Although colchicine is not 100% effective, it markedly reduces the flare rate when started in low doses at the time hypouricemic therapy is initiated.^20,21 (Hypouricemic therapy is discussed below.) We generally try to continue this prophylactic therapy, if the patient tolerates it, for at least 6 months—longer if tophi are still present or if attacks continue to occur.

If renal function is intact, colchicine can be prescribed at a dosage of 0.6 mg orally once or twice daily.²¹ In CKD, since the clearance of colchicine is reduced,⁴ the dosage should be reduced. Patients on colchicine for prophylaxis must be carefully monitored if the glomerular filtration rate is less than 50 mL/minute, or colchicine should be avoided altogether.⁶ Laboratory testing for colchicine levels is not routinely available and may be of limited value in predicting adverse effects; thus, recommendations about dose adjustments in CKD are empiric.

Wallace et al²² recommended a dose of 0.6 mg once daily if the creatinine clearance is 35 to 49 mL/minute and 0.6 mg every 2 to 3 days if it is 10 to 34 mL/minute, but there are no published long-term safety or efficacy data validating these reasonable (based on available information) dosing regimens.

Even with dose adjustment, caution is needed. Low-dose daily colchicine may be associated with reversible neuromyopathy and bone marrow suppression.^7,23 Patients with neuromyopathy may complain of myalgias, proximal muscle weakness, and numbness and may have areflexia and decreased sensation. Laboratory findings include elevated creatine kinase and aminotransferase levels. We regularly check for leukopenia or elevated creatine kinase and aspartate aminotransferase levels in patients with CKD who are receiving colchicine in any dose.

Prolonged colchicine therapy should probably be avoided in patients on hemodialysis, as this drug is not removed by dialysis or by exchange transfusion, and the risk of toxicity under these circumstances may be high.²² When there is no viable alternative and the drug is given, patients should be closely monitored for signs of toxicity.

Concurrent (even short-term) treatment with most macrolide antibiotics, particularly clarithromycin (Biaxin), most statin drugs, ketoconazole (Nizoral), cyclosporine, and likely other drugs predisposes to colchicine toxicity by altering its distribution and elimination, and can in rare cases cause morbidity or death.^24–26

NSAIDs are not optimal as prophylaxis in patients with chronic kidney disease

Little information has been published about using NSAIDs chronically to prevent flares, but they are not the optimal drugs to use in patients with CKD, as discussed above. In patients with end-stage renal disease, there are also concerns about NSAID-induced gastric and intestinal bleeding.

Low-dose steroids may not be effective as prophylaxis

Lower doses of steroids may not be effective as prophylaxis against gout flares, consistent with the common observation that gout flares still occur in organ transplant recipients who are taking maintenance doses of prednisone.¹³

 

PREVENTING FLARES BY LOWERING SERUM URATE LEVELS

If tophi are present, if radiography shows evidence of damage, if attacks are frequent or disabling, or if there are relative contraindications to the drugs that would be needed to treat acute attacks, then hypouricemic therapy should be strongly considered to reduce the burden of urate in the body, resorb tophi, and ultimately reduce the frequency of gout flares.²⁰

Although intermittent therapy for attacks or prolonged prophylactic use of colchicine may prevent recurrent episodes of gouty arthritis and may be reasonable for many patients, this approach does not prevent continued urate deposition, with the potential development of bony erosions, tophaceous deposits, and chronic arthritis.

The definitive therapy for gouty arthritis is to deplete the periarticular deposits of urate by maintaining a low serum urate level. Urate-lowering therapy, when indicated, is almost always lifelong.

Four strategies for lowering serum urate

The serum urate concentration can be lowered in four ways:

• Increasing renal uric acid excretion
• Altering the diet
• Decreasing urate synthesis
• Converting urate to a more soluble metabolite.

Increasing uric acid excretion is rarely effective if renal function is impaired

Probenecid, sulfinpyrazone (Anturane), and losartan (Cozaar) modestly increase uric acid secretion and reduce serum urate levels, but they are rarely effective if the creatinine clearance rate is less than 60 mL/minute, and they require significant fluid intake for maximal efficacy.

Uricosuric drugs probably should be avoided in patients who excrete more than 1,000 mg of uric acid per day on a normal diet, since urinary uric acid stones may form. In practice, however, patients are given losartan to treat hypertension without attention to uric acid excretion.

More-potent urocosuric drugs are being tested in clinical trials.

Altering the diet: Traditional advice confirmed

The Health Professionals Follow-up Study^27,28 prospectively examined the relation between diet and gout over 12 years in 47,150 men. The study confirmed some long-standing beliefs, such as that consuming meat, seafood, beer, and liquor increases the risk. Other risk factors were consumption of sugar-sweetened soft drinks and fructose, adiposity, weight gain, hypertension, and diuretic use. On the other hand, protein, wine, and purine-rich vegetables were not associated with gout flares. Low-fat dairy products may have a protective effect. Weight loss was found to be protective.

Low-purine diets are not very palatable, are difficult to adhere to, and are at best only minimally effective, lowering serum urate by 1 to 2 mg/dL. Low-protein diets designed to slow progression of CKD will likely also have only a slight effect on serum urate. Dietary change alone is not likely to dramatically lower serum urate levels.

Metabolizing urate with exogenous uricase

Rasburicase (Elitek) effectively converts urate to allantoin, which is more soluble, but rasburicase is fraught with allergic reactions and cannot be used as chronic therapy.

A pegylated intravenous uricase²⁹ has just been approved by the US Food and Drug Administration (FDA); the retail cost is not yet known. It is dramatically effective in those patients able to use it chronically, but it has not been fully evaluated in patients with CKD.

Decreasing urate synthesis with allopurinol

Allopurinol acts by competitively inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The drug, a structural analogue of hypoxanthine, is converted by xanthine oxidase to oxypurinol, which is an even more effective inhibitor of xanthine oxidase than allopurinol.

Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol can usually be given once daily, and the dosage required to reduce serum urate levels should in theory be lower in patients with lower glomerular filtration rates.

Allopurinol (100- and 300-mg tablets) is approved by the FDA in doses of up to 800 mg/day to treat hyperuricemia in patients with gout,³⁰ while guidelines from the British Society of Rheumatology advocate a maximum dose of 900 mg/day.³¹ These maximum doses are based on the limited amount of data with higher doses, not on documented toxicity.

Practice survey data in the United States indicate that most physicians prescribe no greater than 300 mg daily, although this dosage is likely to reduce the serum urate to less than 6 mg/dL—the goal level—in fewer than 50% of patients.^20,32 Patients with normal renal function occasionally require more than 1,000 mg daily to reduce the serum urate level to less than 6 mg/dL.

How low should the serum urate level be?

Ideally, therapy should keep the serum urate level significantly below 6.7 mg/dL, the approximate saturation point of urate in physiologic fluids.

Lowering the serum urate level from 10 mg/dL to 7 mg/dL may seem encouraging, and the urate level may be in the laboratory “normal” range; however, urate may continue to precipitate in tissues if the concentration is greater than 6.7 mg/dL. A target of 6 mg/dL, used in clinical studies, is far enough below the saturation level to provide some margin for fluctuations in serum levels. A serum level of 6.0 mg/dL has thus been arbitrarily proposed as a reasonable therapeutic target.

The lower the serum urate level achieved during hypouricemic therapy, the faster the reduction in tophaceous deposits. With adequate urate lowering, tophi can be visibly reduced in less than a year of hypouricemic therapy.^33,34

We have as yet no convincing evidence that lowering the serum urate level to less than 6.0 mg/dL is harmful, despite theoretical concerns that urate is a beneficial circulating antioxidant and epidemiologic observations that urate levels have been inversely correlated with progression of Parkinson disease.

 

 

Start low, go slow to avoid a flare

Rapid reduction of the serum urate level in a patient with chronic hyperuricemia and gout is likely to induce an acute flare.²⁰ We have traditionally used a “start low and increase slowly” approach to escalating hypouricemic therapy in hopes of reducing the likelihood of causing a gout flare.

Without anti-inflammatory prophylaxis, acute flares associated with urate-lowering are extremely likely. In a 28-week trial of allopurinol, febuxostat, and placebo by Schumacher et al,³³ during the first 8 weeks, when prophylaxis against gout flare was provided with either colchicine 0.6 mg once daily or naproxen (Naprosyn) 250 mg twice daily, the proportion of patients requiring treatment of gout flares was still 23% to 46%. When prophylaxis was stopped, the flare rate increased further.³³

The more we acutely lower serum urate levels, the more likely flares are to occur. In the study by Schumacher et al,³³ the percentage of patients needing treatment for gout flares during the first 8 weeks of the study, despite gout flare prophylaxis, was related to the percent reduction in serum urate by week 28 of the trial (Table 2).

IS IT NECESSARY TO ADJUST THE ALLOPURINOL DOSE IN CHRONIC KIDNEY DISEASE?

In 1984, Hande et al³⁵ proposed that allopurinol doses be lower in patients with renal insufficiency, with a dosage scale based on creatinine clearance.

Their thoughtful proposal was based on data from six of their own patients and 72 others with severe allopurinol toxicity, mainly allopurinol hypersensitivity syndrome, reported in the literature.

Perez-Ruiz et al³⁶ noted that patients who had experienced adverse effects from allopurinol in their series were likely to have had received “higher” doses of allopurinol, if the dosage was corrected for reduced oxypurinol elimination based on their estimated creatinine clearance.

However, most of these reactions occurred soon after initiating therapy, a temporal pattern more typical of non-dose-dependent allergic reactions. Additionally, allopurinol hypersensitivity has been linked to T-cell-mediated immune reactions to oxypurinol,³⁷ a mechanism not likely linked to drug levels.

Arguments against dose adjustment

Despite the compelling information that allopurinol reactions are more common in CKD, adjusting the dosage of allopurinol has not been clearly shown to reduce the frequency of these reactions.

In a small retrospective analysis, Vázquez-Mellado et al³⁸ reported that adjusting the allopurinol dosage according to creatinine clearance did not decrease the incidence of allopurinol hypersensitivity.

In a study in 250 patients, Dalbeth et al³⁹ showed that the overall incidence of hypersensitivity reaction was 1.6%, and the incidence of allergic reactions did not decrease when allopurinol was given according to the dosing guidelines proposed by Hande et al.³⁵ However, it is worth noting that, of the patients who received the recommended lower doses, only 19% achieved the target serum urate level of 6 mg/dL.³⁹

Silverberg et al⁴⁰ found that of 15 patients who developed hypersensitivity reactions to allopurinol, 10 had received doses that were low or appropriate according to the guidelines of Hande et al.³⁵

More recently, Stamp et al⁴¹ found that gradually increasing the allopurinol dose above the proposed creatinine clearance-based dose was safe and effective. Thirty-one (89%) of the 35 patients who completed the study achieved the target serum urate level of 6 mg/dL, while only 3 of 45 who started the study developed rashes, which were not serious.

The small number of patients in these studies limits any strong conclusion, but at present there is no interventional study showing that allopurinol dosing adjustment based on glomerular filtration rate is effective or safer than dosing based on the serum urate level.

Our view on allopurinol dosing adjustment

We believe the initial observations of Hande et al³⁵ and the subsequent meticulous data from Perez-Ruiz et al³⁶ suggest a relationship between CKD and the occurrence of severe allopurinol reactions. However, these observations do not prove that dose adjustment will prevent these reactions.

In patients with normal kidney function, the FDA³⁰ and the European League Against Rheumatism (EULAR)⁴² recommend slow upward titration, starting with 100 to 200 mg/day, which we agree should decrease the frequency of acute gout flares. The dose is increased by increments of 100 mg/day at intervals of 1 week (FDA recommendation) or 2 to 4 weeks (EULAR recommendation) until the serum urate level is lower than 6 mg/dL.

We believe the optimal approach to allopurinol dosing in patients with CKD remains uncertain. We generally escalate the dose slowly, with ongoing frequent laboratory and clinical monitoring, and we do not limit the maximal dose as suggested by Hande et al.³⁵

An alternative strategy is to use the newer, far more expensive xanthine oxidase inhibitor febuxostat in patients with CKD, since it is not excreted by the kidney. We usually first try escalating doses of allopurinol.

