In May and June, U.S. Department of Health and Human Services (HHS) Secretary Kathleen Sebelius in May and June announced 107 healthcare innovations grants to improve coordination of care and reduce costs. The grants, a provision of the Affordable Care Act (ACA), range from $1 million to $30 million. HHS anticipates that the projects will reduce healthcare spending by $254 million over the next three years and provide "new ideas on how to deliver better health, improved care, and lower costs to people enrolled in Medicare, Medicaid and [the] Children's Health Insurance Program (CHIP)."

Hospitalists played key roles in planning and developing several of the projects. Common themes include coordination and integration of services, promotion of community collaborations, integrating behavioral and physical care, and the use of telemedicine—many of the same approaches utilized by SHM's Project BOOST and other national initiatives for preventing unnecessary readmissions.

In Atlanta, Emory University's Center for Critical Care received a $10.7 million grant to deploy 40 nurse practitioners (NPs) and physician assistants (PAs) trained in critical care to underserved and rural ICUs in Georgia. In many of the targeted hospitals, hospitalists manage patients in the ICU, but this program brings an additional layer of staffing and expertise to the care, allowing patients to stay in their beds rather than having to be transferred, says Daniel Owens, MBA, the center’s director of operations and senior administrator of the division of hospital medicine at Emory.

The project will bring NPs and PAs from participating hospitals to Emory for an intensive, six-month, critical-care residency. "If they don't have these folks, we'll help to identify staff for the jobs," he adds.

At Vanderbilt University Medical Center in Nashville, Tenn., a $2.4 million project to reduce rehospitalizations for a high-risk geriatric patients aims to close the gaps in care transitions between hospital, outpatient, post-acute, and extended-care settings, says Vanderbilt hospitalist Eduard Vasilevskis, MD. The project will employ transition advocates or coordinators in the hospital to improve communication at both ends, with evidence-based protocols to improve discharge planning. Long-term care providers will be offered Web-based training and video conferencing.

"The goal is to break the cycle of rehospitalization," says Dr. Vasilevskis, "but if patients need to come back to the hospital, there will be someone involved in their care who is familiar with the settings where they’ve come from."

Beth Israel Deaconess Medical Center (BIDMC) in Boston received $4.9 million for its Post-Acute Care Transitions program (PACT), which links the hospital to six affiliated primary care practices using a bundle of post-acute care interventions, care-transition specialists, and dedicated clinical pharmacists. Nurses remain in contact with patients by telephone for 30 days post-hospital discharge and coordinate the services of extended-care facilities and visiting nurses. Pharmacists perform in-hospital medication reconciliation and patient education, says hospitalist Lauren Doctoroff, MD, FHM. She and Julius Yang, MD, BIDMC medical director of inpatient quality, helped develop the pilot program, which began in August 2011.

"These care-transitions specialists offer us an added level of patient support and a different level of integration focused on risk assessment of such issues as social supports and problems with medical compliance, which can be used by the inpatient team to come up with the most rational and ideal discharge plan," Dr. Doctoroff says. "One of my colleagues said to me, ‘I feel so much better knowing there is this added level of support for patients after discharge.'"

The HHS grants reflect an important recognition that what happens to patients following discharge partly reflects what happens in the hospital but also depends on collaborations with post-acute providers, Dr. Doctoroff says.

"Hospitalists can't do everything, but they need their eye out of the hospital on post-acute providers in order to deliver the best care," she adds.

In May and June, U.S. Department of Health and Human Services (HHS) Secretary Kathleen Sebelius in May and June announced 107 healthcare innovations grants to improve coordination of care and reduce costs. The grants, a provision of the Affordable Care Act (ACA), range from $1 million to $30 million. HHS anticipates that the projects will reduce healthcare spending by $254 million over the next three years and provide "new ideas on how to deliver better health, improved care, and lower costs to people enrolled in Medicare, Medicaid and [the] Children's Health Insurance Program (CHIP)."

Hospitalists played key roles in planning and developing several of the projects. Common themes include coordination and integration of services, promotion of community collaborations, integrating behavioral and physical care, and the use of telemedicine—many of the same approaches utilized by SHM's Project BOOST and other national initiatives for preventing unnecessary readmissions.

In Atlanta, Emory University's Center for Critical Care received a $10.7 million grant to deploy 40 nurse practitioners (NPs) and physician assistants (PAs) trained in critical care to underserved and rural ICUs in Georgia. In many of the targeted hospitals, hospitalists manage patients in the ICU, but this program brings an additional layer of staffing and expertise to the care, allowing patients to stay in their beds rather than having to be transferred, says Daniel Owens, MBA, the center’s director of operations and senior administrator of the division of hospital medicine at Emory.

The project will bring NPs and PAs from participating hospitals to Emory for an intensive, six-month, critical-care residency. "If they don't have these folks, we'll help to identify staff for the jobs," he adds.

At Vanderbilt University Medical Center in Nashville, Tenn., a $2.4 million project to reduce rehospitalizations for a high-risk geriatric patients aims to close the gaps in care transitions between hospital, outpatient, post-acute, and extended-care settings, says Vanderbilt hospitalist Eduard Vasilevskis, MD. The project will employ transition advocates or coordinators in the hospital to improve communication at both ends, with evidence-based protocols to improve discharge planning. Long-term care providers will be offered Web-based training and video conferencing.

"The goal is to break the cycle of rehospitalization," says Dr. Vasilevskis, "but if patients need to come back to the hospital, there will be someone involved in their care who is familiar with the settings where they’ve come from."

Beth Israel Deaconess Medical Center (BIDMC) in Boston received $4.9 million for its Post-Acute Care Transitions program (PACT), which links the hospital to six affiliated primary care practices using a bundle of post-acute care interventions, care-transition specialists, and dedicated clinical pharmacists. Nurses remain in contact with patients by telephone for 30 days post-hospital discharge and coordinate the services of extended-care facilities and visiting nurses. Pharmacists perform in-hospital medication reconciliation and patient education, says hospitalist Lauren Doctoroff, MD, FHM. She and Julius Yang, MD, BIDMC medical director of inpatient quality, helped develop the pilot program, which began in August 2011.

"These care-transitions specialists offer us an added level of patient support and a different level of integration focused on risk assessment of such issues as social supports and problems with medical compliance, which can be used by the inpatient team to come up with the most rational and ideal discharge plan," Dr. Doctoroff says. "One of my colleagues said to me, ‘I feel so much better knowing there is this added level of support for patients after discharge.'"

The HHS grants reflect an important recognition that what happens to patients following discharge partly reflects what happens in the hospital but also depends on collaborations with post-acute providers, Dr. Doctoroff says.

"Hospitalists can't do everything, but they need their eye out of the hospital on post-acute providers in order to deliver the best care," she adds.

In May and June, U.S. Department of Health and Human Services (HHS) Secretary Kathleen Sebelius in May and June announced 107 healthcare innovations grants to improve coordination of care and reduce costs. The grants, a provision of the Affordable Care Act (ACA), range from $1 million to $30 million. HHS anticipates that the projects will reduce healthcare spending by $254 million over the next three years and provide "new ideas on how to deliver better health, improved care, and lower costs to people enrolled in Medicare, Medicaid and [the] Children's Health Insurance Program (CHIP)."

Hospitalists played key roles in planning and developing several of the projects. Common themes include coordination and integration of services, promotion of community collaborations, integrating behavioral and physical care, and the use of telemedicine—many of the same approaches utilized by SHM's Project BOOST and other national initiatives for preventing unnecessary readmissions.

In Atlanta, Emory University's Center for Critical Care received a $10.7 million grant to deploy 40 nurse practitioners (NPs) and physician assistants (PAs) trained in critical care to underserved and rural ICUs in Georgia. In many of the targeted hospitals, hospitalists manage patients in the ICU, but this program brings an additional layer of staffing and expertise to the care, allowing patients to stay in their beds rather than having to be transferred, says Daniel Owens, MBA, the center’s director of operations and senior administrator of the division of hospital medicine at Emory.