 

FEBUXOSTAT, AN ALTERNATIVE TO ALLOPURINOL

Febuxostat is an oral nonpurine inhibitor of xanthine oxidase.⁴³ Approved by the FDA in 2009, it is available in 40- and 80-mg tablets.

Unlike allopurinol, febuxostat is metabolized primarily by hepatic glucuronide formation and oxidation and then excreted in stool and urine,⁴⁴ making it in theory an attractive agent in patients with renal insufficiency, bypassing the controversial dose-adjustment issue with allopurinol.

In the Febuxostat Versus Allopurinol Controlled Trial (FACT),²⁰ a 52-week randomized, double-blind study in hyperuricemic patients with gout, serum urate levels were reduced to less than 6.0 mg/dL in over 50% of patients receiving febuxostat 80 mg or 120 mg once daily, while only 21% of patients receiving 300 mg of allopurinol achieved this goal. This does not imply that allopurinol at higher doses, as should be used in clinical practice,⁴⁵ would not be equally effective. Patients with CKD were not included in this trial.

In the study by Schumacher et al,³³ febuxostat 80, 120, or 240 mg once daily reduced serum urate. A small subset (35 patients) had mild to moderate renal insufficiency (serum creatinine 1.5–2 mg/dL).³³ The number of patients with renal insufficiency who achieved the primary end point of a serum urate level lower than 6 mg/dL was 4 (44%) of 9 in the febuxostat 80-mg group, 5 (46%) of 11 in the 120-mg group, and 3 (60%) of 5 in the 240-mg group, while none of the 10 patients in the dose-adjusted allopurinol group achieved the primary end point (P < .05). Of note, 41% of the patients with normal renal function who received allopurinol achieved the primary end point.³³ As proposed above, if the allopurinol dose had been slowly increased in the patients with renal insufficiency, it might have been equally effective.

Febuxostat has not been thoroughly evaluated in patients with severe CKD or in patients on hemodialysis.

A presumed niche indication of febuxostat is in patients allergic to allopurinol, since the drugs are not similar in chemical structure. However, at present, experience with this use is limited. Allopurinol-allergic patients were excluded from the clinical trials; thus, if there is any allergic overlap, it would not likely have been recognized in those studies. The FDA has received reports of patients who were allergic to allopurinol also having reactions to febuxostat, and it is currently evaluating these reports (personal communication).

Concern was raised over cardiovascular adverse events in patients treated with febuxostat during clinical trials. In the FACT trial, two patients died of cardiac causes.²⁰ In the study by Schumacher et al,³³ 11 of 670 patients experienced cardiac adverse events in the febuxostat group vs 3 of 268 in the allopurinol group. Events included atrial fibrillation, chest pain, coronary artery disease, and myocardial infarction. However, this difference was not statistically significant.

Febuxostat costs much more than allopurinol. Currently, patients pay $153.88 for 1 month of febuxostat 40 or 80 mg from Cleveland Clinic pharmacy; 1 month of allopurinol costs $17.45 (300 mg) or $14.00 (100 mg). We believe febuxostat should be reserved for patients with documented intolerance to allopurinol in effective doses.

Monitoring serum urate levels is important in all patients on hypouricemic therapy so that dosage adjustments can be made until the target serum urate concentration is reached. In patients failing to meet target serum urate levels, patient adherence with the prescribed dosing should be specifically addressed because as many as 50% of patients do not adhere to their prescribed regimen.

DOES URATE-LOWERING THERAPY HAVE BENEFITS BEYOND GOUT?

Despite experimental animal data and a strong epidemiologic association between hyperuri-cemia and hypertension,⁴⁶ metabolic syndrome, and rates of cardiovascular and all-cause mortality,⁴⁷ the evidence from interventional trials so far does not support the routine use of hypo-uricemic therapy to prevent these outcomes.

Similarly, hyperuricemia has long been associated with renal disease, and there has been debate as to whether hyperuricemia is a result of kidney dysfunction or a contributing factor.^46,48–51 A few studies have documented improvement of renal function after initiation of hypouricemic therapy.⁵² However, treating asymptomatic hyperuricemia to preserve kidney function remains controversial.

A recent study indicates that lowering the serum urate level with allopurinol can lower the blood pressure in hyperuricemic adolescents who have newly diagnosed primary hypertension.⁵³ This does not indicate, however, that initiating hypouricemic therapy in patients with preexisting, long-standing hypertension will be successful.

RECOMMENDED FOR OUR PATIENT

As for our diabetic patient with an acute gout flare and creatinine clearance rate of 45 mL/minute, we would recommend:

• Aspirating the knee, sending the fluid for bacterial culture, and then treating it with a local glucocorticoid injection
• Starting colchicine 0.6 mg every day, with frequent monitoring for signs of toxicity (muscle pain, weakness, leukopenia, and elevations of creatine kinase and aspartate aminotransferase)
• Increasing his allopurinol dose by 100 mg every 2 to 4 weeks until the target serum urate level of less than 6.0 mg/dL is reached
• If he cannot tolerate allopurinol or if the target serum urate level is not achieved despite adequate doses of allopurinol (about 800 mg), we would switch to febuxostat 40 mg and increase the dose as needed to achieve the desired urate level.

You have a 54-year-old black patient with gout, diabetes mellitus, hypertension, and chronic kidney disease (CKD). He has an acute gout flare involving his right knee. In the past year he has had four attacks of gout in the ankles and knees, which you treated with intra-articular glucocorticoid injections. He has been on allopurinol (Zyloprim) 200 mg daily, but his last serum urate level was 9.4 mg/dL (reference range 3.0–8.0). His creatinine clearance is 45 mL/minute (reference range 85–125).

In view of his kidney disease, you are concerned about increasing his dose of allopurinol, but also about the need to treat his frequent attacks. How should you manage this patient?

GOUT IS CHALLENGING TO TREAT IN PATIENTS WITH KIDNEY DISEASE

A major challenge in treating patients with gout is to avoid therapeutic interactions with common comorbidities, including hypertension, insulin resistance, coronary artery disease, heart failure, and especially CKD.¹

In this paper, we discuss approaches to and controversies in the management of gout and hyperuricemia in patients with CKD. Unfortunately, the evidence from clinical trials to guide treatment decisions is limited; therefore, decisions must often be based on experience and pathophysiologic principles.

GENERAL GOALS OF GOUT THERAPY

Depending on the patient and the stage of the disease, the goals in treating patients with gout are to:

• Terminate acute attacks as promptly and safely as possible
• Prevent recurrences of acute gout attacks
• Prevent or reverse complications resulting from deposition of monosodium urate in the joints, in the kidneys, or at other sites.

These goals are more difficult to achieve in patients with CKD because of the potential complications from many of the available drugs.

TERMINATING ACUTE GOUT FLARES

In patients with acute gout, treatment is aimed at quickly resolving pain and inflammation.

Several types of drugs can terminate acute gout flares. The choice in most situations is colchicine (Colcrys); a nonsteroidal anti-inflammatory drug (NSAID); a corticosteroid; or corticotropin (ACTH).

However, in patients with CKD, there are concerns about using colchicine or NSAIDs, and corticotropin is very expensive; thus, corticosteroids are often used.

Colchicine’s clearance is reduced in CKD

Colchicine is somewhat effective in treating acute gout attacks and probably more effective in preventing attacks.

Due to concerns about inappropriate dosing and reported deaths,² the intravenous formulation is not available in many countries, including the United States.

After oral administration, colchicine is rapidly absorbed, with a bioavailability of up to 50%. It undergoes metabolism by the liver, and its metabolites are excreted by renal and biliary-intestinal routes. Up to 20% of the active drug is excreted by the kidneys.³

Colchicine’s clearance is significantly reduced in patients with renal or hepatic insufficiency, and the drug may accumulate in cells, with resultant toxicity.⁴ Colchicine-induced toxicity has been observed when the drug was used for acute treatment, as well as for chronic prophylaxis of gout in patients with CKD; thus, alternative agents for treating acute attacks should be considered.^5,6 With prolonged use, reversible colchicine-induced axonal neuropathy, neutropenia, and vacuolar myopathy can develop in patients with CKD.⁷

In a trial in patients with normal renal function, nearly 100% who received an initial dose of 1 mg followed by 0.5 mg every 2 hours developed diarrhea at a median time of 24 hours.⁸ Emesis may also occur.

A lower dose of 1.8 mg (two 0.6-mg pills followed by one pill an hour later) was well tolerated but only moderately effective in treating acute gout, causing at least a 50% reduction in pain at 24 hours in only 38% of patients.⁹ This study does not clarify the dosage to use to completely resolve attacks. Using additional colchicine likely will increase the response rate, but will also increase side effects. Patients with CKD were not included.

Some patients, as shown in the above trial, can abort attacks by taking only one or two colchicine tablets when they feel the first “twinge” of an attack. This approach is likely to be safe in CKD, but it may be of value to only a few patients.

Nonsteroidal anti-inflammatory drugs can worsen chronic kidney disease

NSAIDs in high doses can effectively treat the pain and inflammation of acute gout. Indomethacin (Indocin) 50 mg three times daily has been standard NSAID therapy.

Other nonselective NSAIDs and NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) are effective, but all can cause acute renal toxicity or worsen CKD.¹⁰ Renal side effects include salt and water retention, acute tubular necrosis, acute interstitial nephritis, proteinuria, hypertension, hyperkalemia, and chronic renal injury.¹¹

Even short-term use of high-dose NSAIDs should generally be avoided in patients with preexisting CKD, for whom there is no established safe threshold dose. When NSAIDs (including selective COX-2 inhibitors) are used, renal function should be monitored closely and the duration limited as much as possible.

 

 

Corticosteroids are often used to treat acute attacks

Due to the concerns about NSAIDs or colchicine to treat acute gout attacks in patients with CKD, corticosteroids are often used in this setting.

Intra-articular steroid injections are useful in treating acute gout limited to a single joint or bursa.¹² However, one should first make sure that the joint is not infected: septic arthritis should ideally be excluded by arthrocentesis, particularly in immunosuppressed patients¹³ or those with end-stage renal disease, who are predisposed to bacteremia.

Oral, intramuscular, or intravenous steroids can provide complete relief from acute gout, although high doses (eg, prednisone 30–60 mg/day or the equivalent) are often needed. Common errors resulting in inefficacy include using too low a dose or not treating for a sufficient time before tapering or stopping. Groff and colleagues¹⁴ described 13 patients who received oral or intravenous steroids for acute gout. Nine patients received an initial single dose of prednisone ranging from 20 to 50 mg, with tapering over a mean of 10 days. Twelve of the 13 patients had improvement within 48 hours, and the signs and symptoms of acute gout resolved completely within 7 to 10 days.

We often give prednisone 40 mg daily until a day after the acute attack resolves and then taper over another 7 to 10 days. There are no data to guide steroid dosing in an evidence-based way, but we believe too short a course of therapy may result in return of symptoms.

Corticotropin and other agents: Effective but costly

Corticotropin shares the same indications as systemic corticosteroids, being used to treat flares when NSAIDs, intra-articular steroids, and colchicine are contraindicated. However, corticotropin is far more expensive than generic corticosteroids, costing nearly $2,000 for a single 80-IU dose, which may need to be repeated.

Corticotropin is available for subcutaneous or intramuscular injection. A single intramuscular injection of corticotropin gel (H.P. Acthar, 25–80 IU) may terminate an acute gout attack.¹⁵ However, many patients need another injection after 24 to 72 hours, which would require another visit to the physician. This treatment has been touted by some as being more effective than corticosteroid therapy, possibly because of a unique peripheral mechanism of action in addition to stimulating cortisol release.¹⁶

We rarely use corticotropin, in view of its cost as well as concerns about excessive sodium and water retention due to the release of multiple hormones from the adrenal gland. This may be especially deleterious in patients with CKD or congestive heart failure.¹⁷

Parenteral anti-tumor necrosis factor agents or interleukin 1 antagonists can be dramatically effective but are also expensive.^18,19 For example, anakinra (Kineret) 100 mg costs about $73, and multiple daily doses may be necessary.

Under unique conditions in which they can be safely used (eg, patients with CKD, diabetes mellitus, liver disease), they may be cost-effective if they can shorten the stay of a hospitalized patient with acute gout.

PROPHYLACTIC ANTI-INFLAMMATORY THERAPY FOR PATIENTS WITH GOUT

Between attacks, the goal is to prevent new attacks through prophylactic management, which may include anti-inflammatory and hypouricemic therapy along with dietary instruction (such as avoiding excessive beer, liquor, and fructose ingestion).

Colchicine can be used as prophylaxis, with caution and monitoring

Although colchicine is not 100% effective, it markedly reduces the flare rate when started in low doses at the time hypouricemic therapy is initiated.^20,21 (Hypouricemic therapy is discussed below.) We generally try to continue this prophylactic therapy, if the patient tolerates it, for at least 6 months—longer if tophi are still present or if attacks continue to occur.

If renal function is intact, colchicine can be prescribed at a dosage of 0.6 mg orally once or twice daily.²¹ In CKD, since the clearance of colchicine is reduced,⁴ the dosage should be reduced. Patients on colchicine for prophylaxis must be carefully monitored if the glomerular filtration rate is less than 50 mL/minute, or colchicine should be avoided altogether.⁶ Laboratory testing for colchicine levels is not routinely available and may be of limited value in predicting adverse effects; thus, recommendations about dose adjustments in CKD are empiric.

Wallace et al²² recommended a dose of 0.6 mg once daily if the creatinine clearance is 35 to 49 mL/minute and 0.6 mg every 2 to 3 days if it is 10 to 34 mL/minute, but there are no published long-term safety or efficacy data validating these reasonable (based on available information) dosing regimens.

Even with dose adjustment, caution is needed. Low-dose daily colchicine may be associated with reversible neuromyopathy and bone marrow suppression.^7,23 Patients with neuromyopathy may complain of myalgias, proximal muscle weakness, and numbness and may have areflexia and decreased sensation. Laboratory findings include elevated creatine kinase and aminotransferase levels. We regularly check for leukopenia or elevated creatine kinase and aspartate aminotransferase levels in patients with CKD who are receiving colchicine in any dose.

Prolonged colchicine therapy should probably be avoided in patients on hemodialysis, as this drug is not removed by dialysis or by exchange transfusion, and the risk of toxicity under these circumstances may be high.²² When there is no viable alternative and the drug is given, patients should be closely monitored for signs of toxicity.

Concurrent (even short-term) treatment with most macrolide antibiotics, particularly clarithromycin (Biaxin), most statin drugs, ketoconazole (Nizoral), cyclosporine, and likely other drugs predisposes to colchicine toxicity by altering its distribution and elimination, and can in rare cases cause morbidity or death.^24–26

NSAIDs are not optimal as prophylaxis in patients with chronic kidney disease

Little information has been published about using NSAIDs chronically to prevent flares, but they are not the optimal drugs to use in patients with CKD, as discussed above. In patients with end-stage renal disease, there are also concerns about NSAID-induced gastric and intestinal bleeding.

Low-dose steroids may not be effective as prophylaxis

Lower doses of steroids may not be effective as prophylaxis against gout flares, consistent with the common observation that gout flares still occur in organ transplant recipients who are taking maintenance doses of prednisone.¹³

 

PREVENTING FLARES BY LOWERING SERUM URATE LEVELS

If tophi are present, if radiography shows evidence of damage, if attacks are frequent or disabling, or if there are relative contraindications to the drugs that would be needed to treat acute attacks, then hypouricemic therapy should be strongly considered to reduce the burden of urate in the body, resorb tophi, and ultimately reduce the frequency of gout flares.²⁰

Although intermittent therapy for attacks or prolonged prophylactic use of colchicine may prevent recurrent episodes of gouty arthritis and may be reasonable for many patients, this approach does not prevent continued urate deposition, with the potential development of bony erosions, tophaceous deposits, and chronic arthritis.

The definitive therapy for gouty arthritis is to deplete the periarticular deposits of urate by maintaining a low serum urate level. Urate-lowering therapy, when indicated, is almost always lifelong.

Four strategies for lowering serum urate

The serum urate concentration can be lowered in four ways:

• Increasing renal uric acid excretion
• Altering the diet
• Decreasing urate synthesis
• Converting urate to a more soluble metabolite.

Increasing uric acid excretion is rarely effective if renal function is impaired

Probenecid, sulfinpyrazone (Anturane), and losartan (Cozaar) modestly increase uric acid secretion and reduce serum urate levels, but they are rarely effective if the creatinine clearance rate is less than 60 mL/minute, and they require significant fluid intake for maximal efficacy.

Uricosuric drugs probably should be avoided in patients who excrete more than 1,000 mg of uric acid per day on a normal diet, since urinary uric acid stones may form. In practice, however, patients are given losartan to treat hypertension without attention to uric acid excretion.

More-potent urocosuric drugs are being tested in clinical trials.

Altering the diet: Traditional advice confirmed

The Health Professionals Follow-up Study^27,28 prospectively examined the relation between diet and gout over 12 years in 47,150 men. The study confirmed some long-standing beliefs, such as that consuming meat, seafood, beer, and liquor increases the risk. Other risk factors were consumption of sugar-sweetened soft drinks and fructose, adiposity, weight gain, hypertension, and diuretic use. On the other hand, protein, wine, and purine-rich vegetables were not associated with gout flares. Low-fat dairy products may have a protective effect. Weight loss was found to be protective.

Low-purine diets are not very palatable, are difficult to adhere to, and are at best only minimally effective, lowering serum urate by 1 to 2 mg/dL. Low-protein diets designed to slow progression of CKD will likely also have only a slight effect on serum urate. Dietary change alone is not likely to dramatically lower serum urate levels.

Metabolizing urate with exogenous uricase

Rasburicase (Elitek) effectively converts urate to allantoin, which is more soluble, but rasburicase is fraught with allergic reactions and cannot be used as chronic therapy.

A pegylated intravenous uricase²⁹ has just been approved by the US Food and Drug Administration (FDA); the retail cost is not yet known. It is dramatically effective in those patients able to use it chronically, but it has not been fully evaluated in patients with CKD.

Decreasing urate synthesis with allopurinol

Allopurinol acts by competitively inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The drug, a structural analogue of hypoxanthine, is converted by xanthine oxidase to oxypurinol, which is an even more effective inhibitor of xanthine oxidase than allopurinol.

Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol can usually be given once daily, and the dosage required to reduce serum urate levels should in theory be lower in patients with lower glomerular filtration rates.

Allopurinol (100- and 300-mg tablets) is approved by the FDA in doses of up to 800 mg/day to treat hyperuricemia in patients with gout,³⁰ while guidelines from the British Society of Rheumatology advocate a maximum dose of 900 mg/day.³¹ These maximum doses are based on the limited amount of data with higher doses, not on documented toxicity.

Practice survey data in the United States indicate that most physicians prescribe no greater than 300 mg daily, although this dosage is likely to reduce the serum urate to less than 6 mg/dL—the goal level—in fewer than 50% of patients.^20,32 Patients with normal renal function occasionally require more than 1,000 mg daily to reduce the serum urate level to less than 6 mg/dL.

How low should the serum urate level be?

Ideally, therapy should keep the serum urate level significantly below 6.7 mg/dL, the approximate saturation point of urate in physiologic fluids.

Lowering the serum urate level from 10 mg/dL to 7 mg/dL may seem encouraging, and the urate level may be in the laboratory “normal” range; however, urate may continue to precipitate in tissues if the concentration is greater than 6.7 mg/dL. A target of 6 mg/dL, used in clinical studies, is far enough below the saturation level to provide some margin for fluctuations in serum levels. A serum level of 6.0 mg/dL has thus been arbitrarily proposed as a reasonable therapeutic target.

The lower the serum urate level achieved during hypouricemic therapy, the faster the reduction in tophaceous deposits. With adequate urate lowering, tophi can be visibly reduced in less than a year of hypouricemic therapy.^33,34

We have as yet no convincing evidence that lowering the serum urate level to less than 6.0 mg/dL is harmful, despite theoretical concerns that urate is a beneficial circulating antioxidant and epidemiologic observations that urate levels have been inversely correlated with progression of Parkinson disease.

 

 

Start low, go slow to avoid a flare

Rapid reduction of the serum urate level in a patient with chronic hyperuricemia and gout is likely to induce an acute flare.²⁰ We have traditionally used a “start low and increase slowly” approach to escalating hypouricemic therapy in hopes of reducing the likelihood of causing a gout flare.

Without anti-inflammatory prophylaxis, acute flares associated with urate-lowering are extremely likely. In a 28-week trial of allopurinol, febuxostat, and placebo by Schumacher et al,³³ during the first 8 weeks, when prophylaxis against gout flare was provided with either colchicine 0.6 mg once daily or naproxen (Naprosyn) 250 mg twice daily, the proportion of patients requiring treatment of gout flares was still 23% to 46%. When prophylaxis was stopped, the flare rate increased further.³³

The more we acutely lower serum urate levels, the more likely flares are to occur. In the study by Schumacher et al,³³ the percentage of patients needing treatment for gout flares during the first 8 weeks of the study, despite gout flare prophylaxis, was related to the percent reduction in serum urate by week 28 of the trial (Table 2).

IS IT NECESSARY TO ADJUST THE ALLOPURINOL DOSE IN CHRONIC KIDNEY DISEASE?

In 1984, Hande et al³⁵ proposed that allopurinol doses be lower in patients with renal insufficiency, with a dosage scale based on creatinine clearance.

Their thoughtful proposal was based on data from six of their own patients and 72 others with severe allopurinol toxicity, mainly allopurinol hypersensitivity syndrome, reported in the literature.

Perez-Ruiz et al³⁶ noted that patients who had experienced adverse effects from allopurinol in their series were likely to have had received “higher” doses of allopurinol, if the dosage was corrected for reduced oxypurinol elimination based on their estimated creatinine clearance.

However, most of these reactions occurred soon after initiating therapy, a temporal pattern more typical of non-dose-dependent allergic reactions. Additionally, allopurinol hypersensitivity has been linked to T-cell-mediated immune reactions to oxypurinol,³⁷ a mechanism not likely linked to drug levels.

Arguments against dose adjustment

Despite the compelling information that allopurinol reactions are more common in CKD, adjusting the dosage of allopurinol has not been clearly shown to reduce the frequency of these reactions.

In a small retrospective analysis, Vázquez-Mellado et al³⁸ reported that adjusting the allopurinol dosage according to creatinine clearance did not decrease the incidence of allopurinol hypersensitivity.

In a study in 250 patients, Dalbeth et al³⁹ showed that the overall incidence of hypersensitivity reaction was 1.6%, and the incidence of allergic reactions did not decrease when allopurinol was given according to the dosing guidelines proposed by Hande et al.³⁵ However, it is worth noting that, of the patients who received the recommended lower doses, only 19% achieved the target serum urate level of 6 mg/dL.³⁹

Silverberg et al⁴⁰ found that of 15 patients who developed hypersensitivity reactions to allopurinol, 10 had received doses that were low or appropriate according to the guidelines of Hande et al.³⁵

More recently, Stamp et al⁴¹ found that gradually increasing the allopurinol dose above the proposed creatinine clearance-based dose was safe and effective. Thirty-one (89%) of the 35 patients who completed the study achieved the target serum urate level of 6 mg/dL, while only 3 of 45 who started the study developed rashes, which were not serious.

The small number of patients in these studies limits any strong conclusion, but at present there is no interventional study showing that allopurinol dosing adjustment based on glomerular filtration rate is effective or safer than dosing based on the serum urate level.

Our view on allopurinol dosing adjustment

We believe the initial observations of Hande et al³⁵ and the subsequent meticulous data from Perez-Ruiz et al³⁶ suggest a relationship between CKD and the occurrence of severe allopurinol reactions. However, these observations do not prove that dose adjustment will prevent these reactions.

In patients with normal kidney function, the FDA³⁰ and the European League Against Rheumatism (EULAR)⁴² recommend slow upward titration, starting with 100 to 200 mg/day, which we agree should decrease the frequency of acute gout flares. The dose is increased by increments of 100 mg/day at intervals of 1 week (FDA recommendation) or 2 to 4 weeks (EULAR recommendation) until the serum urate level is lower than 6 mg/dL.