The project will bring NPs and PAs from participating hospitals to Emory for an intensive, six-month, critical-care residency. "If they don't have these folks, we'll help to identify staff for the jobs," he adds.

At Vanderbilt University Medical Center in Nashville, Tenn., a $2.4 million project to reduce rehospitalizations for a high-risk geriatric patients aims to close the gaps in care transitions between hospital, outpatient, post-acute, and extended-care settings, says Vanderbilt hospitalist Eduard Vasilevskis, MD. The project will employ transition advocates or coordinators in the hospital to improve communication at both ends, with evidence-based protocols to improve discharge planning. Long-term care providers will be offered Web-based training and video conferencing.

"The goal is to break the cycle of rehospitalization," says Dr. Vasilevskis, "but if patients need to come back to the hospital, there will be someone involved in their care who is familiar with the settings where they’ve come from."

Beth Israel Deaconess Medical Center (BIDMC) in Boston received $4.9 million for its Post-Acute Care Transitions program (PACT), which links the hospital to six affiliated primary care practices using a bundle of post-acute care interventions, care-transition specialists, and dedicated clinical pharmacists. Nurses remain in contact with patients by telephone for 30 days post-hospital discharge and coordinate the services of extended-care facilities and visiting nurses. Pharmacists perform in-hospital medication reconciliation and patient education, says hospitalist Lauren Doctoroff, MD, FHM. She and Julius Yang, MD, BIDMC medical director of inpatient quality, helped develop the pilot program, which began in August 2011.

"These care-transitions specialists offer us an added level of patient support and a different level of integration focused on risk assessment of such issues as social supports and problems with medical compliance, which can be used by the inpatient team to come up with the most rational and ideal discharge plan," Dr. Doctoroff says. "One of my colleagues said to me, ‘I feel so much better knowing there is this added level of support for patients after discharge.'"

The HHS grants reflect an important recognition that what happens to patients following discharge partly reflects what happens in the hospital but also depends on collaborations with post-acute providers, Dr. Doctoroff says.

"Hospitalists can't do everything, but they need their eye out of the hospital on post-acute providers in order to deliver the best care," she adds.

Clinical question: Does treatment with drotrecogin alfa (activated) reduce mortality in patients with septic shock?

Background: Recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), was approved for the treatment of patients with severe sepsis in 2001 on the basis of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study. Since approval, conflicting reports about its efficacy have surfaced.

Study design: Double-blind, randomized-controlled trial.

Setting: Multicenter, multinational trial.

Synopsis: This trial enrolled 1,697 patients with septic shock to receive either DrotAA or placebo. At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval, 0.92 to 1.28; P=0.31). At 90 days, there was still no significant difference in mortality. Mortality was also unchanged in patients with severe protein C deficiency at baseline. This lack of mortality benefit with either therapy persisted across all predefined subgroups in this study.

The incidence of non-serious bleeding was more common among patients who received DrotAA than among those in the placebo group (8.6% vs. 4.8%, P=0.002), but the incidence of serious bleeding events was similar in both groups. This study was appropriately powered after adjusting the sample size when aggregate mortality was found to be lower than anticipated.

Bottom line: DrotAA does not significantly reduce mortality at 28 or 90 days in patients with septic shock.

Citation: Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055-2064.

Read more of our physician reviews of recent, HM-relevant literature.

Clinical question: Does treatment with drotrecogin alfa (activated) reduce mortality in patients with septic shock?

Background: Recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), was approved for the treatment of patients with severe sepsis in 2001 on the basis of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study. Since approval, conflicting reports about its efficacy have surfaced.

Study design: Double-blind, randomized-controlled trial.

Setting: Multicenter, multinational trial.

Synopsis: This trial enrolled 1,697 patients with septic shock to receive either DrotAA or placebo. At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval, 0.92 to 1.28; P=0.31). At 90 days, there was still no significant difference in mortality. Mortality was also unchanged in patients with severe protein C deficiency at baseline. This lack of mortality benefit with either therapy persisted across all predefined subgroups in this study.

The incidence of non-serious bleeding was more common among patients who received DrotAA than among those in the placebo group (8.6% vs. 4.8%, P=0.002), but the incidence of serious bleeding events was similar in both groups. This study was appropriately powered after adjusting the sample size when aggregate mortality was found to be lower than anticipated.

Bottom line: DrotAA does not significantly reduce mortality at 28 or 90 days in patients with septic shock.

Citation: Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055-2064.

Read more of our physician reviews of recent, HM-relevant literature.

Clinical question: Does treatment with drotrecogin alfa (activated) reduce mortality in patients with septic shock?

Background: Recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), was approved for the treatment of patients with severe sepsis in 2001 on the basis of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study. Since approval, conflicting reports about its efficacy have surfaced.

Study design: Double-blind, randomized-controlled trial.

Setting: Multicenter, multinational trial.

Synopsis: This trial enrolled 1,697 patients with septic shock to receive either DrotAA or placebo. At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval, 0.92 to 1.28; P=0.31). At 90 days, there was still no significant difference in mortality. Mortality was also unchanged in patients with severe protein C deficiency at baseline. This lack of mortality benefit with either therapy persisted across all predefined subgroups in this study.

The incidence of non-serious bleeding was more common among patients who received DrotAA than among those in the placebo group (8.6% vs. 4.8%, P=0.002), but the incidence of serious bleeding events was similar in both groups. This study was appropriately powered after adjusting the sample size when aggregate mortality was found to be lower than anticipated.

Bottom line: DrotAA does not significantly reduce mortality at 28 or 90 days in patients with septic shock.

Citation: Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055-2064.

Read more of our physician reviews of recent, HM-relevant literature.

For many years, I chaired the office efficiency course at the American Academy of Dermatology’s annual meeting. Each year, I asked how many participants compiled a yearly budget for their practices. In an audience of 400, the largest affirmative response I ever received was three, and some years there were no raised hands at all.

Why do physicians so vigorously resist an exercise that is so basic to every other business and profession on the planet? Typically, I hear one of two reasons: It’s tedious, or my colleagues seem to be doing just fine without one.

But the days of "doing just fine" are coming to an end. As competition for patients increases, expenses continue their upward spiral, and the government continues its steady encroachment on private practice, physicians who plan ahead will have an advantage.

Budgeting need not be tedious; determine what you need to do yourself and what can be delegated. And now, as the year winds down, is an excellent opportunity to map out your finances.

The first step – the basic gathering of numbers that everyone seems to dread – can be delegated. Ask your accountant to compile the practice’s gross income over the last 12 months, in monthly increments.

Break it down by type of service: office visits, hospital visits, surgery, lab fees, and so on, listing both the amounts billed and collected. This is not only for calculations of collection ratios, but to determine your "seasonality" – which I’ll discuss in greater detail next month. Do the same for expenses, and again break them down by category: salaries, rent/mortgage, business and medical supplies, and so on.

In many cases, the mere collection of this raw data will save money. You might discover, for example, that expenditures for business supplies are unexpectedly high. Perhaps a competing vendor can do better, or perhaps you have an overuse or theft problem.

Once the numbers are accumulated, start extrapolating them into next year. If your income rose by, say, 6% this year, can you expect a similar rise next year? Why or why not? To get a fix on a realistic goal, go through each component of your gross income and decide where the increase could come from. Can you raise prices for office visits or cosmetic procedures, renegotiate at least one third-party contract, or add another exam room in order to see more patients?

Perhaps there is an impending change in your area that you can factor in, such as a competitor who is retiring. If that physician is known for a specific service, and it’s not a service you offer, could you start?

You are, I hope, beginning to see that this exercise is well worth the effort. After you have mapped out income, turn to expenses. Perhaps some of the assumptions that you’ve made on income will affect expenses; for example, adding a new procedure may require the purchase of new equipment. If you have a higher census goal, you may need an additional assistant.