We believe the optimal approach to allopurinol dosing in patients with CKD remains uncertain. We generally escalate the dose slowly, with ongoing frequent laboratory and clinical monitoring, and we do not limit the maximal dose as suggested by Hande et al.³⁵

An alternative strategy is to use the newer, far more expensive xanthine oxidase inhibitor febuxostat in patients with CKD, since it is not excreted by the kidney. We usually first try escalating doses of allopurinol.

 

FEBUXOSTAT, AN ALTERNATIVE TO ALLOPURINOL

Febuxostat is an oral nonpurine inhibitor of xanthine oxidase.⁴³ Approved by the FDA in 2009, it is available in 40- and 80-mg tablets.

Unlike allopurinol, febuxostat is metabolized primarily by hepatic glucuronide formation and oxidation and then excreted in stool and urine,⁴⁴ making it in theory an attractive agent in patients with renal insufficiency, bypassing the controversial dose-adjustment issue with allopurinol.

In the Febuxostat Versus Allopurinol Controlled Trial (FACT),²⁰ a 52-week randomized, double-blind study in hyperuricemic patients with gout, serum urate levels were reduced to less than 6.0 mg/dL in over 50% of patients receiving febuxostat 80 mg or 120 mg once daily, while only 21% of patients receiving 300 mg of allopurinol achieved this goal. This does not imply that allopurinol at higher doses, as should be used in clinical practice,⁴⁵ would not be equally effective. Patients with CKD were not included in this trial.

In the study by Schumacher et al,³³ febuxostat 80, 120, or 240 mg once daily reduced serum urate. A small subset (35 patients) had mild to moderate renal insufficiency (serum creatinine 1.5–2 mg/dL).³³ The number of patients with renal insufficiency who achieved the primary end point of a serum urate level lower than 6 mg/dL was 4 (44%) of 9 in the febuxostat 80-mg group, 5 (46%) of 11 in the 120-mg group, and 3 (60%) of 5 in the 240-mg group, while none of the 10 patients in the dose-adjusted allopurinol group achieved the primary end point (P < .05). Of note, 41% of the patients with normal renal function who received allopurinol achieved the primary end point.³³ As proposed above, if the allopurinol dose had been slowly increased in the patients with renal insufficiency, it might have been equally effective.

Febuxostat has not been thoroughly evaluated in patients with severe CKD or in patients on hemodialysis.

A presumed niche indication of febuxostat is in patients allergic to allopurinol, since the drugs are not similar in chemical structure. However, at present, experience with this use is limited. Allopurinol-allergic patients were excluded from the clinical trials; thus, if there is any allergic overlap, it would not likely have been recognized in those studies. The FDA has received reports of patients who were allergic to allopurinol also having reactions to febuxostat, and it is currently evaluating these reports (personal communication).

Concern was raised over cardiovascular adverse events in patients treated with febuxostat during clinical trials. In the FACT trial, two patients died of cardiac causes.²⁰ In the study by Schumacher et al,³³ 11 of 670 patients experienced cardiac adverse events in the febuxostat group vs 3 of 268 in the allopurinol group. Events included atrial fibrillation, chest pain, coronary artery disease, and myocardial infarction. However, this difference was not statistically significant.

Febuxostat costs much more than allopurinol. Currently, patients pay $153.88 for 1 month of febuxostat 40 or 80 mg from Cleveland Clinic pharmacy; 1 month of allopurinol costs $17.45 (300 mg) or $14.00 (100 mg). We believe febuxostat should be reserved for patients with documented intolerance to allopurinol in effective doses.

Monitoring serum urate levels is important in all patients on hypouricemic therapy so that dosage adjustments can be made until the target serum urate concentration is reached. In patients failing to meet target serum urate levels, patient adherence with the prescribed dosing should be specifically addressed because as many as 50% of patients do not adhere to their prescribed regimen.

DOES URATE-LOWERING THERAPY HAVE BENEFITS BEYOND GOUT?

Despite experimental animal data and a strong epidemiologic association between hyperuri-cemia and hypertension,⁴⁶ metabolic syndrome, and rates of cardiovascular and all-cause mortality,⁴⁷ the evidence from interventional trials so far does not support the routine use of hypo-uricemic therapy to prevent these outcomes.

Similarly, hyperuricemia has long been associated with renal disease, and there has been debate as to whether hyperuricemia is a result of kidney dysfunction or a contributing factor.^46,48–51 A few studies have documented improvement of renal function after initiation of hypouricemic therapy.⁵² However, treating asymptomatic hyperuricemia to preserve kidney function remains controversial.

A recent study indicates that lowering the serum urate level with allopurinol can lower the blood pressure in hyperuricemic adolescents who have newly diagnosed primary hypertension.⁵³ This does not indicate, however, that initiating hypouricemic therapy in patients with preexisting, long-standing hypertension will be successful.

RECOMMENDED FOR OUR PATIENT

As for our diabetic patient with an acute gout flare and creatinine clearance rate of 45 mL/minute, we would recommend:

• Aspirating the knee, sending the fluid for bacterial culture, and then treating it with a local glucocorticoid injection
• Starting colchicine 0.6 mg every day, with frequent monitoring for signs of toxicity (muscle pain, weakness, leukopenia, and elevations of creatine kinase and aspartate aminotransferase)
• Increasing his allopurinol dose by 100 mg every 2 to 4 weeks until the target serum urate level of less than 6.0 mg/dL is reached
• If he cannot tolerate allopurinol or if the target serum urate level is not achieved despite adequate doses of allopurinol (about 800 mg), we would switch to febuxostat 40 mg and increase the dose as needed to achieve the desired urate level.

You have a 54-year-old black patient with gout, diabetes mellitus, hypertension, and chronic kidney disease (CKD). He has an acute gout flare involving his right knee. In the past year he has had four attacks of gout in the ankles and knees, which you treated with intra-articular glucocorticoid injections. He has been on allopurinol (Zyloprim) 200 mg daily, but his last serum urate level was 9.4 mg/dL (reference range 3.0–8.0). His creatinine clearance is 45 mL/minute (reference range 85–125).

In view of his kidney disease, you are concerned about increasing his dose of allopurinol, but also about the need to treat his frequent attacks. How should you manage this patient?

GOUT IS CHALLENGING TO TREAT IN PATIENTS WITH KIDNEY DISEASE

A major challenge in treating patients with gout is to avoid therapeutic interactions with common comorbidities, including hypertension, insulin resistance, coronary artery disease, heart failure, and especially CKD.¹

In this paper, we discuss approaches to and controversies in the management of gout and hyperuricemia in patients with CKD. Unfortunately, the evidence from clinical trials to guide treatment decisions is limited; therefore, decisions must often be based on experience and pathophysiologic principles.

GENERAL GOALS OF GOUT THERAPY

Depending on the patient and the stage of the disease, the goals in treating patients with gout are to:

• Terminate acute attacks as promptly and safely as possible
• Prevent recurrences of acute gout attacks
• Prevent or reverse complications resulting from deposition of monosodium urate in the joints, in the kidneys, or at other sites.

These goals are more difficult to achieve in patients with CKD because of the potential complications from many of the available drugs.

TERMINATING ACUTE GOUT FLARES

In patients with acute gout, treatment is aimed at quickly resolving pain and inflammation.

Several types of drugs can terminate acute gout flares. The choice in most situations is colchicine (Colcrys); a nonsteroidal anti-inflammatory drug (NSAID); a corticosteroid; or corticotropin (ACTH).

However, in patients with CKD, there are concerns about using colchicine or NSAIDs, and corticotropin is very expensive; thus, corticosteroids are often used.

Colchicine’s clearance is reduced in CKD

Colchicine is somewhat effective in treating acute gout attacks and probably more effective in preventing attacks.

Due to concerns about inappropriate dosing and reported deaths,² the intravenous formulation is not available in many countries, including the United States.

After oral administration, colchicine is rapidly absorbed, with a bioavailability of up to 50%. It undergoes metabolism by the liver, and its metabolites are excreted by renal and biliary-intestinal routes. Up to 20% of the active drug is excreted by the kidneys.³

Colchicine’s clearance is significantly reduced in patients with renal or hepatic insufficiency, and the drug may accumulate in cells, with resultant toxicity.⁴ Colchicine-induced toxicity has been observed when the drug was used for acute treatment, as well as for chronic prophylaxis of gout in patients with CKD; thus, alternative agents for treating acute attacks should be considered.^5,6 With prolonged use, reversible colchicine-induced axonal neuropathy, neutropenia, and vacuolar myopathy can develop in patients with CKD.⁷

In a trial in patients with normal renal function, nearly 100% who received an initial dose of 1 mg followed by 0.5 mg every 2 hours developed diarrhea at a median time of 24 hours.⁸ Emesis may also occur.

A lower dose of 1.8 mg (two 0.6-mg pills followed by one pill an hour later) was well tolerated but only moderately effective in treating acute gout, causing at least a 50% reduction in pain at 24 hours in only 38% of patients.⁹ This study does not clarify the dosage to use to completely resolve attacks. Using additional colchicine likely will increase the response rate, but will also increase side effects. Patients with CKD were not included.

Some patients, as shown in the above trial, can abort attacks by taking only one or two colchicine tablets when they feel the first “twinge” of an attack. This approach is likely to be safe in CKD, but it may be of value to only a few patients.

Nonsteroidal anti-inflammatory drugs can worsen chronic kidney disease

NSAIDs in high doses can effectively treat the pain and inflammation of acute gout. Indomethacin (Indocin) 50 mg three times daily has been standard NSAID therapy.

Other nonselective NSAIDs and NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) are effective, but all can cause acute renal toxicity or worsen CKD.¹⁰ Renal side effects include salt and water retention, acute tubular necrosis, acute interstitial nephritis, proteinuria, hypertension, hyperkalemia, and chronic renal injury.¹¹

Even short-term use of high-dose NSAIDs should generally be avoided in patients with preexisting CKD, for whom there is no established safe threshold dose. When NSAIDs (including selective COX-2 inhibitors) are used, renal function should be monitored closely and the duration limited as much as possible.

 

 

Corticosteroids are often used to treat acute attacks

Due to the concerns about NSAIDs or colchicine to treat acute gout attacks in patients with CKD, corticosteroids are often used in this setting.

Intra-articular steroid injections are useful in treating acute gout limited to a single joint or bursa.¹² However, one should first make sure that the joint is not infected: septic arthritis should ideally be excluded by arthrocentesis, particularly in immunosuppressed patients¹³ or those with end-stage renal disease, who are predisposed to bacteremia.

Oral, intramuscular, or intravenous steroids can provide complete relief from acute gout, although high doses (eg, prednisone 30–60 mg/day or the equivalent) are often needed. Common errors resulting in inefficacy include using too low a dose or not treating for a sufficient time before tapering or stopping. Groff and colleagues¹⁴ described 13 patients who received oral or intravenous steroids for acute gout. Nine patients received an initial single dose of prednisone ranging from 20 to 50 mg, with tapering over a mean of 10 days. Twelve of the 13 patients had improvement within 48 hours, and the signs and symptoms of acute gout resolved completely within 7 to 10 days.

We often give prednisone 40 mg daily until a day after the acute attack resolves and then taper over another 7 to 10 days. There are no data to guide steroid dosing in an evidence-based way, but we believe too short a course of therapy may result in return of symptoms.

Corticotropin and other agents: Effective but costly

Corticotropin shares the same indications as systemic corticosteroids, being used to treat flares when NSAIDs, intra-articular steroids, and colchicine are contraindicated. However, corticotropin is far more expensive than generic corticosteroids, costing nearly $2,000 for a single 80-IU dose, which may need to be repeated.

Corticotropin is available for subcutaneous or intramuscular injection. A single intramuscular injection of corticotropin gel (H.P. Acthar, 25–80 IU) may terminate an acute gout attack.¹⁵ However, many patients need another injection after 24 to 72 hours, which would require another visit to the physician. This treatment has been touted by some as being more effective than corticosteroid therapy, possibly because of a unique peripheral mechanism of action in addition to stimulating cortisol release.¹⁶

We rarely use corticotropin, in view of its cost as well as concerns about excessive sodium and water retention due to the release of multiple hormones from the adrenal gland. This may be especially deleterious in patients with CKD or congestive heart failure.¹⁷

Parenteral anti-tumor necrosis factor agents or interleukin 1 antagonists can be dramatically effective but are also expensive.^18,19 For example, anakinra (Kineret) 100 mg costs about $73, and multiple daily doses may be necessary.