If you’re considering adding an associate, you can determine if he or she will bring in enough revenue to cover salary and expenses by completing two versions of next year’s projected budget – one with the associate and one without.

Once you have prepared your budget, follow it. Your accountant or manager can generate monthly spreadsheets comparing actual financials with projections, and the year-to-date, compared with previous years. There are many parameters to explore.

Look for deviations from predictions and possible reasons for them, such as factors you didn’t (or couldn’t) anticipate. Make a note of them; it will help you with next year’s projections.

A budget can be justified in two major ways: You’ll better understand where your practice is going, and the forces at work to change it. And you’ll become aware of unexpected events while there is still time to influence them, rather than making such discoveries well after the fact – or worse, never finding out at all.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

For many years, I chaired the office efficiency course at the American Academy of Dermatology’s annual meeting. Each year, I asked how many participants compiled a yearly budget for their practices. In an audience of 400, the largest affirmative response I ever received was three, and some years there were no raised hands at all.

Why do physicians so vigorously resist an exercise that is so basic to every other business and profession on the planet? Typically, I hear one of two reasons: It’s tedious, or my colleagues seem to be doing just fine without one.

But the days of "doing just fine" are coming to an end. As competition for patients increases, expenses continue their upward spiral, and the government continues its steady encroachment on private practice, physicians who plan ahead will have an advantage.

Budgeting need not be tedious; determine what you need to do yourself and what can be delegated. And now, as the year winds down, is an excellent opportunity to map out your finances.

The first step – the basic gathering of numbers that everyone seems to dread – can be delegated. Ask your accountant to compile the practice’s gross income over the last 12 months, in monthly increments.

Break it down by type of service: office visits, hospital visits, surgery, lab fees, and so on, listing both the amounts billed and collected. This is not only for calculations of collection ratios, but to determine your "seasonality" – which I’ll discuss in greater detail next month. Do the same for expenses, and again break them down by category: salaries, rent/mortgage, business and medical supplies, and so on.

In many cases, the mere collection of this raw data will save money. You might discover, for example, that expenditures for business supplies are unexpectedly high. Perhaps a competing vendor can do better, or perhaps you have an overuse or theft problem.

Once the numbers are accumulated, start extrapolating them into next year. If your income rose by, say, 6% this year, can you expect a similar rise next year? Why or why not? To get a fix on a realistic goal, go through each component of your gross income and decide where the increase could come from. Can you raise prices for office visits or cosmetic procedures, renegotiate at least one third-party contract, or add another exam room in order to see more patients?

Perhaps there is an impending change in your area that you can factor in, such as a competitor who is retiring. If that physician is known for a specific service, and it’s not a service you offer, could you start?

You are, I hope, beginning to see that this exercise is well worth the effort. After you have mapped out income, turn to expenses. Perhaps some of the assumptions that you’ve made on income will affect expenses; for example, adding a new procedure may require the purchase of new equipment. If you have a higher census goal, you may need an additional assistant.

If you’re considering adding an associate, you can determine if he or she will bring in enough revenue to cover salary and expenses by completing two versions of next year’s projected budget – one with the associate and one without.

Once you have prepared your budget, follow it. Your accountant or manager can generate monthly spreadsheets comparing actual financials with projections, and the year-to-date, compared with previous years. There are many parameters to explore.

Look for deviations from predictions and possible reasons for them, such as factors you didn’t (or couldn’t) anticipate. Make a note of them; it will help you with next year’s projections.

A budget can be justified in two major ways: You’ll better understand where your practice is going, and the forces at work to change it. And you’ll become aware of unexpected events while there is still time to influence them, rather than making such discoveries well after the fact – or worse, never finding out at all.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

For many years, I chaired the office efficiency course at the American Academy of Dermatology’s annual meeting. Each year, I asked how many participants compiled a yearly budget for their practices. In an audience of 400, the largest affirmative response I ever received was three, and some years there were no raised hands at all.

Why do physicians so vigorously resist an exercise that is so basic to every other business and profession on the planet? Typically, I hear one of two reasons: It’s tedious, or my colleagues seem to be doing just fine without one.

But the days of "doing just fine" are coming to an end. As competition for patients increases, expenses continue their upward spiral, and the government continues its steady encroachment on private practice, physicians who plan ahead will have an advantage.

Budgeting need not be tedious; determine what you need to do yourself and what can be delegated. And now, as the year winds down, is an excellent opportunity to map out your finances.

The first step – the basic gathering of numbers that everyone seems to dread – can be delegated. Ask your accountant to compile the practice’s gross income over the last 12 months, in monthly increments.

Break it down by type of service: office visits, hospital visits, surgery, lab fees, and so on, listing both the amounts billed and collected. This is not only for calculations of collection ratios, but to determine your "seasonality" – which I’ll discuss in greater detail next month. Do the same for expenses, and again break them down by category: salaries, rent/mortgage, business and medical supplies, and so on.

In many cases, the mere collection of this raw data will save money. You might discover, for example, that expenditures for business supplies are unexpectedly high. Perhaps a competing vendor can do better, or perhaps you have an overuse or theft problem.

Once the numbers are accumulated, start extrapolating them into next year. If your income rose by, say, 6% this year, can you expect a similar rise next year? Why or why not? To get a fix on a realistic goal, go through each component of your gross income and decide where the increase could come from. Can you raise prices for office visits or cosmetic procedures, renegotiate at least one third-party contract, or add another exam room in order to see more patients?

Perhaps there is an impending change in your area that you can factor in, such as a competitor who is retiring. If that physician is known for a specific service, and it’s not a service you offer, could you start?

You are, I hope, beginning to see that this exercise is well worth the effort. After you have mapped out income, turn to expenses. Perhaps some of the assumptions that you’ve made on income will affect expenses; for example, adding a new procedure may require the purchase of new equipment. If you have a higher census goal, you may need an additional assistant.

If you’re considering adding an associate, you can determine if he or she will bring in enough revenue to cover salary and expenses by completing two versions of next year’s projected budget – one with the associate and one without.

Once you have prepared your budget, follow it. Your accountant or manager can generate monthly spreadsheets comparing actual financials with projections, and the year-to-date, compared with previous years. There are many parameters to explore.

Look for deviations from predictions and possible reasons for them, such as factors you didn’t (or couldn’t) anticipate. Make a note of them; it will help you with next year’s projections.

A budget can be justified in two major ways: You’ll better understand where your practice is going, and the forces at work to change it. And you’ll become aware of unexpected events while there is still time to influence them, rather than making such discoveries well after the fact – or worse, never finding out at all.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

Until last month, I had only ever had two positive pregnancy test results in women of child-bearing age taking isotretinoin. Both of the previous reports came in on the same day, one after the other. When I called each patient to give her the results, and asked her to repeat the test, neither was at all perturbed. "If I’m pregnant," laughed one, "it would be another Immaculate Conception."

Both results turned out to be laboratory errors committed by a single technician, who was reported and rebuked. Repeat tests were negative.

Then, last month, I got another positive. Victoria had actually completed her treatment course 6 weeks earlier, and had already obtained a 30-day post-treatment test – which was negative. Then, she had another test done a few weeks later, which was positive.

I called and got her mother, who asked, "Is everything all right?" But Victoria is 19, so I just said I needed her daughter’s cell phone number.

"We had a condom accident," Victoria said when I reached her. We reviewed her case, determining the last day she had actually taken the medication. Her sexual activity had clearly taken place more than 30 days later.

I suggested she contact her gynecologist at once, to be evaluated and to have the pregnancy test repeated, and I faxed a note to that physician with the relevant details. "If pregnancy is confirmed," I told her, "I’m sure you’ll consider many things before you decide what to do. But one thing you don’t have to factor in is your isotretinoin treatment, because it was no longer in your blood when you became pregnant."

A few days later, Victoria came to my office. "I’ve decided to end the pregnancy," she said. "This just isn’t the right time."

I told her I understood. "By the way," I said, "you listed your two methods of contraception as the patch and condoms. So even if the condom failed, it looks like the patch did too."

"No," said Victoria, "I wasn’t on the patch anymore."

"What?!" I exclaimed.

"I ran out a month earlier," she said, "and my regular doctor was out on maternity leave."

"Wasn’t there anyone else in her office who could refill it for you?" I asked.

"I guess so," she said, "but I kept calling and pushing the button for ‘prescription refills,’ and no one ever called back."

I tried my best not to shake my head in disbelief. Victoria is an intelligent young woman. There is no language barrier. We had discussed contraception before she started therapy, and she signed all the right forms. Each month she got a pregnancy test. Each month she went online and answered the contraceptive-related questions before she could get more isotretinoin.

And when she ran out of contraceptive patches, she didn’t get them refilled.

Victoria’s story could have been worse. She might have become pregnant while still taking isotretinoin. She might have been forced to make a decision to terminate a pregnancy she otherwise would have wanted to carry to term.

Victoria’s story speaks for itself. Despite our best efforts, persuasive or bureaucratic, people will sometimes act in ways that they themselves know perfectly well are against their own interests.

The newest iPledge program upgrade includes some changes, some of which are helpful. One novelty, however, is that if "Abstinence" is the first form of contraception, "None" automatically becomes the second – there is a new warning that this is "Not recommended." This means we should not rely on a patient’s self-reported abstinence, but are better off relying on her use of artificial contraception. Perhaps. But perhaps not. Contraception only works if you use it.

Humans have what a psychiatrist I know calls "design flaws." If ever called upon to redesign the species, I’m sure many of us would contribute some good ideas. In the meantime, however, all we can do is try to acknowledge these flaws, and do our best to mitigate their impact.

After all, we have them ourselves.

Dr. Rockoff practices dermatology in Brookline, Mass. 

Until last month, I had only ever had two positive pregnancy test results in women of child-bearing age taking isotretinoin. Both of the previous reports came in on the same day, one after the other. When I called each patient to give her the results, and asked her to repeat the test, neither was at all perturbed. "If I’m pregnant," laughed one, "it would be another Immaculate Conception."

Both results turned out to be laboratory errors committed by a single technician, who was reported and rebuked. Repeat tests were negative.

Then, last month, I got another positive. Victoria had actually completed her treatment course 6 weeks earlier, and had already obtained a 30-day post-treatment test – which was negative. Then, she had another test done a few weeks later, which was positive.

I called and got her mother, who asked, "Is everything all right?" But Victoria is 19, so I just said I needed her daughter’s cell phone number.

"We had a condom accident," Victoria said when I reached her. We reviewed her case, determining the last day she had actually taken the medication. Her sexual activity had clearly taken place more than 30 days later.

I suggested she contact her gynecologist at once, to be evaluated and to have the pregnancy test repeated, and I faxed a note to that physician with the relevant details. "If pregnancy is confirmed," I told her, "I’m sure you’ll consider many things before you decide what to do. But one thing you don’t have to factor in is your isotretinoin treatment, because it was no longer in your blood when you became pregnant."

A few days later, Victoria came to my office. "I’ve decided to end the pregnancy," she said. "This just isn’t the right time."

I told her I understood. "By the way," I said, "you listed your two methods of contraception as the patch and condoms. So even if the condom failed, it looks like the patch did too."

"No," said Victoria, "I wasn’t on the patch anymore."

"What?!" I exclaimed.

"I ran out a month earlier," she said, "and my regular doctor was out on maternity leave."

"Wasn’t there anyone else in her office who could refill it for you?" I asked.

"I guess so," she said, "but I kept calling and pushing the button for ‘prescription refills,’ and no one ever called back."

I tried my best not to shake my head in disbelief. Victoria is an intelligent young woman. There is no language barrier. We had discussed contraception before she started therapy, and she signed all the right forms. Each month she got a pregnancy test. Each month she went online and answered the contraceptive-related questions before she could get more isotretinoin.

And when she ran out of contraceptive patches, she didn’t get them refilled.

Victoria’s story could have been worse. She might have become pregnant while still taking isotretinoin. She might have been forced to make a decision to terminate a pregnancy she otherwise would have wanted to carry to term.

Victoria’s story speaks for itself. Despite our best efforts, persuasive or bureaucratic, people will sometimes act in ways that they themselves know perfectly well are against their own interests.

The newest iPledge program upgrade includes some changes, some of which are helpful. One novelty, however, is that if "Abstinence" is the first form of contraception, "None" automatically becomes the second – there is a new warning that this is "Not recommended." This means we should not rely on a patient’s self-reported abstinence, but are better off relying on her use of artificial contraception. Perhaps. But perhaps not. Contraception only works if you use it.

Humans have what a psychiatrist I know calls "design flaws." If ever called upon to redesign the species, I’m sure many of us would contribute some good ideas. In the meantime, however, all we can do is try to acknowledge these flaws, and do our best to mitigate their impact.

After all, we have them ourselves.

Dr. Rockoff practices dermatology in Brookline, Mass. 

Until last month, I had only ever had two positive pregnancy test results in women of child-bearing age taking isotretinoin. Both of the previous reports came in on the same day, one after the other. When I called each patient to give her the results, and asked her to repeat the test, neither was at all perturbed. "If I’m pregnant," laughed one, "it would be another Immaculate Conception."

Both results turned out to be laboratory errors committed by a single technician, who was reported and rebuked. Repeat tests were negative.

Then, last month, I got another positive. Victoria had actually completed her treatment course 6 weeks earlier, and had already obtained a 30-day post-treatment test – which was negative. Then, she had another test done a few weeks later, which was positive.

I called and got her mother, who asked, "Is everything all right?" But Victoria is 19, so I just said I needed her daughter’s cell phone number.

"We had a condom accident," Victoria said when I reached her. We reviewed her case, determining the last day she had actually taken the medication. Her sexual activity had clearly taken place more than 30 days later.

I suggested she contact her gynecologist at once, to be evaluated and to have the pregnancy test repeated, and I faxed a note to that physician with the relevant details. "If pregnancy is confirmed," I told her, "I’m sure you’ll consider many things before you decide what to do. But one thing you don’t have to factor in is your isotretinoin treatment, because it was no longer in your blood when you became pregnant."

A few days later, Victoria came to my office. "I’ve decided to end the pregnancy," she said. "This just isn’t the right time."

I told her I understood. "By the way," I said, "you listed your two methods of contraception as the patch and condoms. So even if the condom failed, it looks like the patch did too."

"No," said Victoria, "I wasn’t on the patch anymore."

"What?!" I exclaimed.

"I ran out a month earlier," she said, "and my regular doctor was out on maternity leave."

"Wasn’t there anyone else in her office who could refill it for you?" I asked.

"I guess so," she said, "but I kept calling and pushing the button for ‘prescription refills,’ and no one ever called back."

I tried my best not to shake my head in disbelief. Victoria is an intelligent young woman. There is no language barrier. We had discussed contraception before she started therapy, and she signed all the right forms. Each month she got a pregnancy test. Each month she went online and answered the contraceptive-related questions before she could get more isotretinoin.

And when she ran out of contraceptive patches, she didn’t get them refilled.

Victoria’s story could have been worse. She might have become pregnant while still taking isotretinoin. She might have been forced to make a decision to terminate a pregnancy she otherwise would have wanted to carry to term.

Victoria’s story speaks for itself. Despite our best efforts, persuasive or bureaucratic, people will sometimes act in ways that they themselves know perfectly well are against their own interests.

The newest iPledge program upgrade includes some changes, some of which are helpful. One novelty, however, is that if "Abstinence" is the first form of contraception, "None" automatically becomes the second – there is a new warning that this is "Not recommended." This means we should not rely on a patient’s self-reported abstinence, but are better off relying on her use of artificial contraception. Perhaps. But perhaps not. Contraception only works if you use it.

Humans have what a psychiatrist I know calls "design flaws." If ever called upon to redesign the species, I’m sure many of us would contribute some good ideas. In the meantime, however, all we can do is try to acknowledge these flaws, and do our best to mitigate their impact.