Under unique conditions in which they can be safely used (eg, patients with CKD, diabetes mellitus, liver disease), they may be cost-effective if they can shorten the stay of a hospitalized patient with acute gout.

PROPHYLACTIC ANTI-INFLAMMATORY THERAPY FOR PATIENTS WITH GOUT

Between attacks, the goal is to prevent new attacks through prophylactic management, which may include anti-inflammatory and hypouricemic therapy along with dietary instruction (such as avoiding excessive beer, liquor, and fructose ingestion).

Colchicine can be used as prophylaxis, with caution and monitoring

Although colchicine is not 100% effective, it markedly reduces the flare rate when started in low doses at the time hypouricemic therapy is initiated.^20,21 (Hypouricemic therapy is discussed below.) We generally try to continue this prophylactic therapy, if the patient tolerates it, for at least 6 months—longer if tophi are still present or if attacks continue to occur.

If renal function is intact, colchicine can be prescribed at a dosage of 0.6 mg orally once or twice daily.²¹ In CKD, since the clearance of colchicine is reduced,⁴ the dosage should be reduced. Patients on colchicine for prophylaxis must be carefully monitored if the glomerular filtration rate is less than 50 mL/minute, or colchicine should be avoided altogether.⁶ Laboratory testing for colchicine levels is not routinely available and may be of limited value in predicting adverse effects; thus, recommendations about dose adjustments in CKD are empiric.

Wallace et al²² recommended a dose of 0.6 mg once daily if the creatinine clearance is 35 to 49 mL/minute and 0.6 mg every 2 to 3 days if it is 10 to 34 mL/minute, but there are no published long-term safety or efficacy data validating these reasonable (based on available information) dosing regimens.

Even with dose adjustment, caution is needed. Low-dose daily colchicine may be associated with reversible neuromyopathy and bone marrow suppression.^7,23 Patients with neuromyopathy may complain of myalgias, proximal muscle weakness, and numbness and may have areflexia and decreased sensation. Laboratory findings include elevated creatine kinase and aminotransferase levels. We regularly check for leukopenia or elevated creatine kinase and aspartate aminotransferase levels in patients with CKD who are receiving colchicine in any dose.

Prolonged colchicine therapy should probably be avoided in patients on hemodialysis, as this drug is not removed by dialysis or by exchange transfusion, and the risk of toxicity under these circumstances may be high.²² When there is no viable alternative and the drug is given, patients should be closely monitored for signs of toxicity.

Concurrent (even short-term) treatment with most macrolide antibiotics, particularly clarithromycin (Biaxin), most statin drugs, ketoconazole (Nizoral), cyclosporine, and likely other drugs predisposes to colchicine toxicity by altering its distribution and elimination, and can in rare cases cause morbidity or death.^24–26

NSAIDs are not optimal as prophylaxis in patients with chronic kidney disease

Little information has been published about using NSAIDs chronically to prevent flares, but they are not the optimal drugs to use in patients with CKD, as discussed above. In patients with end-stage renal disease, there are also concerns about NSAID-induced gastric and intestinal bleeding.

Low-dose steroids may not be effective as prophylaxis

Lower doses of steroids may not be effective as prophylaxis against gout flares, consistent with the common observation that gout flares still occur in organ transplant recipients who are taking maintenance doses of prednisone.¹³

 

PREVENTING FLARES BY LOWERING SERUM URATE LEVELS

If tophi are present, if radiography shows evidence of damage, if attacks are frequent or disabling, or if there are relative contraindications to the drugs that would be needed to treat acute attacks, then hypouricemic therapy should be strongly considered to reduce the burden of urate in the body, resorb tophi, and ultimately reduce the frequency of gout flares.²⁰

Although intermittent therapy for attacks or prolonged prophylactic use of colchicine may prevent recurrent episodes of gouty arthritis and may be reasonable for many patients, this approach does not prevent continued urate deposition, with the potential development of bony erosions, tophaceous deposits, and chronic arthritis.

The definitive therapy for gouty arthritis is to deplete the periarticular deposits of urate by maintaining a low serum urate level. Urate-lowering therapy, when indicated, is almost always lifelong.

Four strategies for lowering serum urate

The serum urate concentration can be lowered in four ways:

• Increasing renal uric acid excretion
• Altering the diet
• Decreasing urate synthesis
• Converting urate to a more soluble metabolite.

Increasing uric acid excretion is rarely effective if renal function is impaired

Probenecid, sulfinpyrazone (Anturane), and losartan (Cozaar) modestly increase uric acid secretion and reduce serum urate levels, but they are rarely effective if the creatinine clearance rate is less than 60 mL/minute, and they require significant fluid intake for maximal efficacy.

Uricosuric drugs probably should be avoided in patients who excrete more than 1,000 mg of uric acid per day on a normal diet, since urinary uric acid stones may form. In practice, however, patients are given losartan to treat hypertension without attention to uric acid excretion.

More-potent urocosuric drugs are being tested in clinical trials.

Altering the diet: Traditional advice confirmed

The Health Professionals Follow-up Study^27,28 prospectively examined the relation between diet and gout over 12 years in 47,150 men. The study confirmed some long-standing beliefs, such as that consuming meat, seafood, beer, and liquor increases the risk. Other risk factors were consumption of sugar-sweetened soft drinks and fructose, adiposity, weight gain, hypertension, and diuretic use. On the other hand, protein, wine, and purine-rich vegetables were not associated with gout flares. Low-fat dairy products may have a protective effect. Weight loss was found to be protective.

Low-purine diets are not very palatable, are difficult to adhere to, and are at best only minimally effective, lowering serum urate by 1 to 2 mg/dL. Low-protein diets designed to slow progression of CKD will likely also have only a slight effect on serum urate. Dietary change alone is not likely to dramatically lower serum urate levels.

Metabolizing urate with exogenous uricase

Rasburicase (Elitek) effectively converts urate to allantoin, which is more soluble, but rasburicase is fraught with allergic reactions and cannot be used as chronic therapy.

A pegylated intravenous uricase²⁹ has just been approved by the US Food and Drug Administration (FDA); the retail cost is not yet known. It is dramatically effective in those patients able to use it chronically, but it has not been fully evaluated in patients with CKD.

Decreasing urate synthesis with allopurinol

Allopurinol acts by competitively inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The drug, a structural analogue of hypoxanthine, is converted by xanthine oxidase to oxypurinol, which is an even more effective inhibitor of xanthine oxidase than allopurinol.

Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol can usually be given once daily, and the dosage required to reduce serum urate levels should in theory be lower in patients with lower glomerular filtration rates.

Allopurinol (100- and 300-mg tablets) is approved by the FDA in doses of up to 800 mg/day to treat hyperuricemia in patients with gout,³⁰ while guidelines from the British Society of Rheumatology advocate a maximum dose of 900 mg/day.³¹ These maximum doses are based on the limited amount of data with higher doses, not on documented toxicity.

Practice survey data in the United States indicate that most physicians prescribe no greater than 300 mg daily, although this dosage is likely to reduce the serum urate to less than 6 mg/dL—the goal level—in fewer than 50% of patients.^20,32 Patients with normal renal function occasionally require more than 1,000 mg daily to reduce the serum urate level to less than 6 mg/dL.

How low should the serum urate level be?

Ideally, therapy should keep the serum urate level significantly below 6.7 mg/dL, the approximate saturation point of urate in physiologic fluids.

Lowering the serum urate level from 10 mg/dL to 7 mg/dL may seem encouraging, and the urate level may be in the laboratory “normal” range; however, urate may continue to precipitate in tissues if the concentration is greater than 6.7 mg/dL. A target of 6 mg/dL, used in clinical studies, is far enough below the saturation level to provide some margin for fluctuations in serum levels. A serum level of 6.0 mg/dL has thus been arbitrarily proposed as a reasonable therapeutic target.

The lower the serum urate level achieved during hypouricemic therapy, the faster the reduction in tophaceous deposits. With adequate urate lowering, tophi can be visibly reduced in less than a year of hypouricemic therapy.^33,34

We have as yet no convincing evidence that lowering the serum urate level to less than 6.0 mg/dL is harmful, despite theoretical concerns that urate is a beneficial circulating antioxidant and epidemiologic observations that urate levels have been inversely correlated with progression of Parkinson disease.

 

 

Start low, go slow to avoid a flare

Rapid reduction of the serum urate level in a patient with chronic hyperuricemia and gout is likely to induce an acute flare.²⁰ We have traditionally used a “start low and increase slowly” approach to escalating hypouricemic therapy in hopes of reducing the likelihood of causing a gout flare.

Without anti-inflammatory prophylaxis, acute flares associated with urate-lowering are extremely likely. In a 28-week trial of allopurinol, febuxostat, and placebo by Schumacher et al,³³ during the first 8 weeks, when prophylaxis against gout flare was provided with either colchicine 0.6 mg once daily or naproxen (Naprosyn) 250 mg twice daily, the proportion of patients requiring treatment of gout flares was still 23% to 46%. When prophylaxis was stopped, the flare rate increased further.³³

The more we acutely lower serum urate levels, the more likely flares are to occur. In the study by Schumacher et al,³³ the percentage of patients needing treatment for gout flares during the first 8 weeks of the study, despite gout flare prophylaxis, was related to the percent reduction in serum urate by week 28 of the trial (Table 2).

IS IT NECESSARY TO ADJUST THE ALLOPURINOL DOSE IN CHRONIC KIDNEY DISEASE?

In 1984, Hande et al³⁵ proposed that allopurinol doses be lower in patients with renal insufficiency, with a dosage scale based on creatinine clearance.

Their thoughtful proposal was based on data from six of their own patients and 72 others with severe allopurinol toxicity, mainly allopurinol hypersensitivity syndrome, reported in the literature.

Perez-Ruiz et al³⁶ noted that patients who had experienced adverse effects from allopurinol in their series were likely to have had received “higher” doses of allopurinol, if the dosage was corrected for reduced oxypurinol elimination based on their estimated creatinine clearance.

However, most of these reactions occurred soon after initiating therapy, a temporal pattern more typical of non-dose-dependent allergic reactions. Additionally, allopurinol hypersensitivity has been linked to T-cell-mediated immune reactions to oxypurinol,³⁷ a mechanism not likely linked to drug levels.

Arguments against dose adjustment

Despite the compelling information that allopurinol reactions are more common in CKD, adjusting the dosage of allopurinol has not been clearly shown to reduce the frequency of these reactions.

In a small retrospective analysis, Vázquez-Mellado et al³⁸ reported that adjusting the allopurinol dosage according to creatinine clearance did not decrease the incidence of allopurinol hypersensitivity.

In a study in 250 patients, Dalbeth et al³⁹ showed that the overall incidence of hypersensitivity reaction was 1.6%, and the incidence of allergic reactions did not decrease when allopurinol was given according to the dosing guidelines proposed by Hande et al.³⁵ However, it is worth noting that, of the patients who received the recommended lower doses, only 19% achieved the target serum urate level of 6 mg/dL.³⁹

Silverberg et al⁴⁰ found that of 15 patients who developed hypersensitivity reactions to allopurinol, 10 had received doses that were low or appropriate according to the guidelines of Hande et al.³⁵

More recently, Stamp et al⁴¹ found that gradually increasing the allopurinol dose above the proposed creatinine clearance-based dose was safe and effective. Thirty-one (89%) of the 35 patients who completed the study achieved the target serum urate level of 6 mg/dL, while only 3 of 45 who started the study developed rashes, which were not serious.

The small number of patients in these studies limits any strong conclusion, but at present there is no interventional study showing that allopurinol dosing adjustment based on glomerular filtration rate is effective or safer than dosing based on the serum urate level.

Our view on allopurinol dosing adjustment

We believe the initial observations of Hande et al³⁵ and the subsequent meticulous data from Perez-Ruiz et al³⁶ suggest a relationship between CKD and the occurrence of severe allopurinol reactions. However, these observations do not prove that dose adjustment will prevent these reactions.