After all, we have them ourselves.

Dr. Rockoff practices dermatology in Brookline, Mass. 

Managing chronic pain in an older adult can be a complicated task, with risks for adverse effects, under- or overmedication, and nonadherence. Pain can be alleviated in many cases, however, if you address potential complications and barriers to effective treatment when prescribing analgesic medications.

Pain is a part of daily life for many older adults

As many as 50% of community-dwelling older adults experience a chronic pain disorder, defined as pain on most days for at least 3 consecutive months.¹ Prevalence rates are typically higher (49%-84%) among residents of long-term care facilities.² Untreated chronic pain can lead to health consequences such as depression, decreased ability to socialize, impaired ambulation, impaired sleep, increased falls, malnutrition, and decreased quality of life.^1,3 Among older women, pain is the most common reported cause of impairment in activities of daily living.⁴

Arthritis and arthritis-related diseases (such as back pain) are common causes of chronic pain in older adults.⁵ Other causes include neuropathies, vertebral compression fractures, cancer and cancer treatments, and advanced chronic diseases such as end-stage heart, lung, and kidney disease.^6-10

Substantial literature documents that chronic pain is underdetected and undertreated with advancing age^11,12 and strongly supports efforts to improve pain care in later life. Treatment guidelines recommend a multimodal approach, including evidence-based nonpharmacologic treatments such as cognitive-behavioral therapy, exercise, and physical therapy.¹ At the same time, pharmacotherapies remain the primary treatment used by physicians,¹³ and studies indicate that older people use analgesics frequently:

• When 551 older black and non-Hispanic white adults with osteoarthritis were interviewed, more than 80% of each group reported regular use of prescription and over-the-counter (OTC) analgesic medications.¹⁴
• In a cross-sectional study of 272 community-dwelling older adults with chronic pain from diverse causes, 59% reported routine use of an analgesic medication.¹⁵

The following 6 steps can improve the likelihood of a successful analgesic trial when managing chronic pain in people ages 65 and older. They take into account barriers you are likely to encounter, including polypharmacy, multimorbidity, cognitive and sensory impairment, sociodemographic factors, specific health beliefs about pain and pain treatments, and age-related physiologic changes.

TABLE

Refine your approach to chronic pain in older patients with these 6 steps

Step 1. Conduct a comprehensive pain history

The first step in pain management is to perform a comprehensive pain assessment. Without a proper pain assessment, it will be difficult to effectively treat and monitor response to treatment. Whichever pain scale you decide to use, it is important to use the same pain scale consistently each time a pain assessment takes place.³ The numeric rating scale and verbal descriptor scales (or pain thermometer) are widely used and have been shown to be preferred in the older adult population.^3,16 The numeric rating scale asks a patient to rate his or her pain on a scale of 0 to 10, with 0 being no pain and 10 being the most severe pain imaginable. The verbal descriptor scale is a measure of pain intensity on a vertical scale (typically a thermometer) from “no pain” to “excruciating.”³

Recommendations. In addition to assessing the intensity of the pain using a pain assessment tool, it is important to determine certain characteristics of the pain. What is the location and quality of the pain? Ask patients how the pain limits them. What prior treatments have been tried and failed? What has worked the best? What treatment/coping strategies are they using now? Have they had any intolerable adverse effects from specific treatments? Reliable predictors of treatment response require further definition,¹⁷ but a successful trial of a given analgesic in the past is often a good indicator of what might work again.

Step 2. Review the patient’s problem list

Use of multiple medications. Polypharmacy—with 5 or more being a typical threshold criterion—is common in people ages 65 and older and frequently complicates the pharmacologic management of chronic pain.^16,18 Complications most often occur as a result of drug-drug interactions.

Multiple coexisting chronic conditions. Multimorbidity is common in older adults with chronic pain. Consider co-occurring diabetes, hypertension, and osteoporosis when initiating any trial of a pain medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in treating pain syndromes, but their use can be hazardous in older individuals, particularly those with coexisting hypertension, cardiovascular disease, history of peptic ulcer disease or gastropathy, or impaired renal function. NSAID use has been implicated as a cause of approximately one-quarter of all hospitalizations related to drug adverse effects among adults over age 65.¹

The geriatric syndrome of frailty is defined by deficits in physiologic reserve and decreased resistance to multiple stressors.¹⁹ Risk of fracture is a particular concern of clinicians, older patients, and their caregivers. Opioids are the analgesic medications most often associated with increased fracture risk. In a recent analysis of Medicare claims data, opioid users were found to have a significantly increased fracture risk compared with users of nonselective NSAIDs.²⁰ Mechanisms underlying this association include opioid-associated cognitive dysfunction and worsening gait/balance function.

Recommendations. Obtain a full list of the patient’s medications, including all OTC and complementary preparations. Also consider chronic kidney problems, liver disease, movement disorders, and neurologic problems when selecting a pharmacologic agent. Consider what chronic conditions might be made worse by an analgesic trial or would operate as a contraindication to starting a specific pain medication. Establish which medications or comorbidities might modify your treatment choices.

Step 3. Establish the patient’s treatment goals

We recommend shared decision-making when planning treatment and monitoring outcomes for older adults with chronic pain. Use your patient’s reports of the experience of pain— including pain intensity and how pain affects daily functioning¹ —and identify his or her treatment goals, which might differ from yours. You may be aiming for the best pain relief possible, but your patient might be focused on practical issues such as increased mobility or ability to socialize. By talking openly, you can reach consensus and agree upon realistic treatment goals.

This approach can improve patients’ outcomes and satisfaction with treatment; it also has been shown to improve physician satisfaction when treating patients with chronic pain.²¹ In a recent qualitative study, older individuals varied in how much they wanted to participate in making decisions and being a “source of control” in their pain treatment. ²² Some patients—particularly those ages 80 and older—prefer to have their physicians make treatment decisions for them, whereas others embrace active participation. Regardless of how much older individuals wish to share in treatment decisions, they all value being listened to and understood by their physicians.²¹

Recommendations. The patient’s goals and expectations for treatment may or may not be the same as yours. Before starting a medication trial, address potential unrealistic expectations such as complete relief of pain or a belief that treatment is not likely to help. Come to a mutual decision as to what constitutes the most important outcomes, and you will then be able to monitor and assess treatment success.

Step 4. Identify barriers to initiating and adhering to therapy

Cognitive impairment is a strong risk factor for undertreatment of pain. It can lead to underreporting of pain by patients or difficulty for clinicians in assessing treatment response from those who are unable to communicate pain effectively. A study of nursing home residents found that only 56% of those with cognitive impairment received pain medications, compared with 80% of those with intact cognition.²³ Older patients with cognitive deficits and memory loss also may take analgesic medications inappropriately or forget when/if they took them, increasing the risk of undertreatment or overdosing.

Sensory impairment. Patients with visual deficits may have difficulty reading prescription bottle labels and information sheets. Those with auditory deficits may have trouble hearing, communicating, and understanding treatment instructions during a busy clinical encounter.

Sociodemographic factors. Many older adults live alone and have limited social support to encourage medication adherence.²⁴ Some have significant caregiving responsibilities of their own (such as a spouse in poor health), which can lead to stress and inconsistent use of prescribed medications.²⁵ Some older adults can’t afford the costs of certain pain medications and may take less than the prescribed amount.

Many older adults lack the necessary skills to read and process basic health care information, including understanding pill bottle instructions, information that appears in patient handouts, and clinicians’ instructions about possible adverse effects.^26,27 Low health literacy can lead to problems with medication adherence (taking too much or too little of an analgesic medication) and associated complications.

Health beliefs. Many older adults believe chronic pain is a natural part of aging; in one study, this was true of 61% of approximately 700 primary care patients with osteoarthritis pain.²⁸ Some older adults believe pain only gets worse over time,²⁸ and others believe treatment for pain is not likely to provide any meaningful benefit.^29,30 Beliefs such as these can lead to stoicism or acceptance of the status quo.³¹

Older adults also may endorse beliefs about pain medications that are likely to decrease their willingness to engage in, or adhere to, recommended pharmacologic interventions. Some use pain medicines sparingly because they fear addiction or dependence.^32,33 Caregivers—often a spouse or adult child—also may express fears about the possibility of addiction.³² Finally, some older adults believe that using prescription analgesic medications invariably results in adverse effects;³² those who endorse this belief report minimizing medication use except when the pain is “very bad.”³⁴

Recommendations. Elicit concerns patients may have about using analgesic medications and discuss them openly. Although not all barriers (such as economic issues) are modifiable, most (such as beliefs that pain medications are addictive) can be successfully addressed through patient education.

If other social support, such as a family member or caregiver in the home, could positively affect analgesic engagement/adherence, include these facilitators when discussing treatment decisions and in monitoring for medication effectiveness and adverse effects.

Step 5. Start low and go slow when initiating analgesia

Advancing age is associated with increased sensitivity to the anticholinergic effects of many commonly prescribed and OTC medications, including NSAIDs and opioids.³⁵ Increasing the anticholinergic load can lead to cognitive impairments, including confusion, which can be particularly troublesome for older adults.¹

Changes in pharmacokinetics (what the body does to the drug in terms of altering absorption, distribution, metabolism and excretion) and pharmacodynamics (what the drug does to the body in the form of adverse effects) occur as a function of advancing age. ¹ Body fat increases by 20% to 40% on average, which increases the volume of distribution for fat-soluble medications.¹⁶ Hepatic and renal clearance decrease, leading to an increased half-life and decreased excretion of medications cleared by the liver or kidneys. Age-associated changes in gastrointestinal (GI) absorption and function include slower GI transit times and the possibility of increased opioid-related constipation from dysmotility problems.¹

As a result of these physiologic changes, advancing age is associated with a greater incidence of drug-related adverse effects. Even so, individuals within the older population are highly heterogeneous, and no geriatric-specific dosing guidelines exist for prescribing pain medications to older adults.

Recommendations. We recommend the adage “start low and go slow” when initiating an analgesic trial for an older patient with chronic pain. This does not mean you should “start low and stay low,” which can contribute to undertreatment.³⁶ If treatment goals are not being met and the patient is tolerating the therapy, advancing the dose is reasonable before moving on to another intervention.

Step 6. Assess for effects and outcomes outside the office

Adverse effects are a primary reason older adults discontinue an analgesic trial.³⁷ Make certain the patient (or caregiver, as appropriate) understands what adverse effects might occur, and create a plan to address them if they do.

Recommendations. Because many older people are reluctant to communicate with their physicians outside of an office visit, establish how often and when communication should occur. Telephone calls and/or e-mail are practical tools for patients to communicate questions or concerns to you, and you can enhance treatment outcomes with timely replies. In the near future, mobile health technologies may play a key role in monitoring for adverse effects and communicating positive treatment outcomes.

Managing chronic pain in an older adult can be a complicated task, with risks for adverse effects, under- or overmedication, and nonadherence. Pain can be alleviated in many cases, however, if you address potential complications and barriers to effective treatment when prescribing analgesic medications.

Pain is a part of daily life for many older adults

As many as 50% of community-dwelling older adults experience a chronic pain disorder, defined as pain on most days for at least 3 consecutive months.¹ Prevalence rates are typically higher (49%-84%) among residents of long-term care facilities.² Untreated chronic pain can lead to health consequences such as depression, decreased ability to socialize, impaired ambulation, impaired sleep, increased falls, malnutrition, and decreased quality of life.^1,3 Among older women, pain is the most common reported cause of impairment in activities of daily living.⁴

Arthritis and arthritis-related diseases (such as back pain) are common causes of chronic pain in older adults.⁵ Other causes include neuropathies, vertebral compression fractures, cancer and cancer treatments, and advanced chronic diseases such as end-stage heart, lung, and kidney disease.^6-10

Substantial literature documents that chronic pain is underdetected and undertreated with advancing age^11,12 and strongly supports efforts to improve pain care in later life. Treatment guidelines recommend a multimodal approach, including evidence-based nonpharmacologic treatments such as cognitive-behavioral therapy, exercise, and physical therapy.¹ At the same time, pharmacotherapies remain the primary treatment used by physicians,¹³ and studies indicate that older people use analgesics frequently:

• When 551 older black and non-Hispanic white adults with osteoarthritis were interviewed, more than 80% of each group reported regular use of prescription and over-the-counter (OTC) analgesic medications.¹⁴
• In a cross-sectional study of 272 community-dwelling older adults with chronic pain from diverse causes, 59% reported routine use of an analgesic medication.¹⁵

The following 6 steps can improve the likelihood of a successful analgesic trial when managing chronic pain in people ages 65 and older. They take into account barriers you are likely to encounter, including polypharmacy, multimorbidity, cognitive and sensory impairment, sociodemographic factors, specific health beliefs about pain and pain treatments, and age-related physiologic changes.

TABLE

Refine your approach to chronic pain in older patients with these 6 steps

Step 1. Conduct a comprehensive pain history

The first step in pain management is to perform a comprehensive pain assessment. Without a proper pain assessment, it will be difficult to effectively treat and monitor response to treatment. Whichever pain scale you decide to use, it is important to use the same pain scale consistently each time a pain assessment takes place.³ The numeric rating scale and verbal descriptor scales (or pain thermometer) are widely used and have been shown to be preferred in the older adult population.^3,16 The numeric rating scale asks a patient to rate his or her pain on a scale of 0 to 10, with 0 being no pain and 10 being the most severe pain imaginable. The verbal descriptor scale is a measure of pain intensity on a vertical scale (typically a thermometer) from “no pain” to “excruciating.”³

Recommendations. In addition to assessing the intensity of the pain using a pain assessment tool, it is important to determine certain characteristics of the pain. What is the location and quality of the pain? Ask patients how the pain limits them. What prior treatments have been tried and failed? What has worked the best? What treatment/coping strategies are they using now? Have they had any intolerable adverse effects from specific treatments? Reliable predictors of treatment response require further definition,¹⁷ but a successful trial of a given analgesic in the past is often a good indicator of what might work again.

Step 2. Review the patient’s problem list

Use of multiple medications. Polypharmacy—with 5 or more being a typical threshold criterion—is common in people ages 65 and older and frequently complicates the pharmacologic management of chronic pain.^16,18 Complications most often occur as a result of drug-drug interactions.

Multiple coexisting chronic conditions. Multimorbidity is common in older adults with chronic pain. Consider co-occurring diabetes, hypertension, and osteoporosis when initiating any trial of a pain medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in treating pain syndromes, but their use can be hazardous in older individuals, particularly those with coexisting hypertension, cardiovascular disease, history of peptic ulcer disease or gastropathy, or impaired renal function. NSAID use has been implicated as a cause of approximately one-quarter of all hospitalizations related to drug adverse effects among adults over age 65.¹

The geriatric syndrome of frailty is defined by deficits in physiologic reserve and decreased resistance to multiple stressors.¹⁹ Risk of fracture is a particular concern of clinicians, older patients, and their caregivers. Opioids are the analgesic medications most often associated with increased fracture risk. In a recent analysis of Medicare claims data, opioid users were found to have a significantly increased fracture risk compared with users of nonselective NSAIDs.²⁰ Mechanisms underlying this association include opioid-associated cognitive dysfunction and worsening gait/balance function.

Recommendations. Obtain a full list of the patient’s medications, including all OTC and complementary preparations. Also consider chronic kidney problems, liver disease, movement disorders, and neurologic problems when selecting a pharmacologic agent. Consider what chronic conditions might be made worse by an analgesic trial or would operate as a contraindication to starting a specific pain medication. Establish which medications or comorbidities might modify your treatment choices.