In patients with normal kidney function, the FDA³⁰ and the European League Against Rheumatism (EULAR)⁴² recommend slow upward titration, starting with 100 to 200 mg/day, which we agree should decrease the frequency of acute gout flares. The dose is increased by increments of 100 mg/day at intervals of 1 week (FDA recommendation) or 2 to 4 weeks (EULAR recommendation) until the serum urate level is lower than 6 mg/dL.

We believe the optimal approach to allopurinol dosing in patients with CKD remains uncertain. We generally escalate the dose slowly, with ongoing frequent laboratory and clinical monitoring, and we do not limit the maximal dose as suggested by Hande et al.³⁵

An alternative strategy is to use the newer, far more expensive xanthine oxidase inhibitor febuxostat in patients with CKD, since it is not excreted by the kidney. We usually first try escalating doses of allopurinol.

 

FEBUXOSTAT, AN ALTERNATIVE TO ALLOPURINOL

Febuxostat is an oral nonpurine inhibitor of xanthine oxidase.⁴³ Approved by the FDA in 2009, it is available in 40- and 80-mg tablets.

Unlike allopurinol, febuxostat is metabolized primarily by hepatic glucuronide formation and oxidation and then excreted in stool and urine,⁴⁴ making it in theory an attractive agent in patients with renal insufficiency, bypassing the controversial dose-adjustment issue with allopurinol.

In the Febuxostat Versus Allopurinol Controlled Trial (FACT),²⁰ a 52-week randomized, double-blind study in hyperuricemic patients with gout, serum urate levels were reduced to less than 6.0 mg/dL in over 50% of patients receiving febuxostat 80 mg or 120 mg once daily, while only 21% of patients receiving 300 mg of allopurinol achieved this goal. This does not imply that allopurinol at higher doses, as should be used in clinical practice,⁴⁵ would not be equally effective. Patients with CKD were not included in this trial.

In the study by Schumacher et al,³³ febuxostat 80, 120, or 240 mg once daily reduced serum urate. A small subset (35 patients) had mild to moderate renal insufficiency (serum creatinine 1.5–2 mg/dL).³³ The number of patients with renal insufficiency who achieved the primary end point of a serum urate level lower than 6 mg/dL was 4 (44%) of 9 in the febuxostat 80-mg group, 5 (46%) of 11 in the 120-mg group, and 3 (60%) of 5 in the 240-mg group, while none of the 10 patients in the dose-adjusted allopurinol group achieved the primary end point (P < .05). Of note, 41% of the patients with normal renal function who received allopurinol achieved the primary end point.³³ As proposed above, if the allopurinol dose had been slowly increased in the patients with renal insufficiency, it might have been equally effective.

Febuxostat has not been thoroughly evaluated in patients with severe CKD or in patients on hemodialysis.

A presumed niche indication of febuxostat is in patients allergic to allopurinol, since the drugs are not similar in chemical structure. However, at present, experience with this use is limited. Allopurinol-allergic patients were excluded from the clinical trials; thus, if there is any allergic overlap, it would not likely have been recognized in those studies. The FDA has received reports of patients who were allergic to allopurinol also having reactions to febuxostat, and it is currently evaluating these reports (personal communication).

Concern was raised over cardiovascular adverse events in patients treated with febuxostat during clinical trials. In the FACT trial, two patients died of cardiac causes.²⁰ In the study by Schumacher et al,³³ 11 of 670 patients experienced cardiac adverse events in the febuxostat group vs 3 of 268 in the allopurinol group. Events included atrial fibrillation, chest pain, coronary artery disease, and myocardial infarction. However, this difference was not statistically significant.

Febuxostat costs much more than allopurinol. Currently, patients pay $153.88 for 1 month of febuxostat 40 or 80 mg from Cleveland Clinic pharmacy; 1 month of allopurinol costs $17.45 (300 mg) or $14.00 (100 mg). We believe febuxostat should be reserved for patients with documented intolerance to allopurinol in effective doses.

Monitoring serum urate levels is important in all patients on hypouricemic therapy so that dosage adjustments can be made until the target serum urate concentration is reached. In patients failing to meet target serum urate levels, patient adherence with the prescribed dosing should be specifically addressed because as many as 50% of patients do not adhere to their prescribed regimen.

DOES URATE-LOWERING THERAPY HAVE BENEFITS BEYOND GOUT?

Despite experimental animal data and a strong epidemiologic association between hyperuri-cemia and hypertension,⁴⁶ metabolic syndrome, and rates of cardiovascular and all-cause mortality,⁴⁷ the evidence from interventional trials so far does not support the routine use of hypo-uricemic therapy to prevent these outcomes.

Similarly, hyperuricemia has long been associated with renal disease, and there has been debate as to whether hyperuricemia is a result of kidney dysfunction or a contributing factor.^46,48–51 A few studies have documented improvement of renal function after initiation of hypouricemic therapy.⁵² However, treating asymptomatic hyperuricemia to preserve kidney function remains controversial.

A recent study indicates that lowering the serum urate level with allopurinol can lower the blood pressure in hyperuricemic adolescents who have newly diagnosed primary hypertension.⁵³ This does not indicate, however, that initiating hypouricemic therapy in patients with preexisting, long-standing hypertension will be successful.

RECOMMENDED FOR OUR PATIENT

As for our diabetic patient with an acute gout flare and creatinine clearance rate of 45 mL/minute, we would recommend:

• Aspirating the knee, sending the fluid for bacterial culture, and then treating it with a local glucocorticoid injection
• Starting colchicine 0.6 mg every day, with frequent monitoring for signs of toxicity (muscle pain, weakness, leukopenia, and elevations of creatine kinase and aspartate aminotransferase)
• Increasing his allopurinol dose by 100 mg every 2 to 4 weeks until the target serum urate level of less than 6.0 mg/dL is reached
• If he cannot tolerate allopurinol or if the target serum urate level is not achieved despite adequate doses of allopurinol (about 800 mg), we would switch to febuxostat 40 mg and increase the dose as needed to achieve the desired urate level.

Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.

Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease^1–3 and that supplementation with folic acid, vitamin B₆, and vitamin B₁₂ lowers homocysteine levels,^4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.

The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B₆, and vitamin B₁₂ for primary or secondary prevention of cardiovascular disease.

HISTORY OF HOMOCYSTEINE AS A RISK MARKER

Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,⁶ it was not until 1964 that Gibson et al⁷ reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully⁸ made the connection between elevated homocysteine levels and the risk of atherosclerosis.

Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.^3,9,10

In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.

CAUSES OF ELEVATED PLASMA HOMOCYSTEINE

An elevated plasma homocysteine level can result from many different factors, including vitamin deficiencies, renal impairment, and inborn errors of homocysteine metabolism (Table 1).^9,11,12

Vitamin deficiencies. Vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.

Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.¹³

Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.

A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia¹⁴), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.¹⁵

A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.¹⁶ The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).¹⁷ Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.¹⁷

ELEVATED HOMOCYSTEINE IS COMMON

In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).^13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.

 

HOW GREAT IS THE RISK?

Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.

However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,^17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.^21,22

Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al¹⁷ found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.

TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS

Primary prevention of cardiovascular disease

Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B₆, and vitamin B₁₂ would decrease the risk of cardiovascular disease.

Little evidence currently exists to guide recommendations for homocysteine-lowering therapy to prevent first attacks of cardiovascular disease. The few studies published to date have been observational studies of dietary intake (not vitamin supplementation), and many were performed before folic acid fortification was mandated for flour and cereal (Table 2).^23–27 Although the studies suggest that higher B-vitamin intake correlates with less vascular disease and its sequelae, there is uncertainty as to whether it is folic acid, vitamin B₆, or vitamin B₁₂ that is responsible, and also whether supplements would provide the same protective benefit as the presence of these nutrients in a varied diet.

Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force ^28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.

In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.³⁰

Secondary prevention of cardiovascular disease

Results have been mixed with regard to the ability of B vitamins to prevent cardiovascular events in patients with known cardiovascular disease (Table 3).^{4,5,11,12,31–46}

Bazzano et al,⁴⁷ in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.³¹

Albert et al⁴ more recently evaluated the effect of a combination pill containing folic acid, vitamin B₆, and vitamin B₁₂ on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.

Ebbing et al,⁵ in a trial published in 2008, investigated the effect of folic acid, vitamin B₁₂, and vitamin B₆ supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.

Mager et al,³² in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.

The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),³³ recently published, was a double-blind, randomized controlled trial of vitamin B₁₂ and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.

Restenosis after angioplasty

Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.

Namazi et al⁴⁸ evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.

Schnyder et al⁴⁹ evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.

Lange et al³⁵ also evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.

 

 

Cerebrovascular and peripheral arterial disease

The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),⁵⁰ a later meta-analysis contradicts this finding.⁵¹

A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.⁵² Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.⁵³

However, immediately after the Cochrane review was published, Khandanpour et al³⁶ published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.

Kidney disease

One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.

However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).³¹ Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.^11,12,37

FUTURE DIRECTIONS AND RECOMMENDATIONS

Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B₆, and vitamin B₁₂ do not lower the risk of cardiovascular disease.^38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.⁶⁰ (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.

At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.^61,62

Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:

• Whether patients with elevated homocysteine would benefit from such treatment
• At what level it would be appropriate to start treatment
• The appropriate target homocysteine level with treatment.

Particularly given the recent finding that folic acid supplementation may increase cancer risk,⁶³ these questions need closer scrutiny.

Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.

Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease^1–3 and that supplementation with folic acid, vitamin B₆, and vitamin B₁₂ lowers homocysteine levels,^4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.

The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B₆, and vitamin B₁₂ for primary or secondary prevention of cardiovascular disease.

HISTORY OF HOMOCYSTEINE AS A RISK MARKER

Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,⁶ it was not until 1964 that Gibson et al⁷ reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully⁸ made the connection between elevated homocysteine levels and the risk of atherosclerosis.

Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.^3,9,10

In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.

CAUSES OF ELEVATED PLASMA HOMOCYSTEINE

An elevated plasma homocysteine level can result from many different factors, including vitamin deficiencies, renal impairment, and inborn errors of homocysteine metabolism (Table 1).^9,11,12

Vitamin deficiencies. Vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.

Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.¹³

Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.

A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia¹⁴), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.¹⁵

A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.¹⁶ The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).¹⁷ Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.¹⁷

ELEVATED HOMOCYSTEINE IS COMMON

In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).^13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.

 

HOW GREAT IS THE RISK?

Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.

However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,^17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.^21,22

Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al¹⁷ found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.

TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS

Primary prevention of cardiovascular disease

Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B₆, and vitamin B₁₂ would decrease the risk of cardiovascular disease.

Little evidence currently exists to guide recommendations for homocysteine-lowering therapy to prevent first attacks of cardiovascular disease. The few studies published to date have been observational studies of dietary intake (not vitamin supplementation), and many were performed before folic acid fortification was mandated for flour and cereal (Table 2).^23–27 Although the studies suggest that higher B-vitamin intake correlates with less vascular disease and its sequelae, there is uncertainty as to whether it is folic acid, vitamin B₆, or vitamin B₁₂ that is responsible, and also whether supplements would provide the same protective benefit as the presence of these nutrients in a varied diet.

Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force ^28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.

In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.³⁰

Secondary prevention of cardiovascular disease

Results have been mixed with regard to the ability of B vitamins to prevent cardiovascular events in patients with known cardiovascular disease (Table 3).^{4,5,11,12,31–46}

Bazzano et al,⁴⁷ in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.³¹

Albert et al⁴ more recently evaluated the effect of a combination pill containing folic acid, vitamin B₆, and vitamin B₁₂ on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.

Ebbing et al,⁵ in a trial published in 2008, investigated the effect of folic acid, vitamin B₁₂, and vitamin B₆ supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.

Mager et al,³² in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.

The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),³³ recently published, was a double-blind, randomized controlled trial of vitamin B₁₂ and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.

Restenosis after angioplasty

Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.

Namazi et al⁴⁸ evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.

Schnyder et al⁴⁹ evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.

Lange et al³⁵ also evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.

 

 

Cerebrovascular and peripheral arterial disease

The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),⁵⁰ a later meta-analysis contradicts this finding.⁵¹

A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.⁵² Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.⁵³

However, immediately after the Cochrane review was published, Khandanpour et al³⁶ published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.

Kidney disease

One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.

However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).³¹ Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.^11,12,37

FUTURE DIRECTIONS AND RECOMMENDATIONS

Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B₆, and vitamin B₁₂ do not lower the risk of cardiovascular disease.^38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.⁶⁰ (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.