Step 3. Establish the patient’s treatment goals

We recommend shared decision-making when planning treatment and monitoring outcomes for older adults with chronic pain. Use your patient’s reports of the experience of pain— including pain intensity and how pain affects daily functioning¹ —and identify his or her treatment goals, which might differ from yours. You may be aiming for the best pain relief possible, but your patient might be focused on practical issues such as increased mobility or ability to socialize. By talking openly, you can reach consensus and agree upon realistic treatment goals.

This approach can improve patients’ outcomes and satisfaction with treatment; it also has been shown to improve physician satisfaction when treating patients with chronic pain.²¹ In a recent qualitative study, older individuals varied in how much they wanted to participate in making decisions and being a “source of control” in their pain treatment. ²² Some patients—particularly those ages 80 and older—prefer to have their physicians make treatment decisions for them, whereas others embrace active participation. Regardless of how much older individuals wish to share in treatment decisions, they all value being listened to and understood by their physicians.²¹

Recommendations. The patient’s goals and expectations for treatment may or may not be the same as yours. Before starting a medication trial, address potential unrealistic expectations such as complete relief of pain or a belief that treatment is not likely to help. Come to a mutual decision as to what constitutes the most important outcomes, and you will then be able to monitor and assess treatment success.

Step 4. Identify barriers to initiating and adhering to therapy

Cognitive impairment is a strong risk factor for undertreatment of pain. It can lead to underreporting of pain by patients or difficulty for clinicians in assessing treatment response from those who are unable to communicate pain effectively. A study of nursing home residents found that only 56% of those with cognitive impairment received pain medications, compared with 80% of those with intact cognition.²³ Older patients with cognitive deficits and memory loss also may take analgesic medications inappropriately or forget when/if they took them, increasing the risk of undertreatment or overdosing.

Sensory impairment. Patients with visual deficits may have difficulty reading prescription bottle labels and information sheets. Those with auditory deficits may have trouble hearing, communicating, and understanding treatment instructions during a busy clinical encounter.

Sociodemographic factors. Many older adults live alone and have limited social support to encourage medication adherence.²⁴ Some have significant caregiving responsibilities of their own (such as a spouse in poor health), which can lead to stress and inconsistent use of prescribed medications.²⁵ Some older adults can’t afford the costs of certain pain medications and may take less than the prescribed amount.

Many older adults lack the necessary skills to read and process basic health care information, including understanding pill bottle instructions, information that appears in patient handouts, and clinicians’ instructions about possible adverse effects.^26,27 Low health literacy can lead to problems with medication adherence (taking too much or too little of an analgesic medication) and associated complications.

Health beliefs. Many older adults believe chronic pain is a natural part of aging; in one study, this was true of 61% of approximately 700 primary care patients with osteoarthritis pain.²⁸ Some older adults believe pain only gets worse over time,²⁸ and others believe treatment for pain is not likely to provide any meaningful benefit.^29,30 Beliefs such as these can lead to stoicism or acceptance of the status quo.³¹

Older adults also may endorse beliefs about pain medications that are likely to decrease their willingness to engage in, or adhere to, recommended pharmacologic interventions. Some use pain medicines sparingly because they fear addiction or dependence.^32,33 Caregivers—often a spouse or adult child—also may express fears about the possibility of addiction.³² Finally, some older adults believe that using prescription analgesic medications invariably results in adverse effects;³² those who endorse this belief report minimizing medication use except when the pain is “very bad.”³⁴

Recommendations. Elicit concerns patients may have about using analgesic medications and discuss them openly. Although not all barriers (such as economic issues) are modifiable, most (such as beliefs that pain medications are addictive) can be successfully addressed through patient education.

If other social support, such as a family member or caregiver in the home, could positively affect analgesic engagement/adherence, include these facilitators when discussing treatment decisions and in monitoring for medication effectiveness and adverse effects.

Step 5. Start low and go slow when initiating analgesia

Advancing age is associated with increased sensitivity to the anticholinergic effects of many commonly prescribed and OTC medications, including NSAIDs and opioids.³⁵ Increasing the anticholinergic load can lead to cognitive impairments, including confusion, which can be particularly troublesome for older adults.¹

Changes in pharmacokinetics (what the body does to the drug in terms of altering absorption, distribution, metabolism and excretion) and pharmacodynamics (what the drug does to the body in the form of adverse effects) occur as a function of advancing age. ¹ Body fat increases by 20% to 40% on average, which increases the volume of distribution for fat-soluble medications.¹⁶ Hepatic and renal clearance decrease, leading to an increased half-life and decreased excretion of medications cleared by the liver or kidneys. Age-associated changes in gastrointestinal (GI) absorption and function include slower GI transit times and the possibility of increased opioid-related constipation from dysmotility problems.¹

As a result of these physiologic changes, advancing age is associated with a greater incidence of drug-related adverse effects. Even so, individuals within the older population are highly heterogeneous, and no geriatric-specific dosing guidelines exist for prescribing pain medications to older adults.

Recommendations. We recommend the adage “start low and go slow” when initiating an analgesic trial for an older patient with chronic pain. This does not mean you should “start low and stay low,” which can contribute to undertreatment.³⁶ If treatment goals are not being met and the patient is tolerating the therapy, advancing the dose is reasonable before moving on to another intervention.

Step 6. Assess for effects and outcomes outside the office

Adverse effects are a primary reason older adults discontinue an analgesic trial.³⁷ Make certain the patient (or caregiver, as appropriate) understands what adverse effects might occur, and create a plan to address them if they do.

Recommendations. Because many older people are reluctant to communicate with their physicians outside of an office visit, establish how often and when communication should occur. Telephone calls and/or e-mail are practical tools for patients to communicate questions or concerns to you, and you can enhance treatment outcomes with timely replies. In the near future, mobile health technologies may play a key role in monitoring for adverse effects and communicating positive treatment outcomes.

Managing chronic pain in an older adult can be a complicated task, with risks for adverse effects, under- or overmedication, and nonadherence. Pain can be alleviated in many cases, however, if you address potential complications and barriers to effective treatment when prescribing analgesic medications.

Pain is a part of daily life for many older adults

As many as 50% of community-dwelling older adults experience a chronic pain disorder, defined as pain on most days for at least 3 consecutive months.¹ Prevalence rates are typically higher (49%-84%) among residents of long-term care facilities.² Untreated chronic pain can lead to health consequences such as depression, decreased ability to socialize, impaired ambulation, impaired sleep, increased falls, malnutrition, and decreased quality of life.^1,3 Among older women, pain is the most common reported cause of impairment in activities of daily living.⁴

Arthritis and arthritis-related diseases (such as back pain) are common causes of chronic pain in older adults.⁵ Other causes include neuropathies, vertebral compression fractures, cancer and cancer treatments, and advanced chronic diseases such as end-stage heart, lung, and kidney disease.^6-10

Substantial literature documents that chronic pain is underdetected and undertreated with advancing age^11,12 and strongly supports efforts to improve pain care in later life. Treatment guidelines recommend a multimodal approach, including evidence-based nonpharmacologic treatments such as cognitive-behavioral therapy, exercise, and physical therapy.¹ At the same time, pharmacotherapies remain the primary treatment used by physicians,¹³ and studies indicate that older people use analgesics frequently:

• When 551 older black and non-Hispanic white adults with osteoarthritis were interviewed, more than 80% of each group reported regular use of prescription and over-the-counter (OTC) analgesic medications.¹⁴
• In a cross-sectional study of 272 community-dwelling older adults with chronic pain from diverse causes, 59% reported routine use of an analgesic medication.¹⁵

The following 6 steps can improve the likelihood of a successful analgesic trial when managing chronic pain in people ages 65 and older. They take into account barriers you are likely to encounter, including polypharmacy, multimorbidity, cognitive and sensory impairment, sociodemographic factors, specific health beliefs about pain and pain treatments, and age-related physiologic changes.