At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.^61,62

Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:

• Whether patients with elevated homocysteine would benefit from such treatment
• At what level it would be appropriate to start treatment
• The appropriate target homocysteine level with treatment.

Particularly given the recent finding that folic acid supplementation may increase cancer risk,⁶³ these questions need closer scrutiny.

Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.

Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease^1–3 and that supplementation with folic acid, vitamin B₆, and vitamin B₁₂ lowers homocysteine levels,^4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.

The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B₆, and vitamin B₁₂ for primary or secondary prevention of cardiovascular disease.

HISTORY OF HOMOCYSTEINE AS A RISK MARKER

Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,⁶ it was not until 1964 that Gibson et al⁷ reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully⁸ made the connection between elevated homocysteine levels and the risk of atherosclerosis.

Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.^3,9,10

In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.

CAUSES OF ELEVATED PLASMA HOMOCYSTEINE

An elevated plasma homocysteine level can result from many different factors, including vitamin deficiencies, renal impairment, and inborn errors of homocysteine metabolism (Table 1).^9,11,12

Vitamin deficiencies. Vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.

Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.¹³

Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.

A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia¹⁴), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.¹⁵

A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.¹⁶ The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).¹⁷ Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.¹⁷

ELEVATED HOMOCYSTEINE IS COMMON

In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).^13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.

 

HOW GREAT IS THE RISK?

Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.

However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,^17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.^21,22

Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al¹⁷ found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.

TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS

Primary prevention of cardiovascular disease

Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B₆, and vitamin B₁₂ would decrease the risk of cardiovascular disease.

Little evidence currently exists to guide recommendations for homocysteine-lowering therapy to prevent first attacks of cardiovascular disease. The few studies published to date have been observational studies of dietary intake (not vitamin supplementation), and many were performed before folic acid fortification was mandated for flour and cereal (Table 2).^23–27 Although the studies suggest that higher B-vitamin intake correlates with less vascular disease and its sequelae, there is uncertainty as to whether it is folic acid, vitamin B₆, or vitamin B₁₂ that is responsible, and also whether supplements would provide the same protective benefit as the presence of these nutrients in a varied diet.

Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force ^28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.

In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.³⁰

Secondary prevention of cardiovascular disease

Results have been mixed with regard to the ability of B vitamins to prevent cardiovascular events in patients with known cardiovascular disease (Table 3).^{4,5,11,12,31–46}

Bazzano et al,⁴⁷ in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.³¹

Albert et al⁴ more recently evaluated the effect of a combination pill containing folic acid, vitamin B₆, and vitamin B₁₂ on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.

Ebbing et al,⁵ in a trial published in 2008, investigated the effect of folic acid, vitamin B₁₂, and vitamin B₆ supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.

Mager et al,³² in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.

The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),³³ recently published, was a double-blind, randomized controlled trial of vitamin B₁₂ and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.

Restenosis after angioplasty

Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.

Namazi et al⁴⁸ evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.

Schnyder et al⁴⁹ evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.

Lange et al³⁵ also evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.

 

 

Cerebrovascular and peripheral arterial disease

The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),⁵⁰ a later meta-analysis contradicts this finding.⁵¹

A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.⁵² Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.⁵³

However, immediately after the Cochrane review was published, Khandanpour et al³⁶ published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.

Kidney disease

One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.

However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).³¹ Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.^11,12,37

FUTURE DIRECTIONS AND RECOMMENDATIONS

Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B₆, and vitamin B₁₂ do not lower the risk of cardiovascular disease.^38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.⁶⁰ (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.

At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.^61,62

Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:

• Whether patients with elevated homocysteine would benefit from such treatment
• At what level it would be appropriate to start treatment
• The appropriate target homocysteine level with treatment.

Particularly given the recent finding that folic acid supplementation may increase cancer risk,⁶³ these questions need closer scrutiny.

Vitamin D is viewed as a promising supplement by the medical, public health, and lay communities, potentially offering many health benefits. But enthusiasm for a new intervention too often gets far ahead of the evidence, as was the case with beta-carotene, selenium, folic acid, and vitamins C and E.

Despite the enthusiasm for vitamin D, there have been no large-scale primary prevention trials that have had either cardiovascular disease or cancer as a prespecified primary outcome. Previous randomized trials of vitamin D have focused primarily on osteoporosis, fracture, falls, and physical function. Although the investigators often reported their findings on vitamin D and cardiovascular disease or cancer, these outcomes were generally secondary or tertiary end points that were not prespecified. These studies should be viewed as hypothesis-generating rather than hypothesis-testing. The increasing prevalence of use of vitamin D supplements underscores the need for rigorous and conclusive evidence from randomized clinical trials that have cardiovascular disease and cancer as primary outcomes.

This article will explain the rationale for a large-scale, randomized clinical trial to evaluate the role of vitamin D in the prevention of cardiovascular disease and cancer. It will also describe the biological mechanisms and currently available evidence relating vitamin D to potential health benefits. Finally, the design, dosage considerations, and logistics of the Vitamin D and Omega-3 Trial (VITAL) will be presented.

EVIDENCE IS MOUNTING FOR VITAMIN D’S BIOLOGICAL IMPORTANCE

Vitamin D is undoubtedly important to health: not only is it produced endogenously, but at least 500 genes have been identified with vitamin D response elements. The vitamin D receptor is found in nearly all cells in the body, and the 1-alpha-hydroxylase enzyme is present in many tissues. Some studies suggest that almost 10% of the human genome may be at least partially regulated by vitamin D.

From Hajjar V, et al. Does vitamin D deficiency play a role in the pathogenesis of chronic heart failure? Do supplements improve survival? Cleve Clin J Med 2010; 77:290–293.

Vitamin D is a prohormone, and people obtain it both endogenously and exogenously (Figure 1). With exposure to ultraviolet B light, 7-dehydrocholesterol in the skin converts to vitamin D₃. We also obtain it through diet or supplements. The plant form (vitamin D₂) and the animal form (vitamin D₃) undergo 25-hydroxylation in the liver. Then, 1-alpha-hydroxylase converts the 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃, primarily in the kidney. Increasing evidence shows that 1-alpha-hydroxylase is present in many other cells and tissues, and that 1,25-dihydroxyvitamin D₃ may be locally produced and possibly even have autocrine effects (acting on surface receptors of the same cell it is secreted by) and paracrine effects (acting on adjacent cells).

Although we know vitamin D is important, what our optimal intake and our blood level of 25-hydroxyvitamin D₃ should be are key unknowns.

RECOMMENDATIONS FOR VITAMIN D INTAKE

During winter, late fall, and early spring, people who live above the 37th parallel (geographically, about one-half of the contiguous United States) do not get enough ultraviolet B energy from the sun to make all the vitamin D they need, even if they spend several hours outside every day. In addition, dark skin pigmentation serves as a sun block, as do sunscreens.

The Institute of Medicine (IOM) provided guidelines for vitamin D intake in 1997 and, most recently, in 2010. However, these guidelines are based on the amount of vitamin D required for bone health and do not address the amount that may be of benefit for prevention of cancer and cardiovascular disease. The latter outcomes are not addressed because the IOM committee believed that evidence was insufficient to determine the role of vitamin D in the prevention of cardiovascular disease, cancer, and other chronic diseases. Thus, current IOM guidelines, which generally recommend less than 1,000 IU of vitamin D daily, are relevant to bone health but not necessarily to other health outcomes. More research is needed to understand whether the guidelines should be modified for the prevention of other chronic diseases.

Moreover, whether or not everyone should be screened for 25-hydroxyvitamin D₃ blood levels is controversial. Most experts agree that a level less than 20 ng/mL is deficient or insufficient. Conversely, potentially harmful are levels 150 ng/mL or more (> 375 nmol/L), which entail the risk of hypercalcemia, vascular soft tissue calcification, and hyperphosphatemia.

People do not reach toxic levels with ultraviolet light exposure because the amount of 25-hydroxyvitamin D₃ synthesis is well regulated. Dietary supplements, however, can bring about toxic levels, and patients taking high doses need to be monitored carefully. The level that should be considered optimal is controversial and requires further study.

 

RISK FACTORS FOR LOW VITAMIN D LEVELS

Risk factors for low vitamin D levels include older age, living in northern latitudes, sun avoidance, dark skin pigmentation, obesity, low dietary intake, and various medical conditions, especially malabsorption syndromes. Some of these are also risk factors for cardiovascular disease, cancer, and other chronic diseases, and potentially confound outcomes in many studies. Older age, which is usually adjusted for in multivariate models, is important to recognize as a major risk factor for vitamin D deficiency, owing to reduced absorption and synthesis, less time outdoors, and low dietary intake.

Wearing sunscreen decreases the synthesis of vitamin D in the skin, but because ultra-violet light has been clearly classified as a carcinogen, it is a not advisable to increase sun exposure for the sake of increasing vitamin D levels. That is a poor trade-off, given the high incidence rate of skin cancer and the adverse effects of solar radiation on skin aging.

Obesity is a risk factor for vitamin D deficiency because vitamin D is fat-soluble and becomes sequestered in fat tissue. Vitamin D may also play a role in the differentiation of adipocytes and may affect their function. In observational studies, it is very important for researchers to adjust for body mass index, physical activity (which may be correlated with more time outdoors), and other potential confounders in their analyses.

HOW VITAMIN D MAY LOWER CANCER RISK

Because of the important effect of vitamin D in regulating cell differentiation and cell growth, there are multiple ways that it may affect cancer risk. Laboratory, cell culture, and animal studies suggest that vitamin D may lower cancer risk by inhibiting cell proliferation, angiogenesis, metastasis, and inflammation and inducing apoptosis and cellular differentiation. Several of these mechanisms are also relevant to atherosclerosis and cardiovascular disease. Although VITAL is addressing the role of vitamin D in preventing both cancer and cardiovascular disease, the remainder of this article will focus on cardiovascular outcomes.

HOW VITAMIN D MAY REDUCE CARDIOVASCULAR RISK

Vitamin D may lower cardiovascular risk via several mechanisms:

Inhibiting inflammation. Vitamin D has a powerful immunomodulatory effect: laboratory studies show that it inhibits prostaglandin and cyclooxygenase 2 pathways, reduces matrix metalloproteinase 9 and several proinflammatory cytokines, and increases interleukin 10, all of which result in suppressed inflammation.¹

Inhibiting vascular muscle proliferation and vascular calcification. Animal studies indicate that in moderate doses vitamin D decreases calcium cellular influx and increases matrix Gla protein, which inhibits vascular smooth muscle proliferation and vascular calcification. These protective effects contrast with the hypercalcemia associated with a high intake of vitamin D, especially in the context of renal failure or other risk factors, which may lead to increased vascular calcification.¹

Regulates blood pressure. Vitamin D decreases renin gene expression and the synthesis of renin, which reduces activity of the renin-angiotensin-aldosterone system, leading to a reduction of blood pressure and a favorable effect on volume homeostasis.¹

Regulates glucose metabolism. Limited evidence shows that vitamin D may increase insulin sensitivity and regulate glucose metabolism.¹

Vitamin D and cardiac hypertrophy

The vitamin D receptor is present in virtually all tissues, including cardiac myocytes and endothelial cells. Animals with vitamin D deficiency have higher blood pressures, and animals genetically altered to have no vitamin D receptors (knock-out models) develop left ventricular hypertrophy and heart failure.

Animals genetically altered to have no 1-alpha-hydroxylase (so that the most active form of vitamin D is not made) also develop left ventricular hypertrophy. They can be rescued by the administration of 1,25-dihydroxy vitamin D₃.¹

These findings are consistent with what is observed in patients with end-stage renal disease, who produce very little 1,25-dihydroxyvitamin D₃: they often develop left ventricular hypertrophy, diastolic heart failure, atherosclerosis, and vascular calcification.

EVIDENCE FOR CARDIOVASCULAR DISEASE REDUCTION

Wang et al¹ recently reviewed available prospective cohort and randomized clinical trials from 1966 to 2009 that examined vitamin D or calcium supplementation and cardiovascular disease. Comparing people with the lowest to the highest levels of serum 25-hydroxyvitamin D₃ indicated that a low level is a risk factor for coronary artery disease and cardiovascular death. Unfortunately, most studies were not designed to assess primary effects on cardiovascular outcomes, and so have many potential confounders.

Prospective observational studies

Observational studies suggest that vitamin D deficiency is associated with an increased risk of cardiovascular disease. Some examples:

The Framingham Offspring Study² followed 1,739 men and women with a mean age of 59 for 5.4 years. The study compared the incidence of cardiovascular events in those with a serum 25-dihydroxyvitamin D level of at least 37.5 nmol/L vs those with lower levels. The risk of cardiovascular disease was 1.62 times higher in those with the lowest levels of vitamin D, a statistically significant difference. However, a threshold effect was apparent (discussed below).

The Health Professionals Follow-up Study³ prospectively evaluated more than 18,000 men ages 40 to 75 for 10 years. The study compared men with a low serum level of vitamin D (< 37.5 nmol/L) to those with a more optimal level (> 75 nmol/L). The incidence of cardiovascular events was 2.09 times higher in men with low levels of vitamin D, a difference that was statistically significant.

The Third National Health and Nutrition Examination Survey (NHANES III) included data for more than 13,300 men and women age 20 years and older. Using a cohort that was followed for 8.7 years, Melamed et al⁴ compared the quartile with the lowest serum vitamin D level (< 44.4 nmol/L) against the quartile with the highest level (> 80.1 nmol/L). The associations were modest: those with low levels had a 1.20-times higher rate of death from cardiovascular disease and a statistically significant 1.26-times higher rate of death from all causes.

 

 

Randomized clinical trials

A meta-analysis of 18 randomized trials⁵ of vitamin D supplementation (300–2,000 IU/day, mean 528 IU/day vs placebo), including 57,311 participants, evaluated the rate of death from all causes and found a modest but significant reduction in risk (relative risk 0.93, 95% confidence interval [CI] 0.87–0.99). These were generally trials looking at fracture rates or physical performance, and a dose-response relationship was not evident. A recent systematic review of randomized controlled trials of vitamin D¹ that included cardiovascular disease as a secondary outcome found a pooled relative risk for cardiovascular disease of 0.90 (95% CI 0.77–1.05) for vitamin D supplementation compared with placebo and 1.04 (95% CI 0.92–1.18) for combination vitamin D plus calcium supplementation vs placebo.¹ Two individual trials are discussed below.

Trivedi et al⁶ randomized 2,686 British men and women to vitamin D₃ 100,000 IU given every 4 months over 5 years (equivalent to 800 IU/day) or placebo. The relative risk of cardiovascular events was 0.90 (95% CI 0.77–1.06) and of cardiovascular deaths 0.84 (95% CI 0.65–1.10). Although the results were promising, the trial was designed to assess fracture risk and was not large enough for the differences in cardiovascular outcomes to reach statistical significance.

The Women’s Health Initiative,^7,8 which included 36,282 postmenopausal women aged 50 to 79, tested combined vitamin D₃ (400 IU/day) with calcium (1,000 mg/day) vs placebo. No benefit was seen for preventing coronary events or stroke, which may be due to the low dosage of vitamin D. The hazard ratio for coronary disease was 1.04 (0.92–1.18). Regarding mortality, the hazard ratio for cardiovascular death was 0.92, for cerebrovascular death 0.89, for cancer death 0.89, and for other deaths 0.95. None of these hazard ratios reached statistical significance.

MORE MAY NOT BE BETTER

As is probably true for everything in biological systems, there apparently is an optimal level of intake to meet vitamin D needs.

The Framingham Offspring Study,² which found a higher risk with vitamin D deficiency, also found a suggestion of a threshold. Participants who had levels of 50 to 65 nmol/L had the lowest risk. Higher levels did not confer lower risk and even suggested a slight upturn.

Evidence from the Women’s Health Initiative⁸ also indicates that high dosages may not be better than moderate dosages. The meta-analysis of vitamin D and all-cause mortality⁵ found a relative risk of 0.93, but one of the largest studies in that meta-analysis tested only 400 IU a day and found a similar relative risk of 0.91 (95% confidence interval, 0.83–1.01).

Moreover, the NHANES study found that with increasing serum 25-hydroxyvitamin D₃ levels, the risk of all-cause mortality fell until about 100 nmol/L, but then plateaued and even increased with higher serum levels.⁴

VITAL: STUDY DESIGN AND LOGISTICS

In VITAL, the investigators aim to recruit 20,000 healthy men (age 60 and older) and women (65 and older) who are representative of the US population (www.vitalstudy.org). Because it is a primary prevention trial, people with a known history of cardiovascular disease or cancer will be excluded. Participants will be randomized to receive either 2,000 IU of vitamin D₃ per day or placebo. Each group will be further randomized to receive either 1 g per day of fish oil (combined eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo. The mean treatment period will be 5 years. Recruitment began in early 2010.

Blood will be collected in about 80% (ideally 100%) of participants, with follow-up blood collection in at least 2,000.

Primary aims of the trial are to test whether vitamin D₃ and the omega-3 fatty acids reduce the risk of total cancer and major cardiovascular events (a composite of myocardial infarction, stroke, and death due to cardiovascular events).

Secondary aims are to test whether these agents lower the risk of:

• Site-specific cancer, including colorectal, breast, and prostate cancer, and the total cancer mortality rate
• An expanded composite outcome including myocardial infarction, stroke, cardiovascular death, coronary artery bypass grafting, percutaneous coronary intervention, and its individual components.

Tertiary aims are to explore whether vitamin D₃ and omega-3 fatty acids have additive effects on the primary and secondary end points. The trial will also explore whether the effects of vitamin D₃ and omega-3 fatty acids on cancer and cardiovascular disease vary by baseline blood levels of these nutrients, and whether race, skin pigmentation, or body mass index modify the effects of vitamin D₃.

Ancillary studies will assess the effect of the interventions on risk of diabetes, hypertension, cognitive decline, depression, fracture, infections, respiratory disorders, and autoimmune diseases. The primary sponsor of this trial is the National Cancer Institute, and the secondary sponsor is the National Heart, Lung and Blood Institute. Other institutes and agencies also are cosponsors of the study.

The timing of VITAL is optimal

There is a limited window of opportunity for conducting a randomized clinical trial: the evidence must be strong enough to justify mounting a very large trial with enough power to look at cardiovascular events and cancer, but the evidence must not be so strong that it would be unethical to have a placebo group. Thus, there must be a state of equipoise. Our trial allows the study population to have a background intake of vitamin D that is currently recommended by national guidelines. Therefore, even the placebo group should have adequate intake of vitamin D.

The growing use of vitamin D supplementation by the public underscores the need for conclusive evidence of its benefits and risks. No previous large-scale randomized clinical trial has tested moderate to high doses of vitamin D for the primary prevention of cancer and cardiovascular disease.

 

 

Setting the dosage

VITAL set the vitamin D₃ dosage at 2,000 IU per day (50 μg/day), which is designed to provide the best balance of efficacy and safety. As a general rule, each microgram of vitamin D₃ is expected to raise the serum 25-hydroxyvitamin D₃ level about 1 nmol/L, although the response is not linear: if baseline levels are lower, the increase is greater. In the United States, people commonly have a baseline level of about 40 nmol/L, so we expect that levels of people treated in the study will reach about 90 nmol/L (range 75–100 nmol/L), about 35 to 50 nmol/L higher than in the placebo group.

The target range of 75 to 100 nmol/L is the level at which greatest efficacy has been suggested in observational studies. Previous randomized trials of vitamin D have not tested high enough doses to achieve this level of 25-hydroxyvitamin D₃. VITAL will test whether reaching this serum level lowers the risk of cardiovascular disease, cancer, and other chronic diseases. This level may be associated with benefit and has minimal risk of hypercalcemia. Risk of hypercalcemia may be present in participants with an occult chronic granulomatous condition such as sarcoidosis or Wegener granulomatosis, in which activated macrophages synthesize 1,25-dihydroxyvitamin D₃. These conditions are very rare, however, and the risk of hypercalcemia in the trial is exceedingly low.

VITAL participants will also be randomized to take placebo or 1 g per day of combined EPA and DHA, about 5 to 10 times more than most Americans consume.

Nationwide recruitment among senior citizens

We aim to recruit 20,000 people (10,000 men and 10,000 women) nationwide who are willing, eligible, and compliant (ie, who take more than two-thirds of study pills during a 3-month placebo “run-in” phase of the trial). The trial aims to enroll 40,000 in the run-in period, and 20,000 will be randomized. To get this many participants, we will send invitational mailings and screening questionnaires to at least 2.5 million people around the United States, with mailing lists selected by age—ie, members of the American Association of Retired Persons, health professionals, teachers, and subscription lists for selected magazines. A pilot study in 5,000 people has indicated that recruiting and randomizing 20,000 participants via large mailings should be possible.

The trial is expected to be extremely cost-effective because it will be conducted largely by mail. Medication will be mailed in calendar blister packs. Participants report outcomes, which are then confirmed by medical record review. The Centers for Medicare and Medicaid Services and the National Death Index will also be used to ascertain outcomes.

We hope to recruit a more racially diverse study population than is typically seen in US trials: 63% (12,620) whites, 25% (5,000) African Americans, 7% (1,400) Hispanics, 2.5% (500) Asians, 2% (400) American Indians and Alaska natives, and 0.4% (80) native Hawaiian and Pacific Islanders.

Eligibility criteria ensure primary prevention is tested

To enter the study, men must be at least 60 years old and women at least 65. At a minimum, a high school education is required due to the detailed forms and questionnaires to be completed. Because this is a primary prevention trial, anyone with a history of cancer (except nonmelanoma skin cancer) or cardiovascular disease (including myocardial infarction, stroke, or coronary revascularization) will be excluded, as will anyone with a history of kidney stones, renal failure or dialysis, hypercalcemia, hypoparathyroidism or hyperparathyroidism, severe liver disease (eg, cirrhosis), sarcoidosis, tuberculosis, or other granulomatous disease. People with an allergy to fish will also be excluded.

We do not expect that those in the placebo group will develop vitamin D deficiency due to their participation in the study. The trial will allow a background intake in the study population of up to 800 IU of vitamin D and 1,200 mg of calcium per day in supplements. Assuming they also get about 200 IU of vitamin D in the diet, the background intake in the placebo group may be close to 1,000 IU of vitamin D. Assuming that the active treatment group has a similar background intake, their total intake will be about 3,000 IU per day (about 1,000 IU/day from background intake plus 2,000 IU/day from the intervention).

Cohort power sufficient to see effect in 5 years

The trial is expected to have sufficient power to evaluate cardiovascular disease and cancer end points as primary outcomes during 5 years of follow-up. The trial is designed to have a power of 91% to 92% to detect a relative risk of 0.85 for the primary cancer end point of total cancer incidence and 0.80 for the cardiovascular disease end point of myocardial infarction, stroke, and cardiovascular mortality. Power will be even greater for the expanded composite outcome for cardiovascular disease.

Ancillary studies

Ancillary studies include evaluating the interventions’ role in preventing diabetes and glucose intolerance, hypertension, heart failure, atrial fibrillation, cognitive decline, mood disorders, osteoporosis and fractures, asthma and respiratory diseases, infections, macular degeneration, rheumatoid arthritis, systemic lupus erythematosus, and a composite of autoimmune diseases. Imaging studies also are planned, including dual energy x-ray absorptiometry, mammographic density, and non-invasive vascular imaging (carotid intima medial thickness, coronary calcium measurements, and two-dimensional echocardiography to assess cardiac function).

Several biomarker and genetic studies will also be carried out. We intend to perform genetic studies on most of the study population to evaluate gene variants in the vitamin D receptor, vitamin D binding protein, and other vitamin-D-related genes that may contribute to lower baseline levels of 25-hydroxyvitamin D₃ or different responses to the interventions.

Clinical and Translational Science Center visits are planned to provide more detailed assessments of 1,000 participants, including blood pressure measurements, height, weight, waist circumference, other anthropometric measurements, a 2-hour glucose tolerance test, a fasting blood collection, hemoglobin A_1c measurements, spirometry, and assessment of physical performance, strength, frailty, cognitive function, mood, and depression. Dual-energy x-ray absorptiometry and noninvasive vascular imaging studies are also planned for those visits.