TABLE

Refine your approach to chronic pain in older patients with these 6 steps

Step 1. Conduct a comprehensive pain history

The first step in pain management is to perform a comprehensive pain assessment. Without a proper pain assessment, it will be difficult to effectively treat and monitor response to treatment. Whichever pain scale you decide to use, it is important to use the same pain scale consistently each time a pain assessment takes place.³ The numeric rating scale and verbal descriptor scales (or pain thermometer) are widely used and have been shown to be preferred in the older adult population.^3,16 The numeric rating scale asks a patient to rate his or her pain on a scale of 0 to 10, with 0 being no pain and 10 being the most severe pain imaginable. The verbal descriptor scale is a measure of pain intensity on a vertical scale (typically a thermometer) from “no pain” to “excruciating.”³

Recommendations. In addition to assessing the intensity of the pain using a pain assessment tool, it is important to determine certain characteristics of the pain. What is the location and quality of the pain? Ask patients how the pain limits them. What prior treatments have been tried and failed? What has worked the best? What treatment/coping strategies are they using now? Have they had any intolerable adverse effects from specific treatments? Reliable predictors of treatment response require further definition,¹⁷ but a successful trial of a given analgesic in the past is often a good indicator of what might work again.

Step 2. Review the patient’s problem list

Use of multiple medications. Polypharmacy—with 5 or more being a typical threshold criterion—is common in people ages 65 and older and frequently complicates the pharmacologic management of chronic pain.^16,18 Complications most often occur as a result of drug-drug interactions.

Multiple coexisting chronic conditions. Multimorbidity is common in older adults with chronic pain. Consider co-occurring diabetes, hypertension, and osteoporosis when initiating any trial of a pain medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in treating pain syndromes, but their use can be hazardous in older individuals, particularly those with coexisting hypertension, cardiovascular disease, history of peptic ulcer disease or gastropathy, or impaired renal function. NSAID use has been implicated as a cause of approximately one-quarter of all hospitalizations related to drug adverse effects among adults over age 65.¹

The geriatric syndrome of frailty is defined by deficits in physiologic reserve and decreased resistance to multiple stressors.¹⁹ Risk of fracture is a particular concern of clinicians, older patients, and their caregivers. Opioids are the analgesic medications most often associated with increased fracture risk. In a recent analysis of Medicare claims data, opioid users were found to have a significantly increased fracture risk compared with users of nonselective NSAIDs.²⁰ Mechanisms underlying this association include opioid-associated cognitive dysfunction and worsening gait/balance function.

Recommendations. Obtain a full list of the patient’s medications, including all OTC and complementary preparations. Also consider chronic kidney problems, liver disease, movement disorders, and neurologic problems when selecting a pharmacologic agent. Consider what chronic conditions might be made worse by an analgesic trial or would operate as a contraindication to starting a specific pain medication. Establish which medications or comorbidities might modify your treatment choices.

Step 3. Establish the patient’s treatment goals

We recommend shared decision-making when planning treatment and monitoring outcomes for older adults with chronic pain. Use your patient’s reports of the experience of pain— including pain intensity and how pain affects daily functioning¹ —and identify his or her treatment goals, which might differ from yours. You may be aiming for the best pain relief possible, but your patient might be focused on practical issues such as increased mobility or ability to socialize. By talking openly, you can reach consensus and agree upon realistic treatment goals.

This approach can improve patients’ outcomes and satisfaction with treatment; it also has been shown to improve physician satisfaction when treating patients with chronic pain.²¹ In a recent qualitative study, older individuals varied in how much they wanted to participate in making decisions and being a “source of control” in their pain treatment. ²² Some patients—particularly those ages 80 and older—prefer to have their physicians make treatment decisions for them, whereas others embrace active participation. Regardless of how much older individuals wish to share in treatment decisions, they all value being listened to and understood by their physicians.²¹

Recommendations. The patient’s goals and expectations for treatment may or may not be the same as yours. Before starting a medication trial, address potential unrealistic expectations such as complete relief of pain or a belief that treatment is not likely to help. Come to a mutual decision as to what constitutes the most important outcomes, and you will then be able to monitor and assess treatment success.

Step 4. Identify barriers to initiating and adhering to therapy

Cognitive impairment is a strong risk factor for undertreatment of pain. It can lead to underreporting of pain by patients or difficulty for clinicians in assessing treatment response from those who are unable to communicate pain effectively. A study of nursing home residents found that only 56% of those with cognitive impairment received pain medications, compared with 80% of those with intact cognition.²³ Older patients with cognitive deficits and memory loss also may take analgesic medications inappropriately or forget when/if they took them, increasing the risk of undertreatment or overdosing.

Sensory impairment. Patients with visual deficits may have difficulty reading prescription bottle labels and information sheets. Those with auditory deficits may have trouble hearing, communicating, and understanding treatment instructions during a busy clinical encounter.

Sociodemographic factors. Many older adults live alone and have limited social support to encourage medication adherence.²⁴ Some have significant caregiving responsibilities of their own (such as a spouse in poor health), which can lead to stress and inconsistent use of prescribed medications.²⁵ Some older adults can’t afford the costs of certain pain medications and may take less than the prescribed amount.

Many older adults lack the necessary skills to read and process basic health care information, including understanding pill bottle instructions, information that appears in patient handouts, and clinicians’ instructions about possible adverse effects.^26,27 Low health literacy can lead to problems with medication adherence (taking too much or too little of an analgesic medication) and associated complications.

Health beliefs. Many older adults believe chronic pain is a natural part of aging; in one study, this was true of 61% of approximately 700 primary care patients with osteoarthritis pain.²⁸ Some older adults believe pain only gets worse over time,²⁸ and others believe treatment for pain is not likely to provide any meaningful benefit.^29,30 Beliefs such as these can lead to stoicism or acceptance of the status quo.³¹

Older adults also may endorse beliefs about pain medications that are likely to decrease their willingness to engage in, or adhere to, recommended pharmacologic interventions. Some use pain medicines sparingly because they fear addiction or dependence.^32,33 Caregivers—often a spouse or adult child—also may express fears about the possibility of addiction.³² Finally, some older adults believe that using prescription analgesic medications invariably results in adverse effects;³² those who endorse this belief report minimizing medication use except when the pain is “very bad.”³⁴

Recommendations. Elicit concerns patients may have about using analgesic medications and discuss them openly. Although not all barriers (such as economic issues) are modifiable, most (such as beliefs that pain medications are addictive) can be successfully addressed through patient education.

If other social support, such as a family member or caregiver in the home, could positively affect analgesic engagement/adherence, include these facilitators when discussing treatment decisions and in monitoring for medication effectiveness and adverse effects.

Step 5. Start low and go slow when initiating analgesia

Advancing age is associated with increased sensitivity to the anticholinergic effects of many commonly prescribed and OTC medications, including NSAIDs and opioids.³⁵ Increasing the anticholinergic load can lead to cognitive impairments, including confusion, which can be particularly troublesome for older adults.¹

Changes in pharmacokinetics (what the body does to the drug in terms of altering absorption, distribution, metabolism and excretion) and pharmacodynamics (what the drug does to the body in the form of adverse effects) occur as a function of advancing age. ¹ Body fat increases by 20% to 40% on average, which increases the volume of distribution for fat-soluble medications.¹⁶ Hepatic and renal clearance decrease, leading to an increased half-life and decreased excretion of medications cleared by the liver or kidneys. Age-associated changes in gastrointestinal (GI) absorption and function include slower GI transit times and the possibility of increased opioid-related constipation from dysmotility problems.¹

As a result of these physiologic changes, advancing age is associated with a greater incidence of drug-related adverse effects. Even so, individuals within the older population are highly heterogeneous, and no geriatric-specific dosing guidelines exist for prescribing pain medications to older adults.

Recommendations. We recommend the adage “start low and go slow” when initiating an analgesic trial for an older patient with chronic pain. This does not mean you should “start low and stay low,” which can contribute to undertreatment.³⁶ If treatment goals are not being met and the patient is tolerating the therapy, advancing the dose is reasonable before moving on to another intervention.

Step 6. Assess for effects and outcomes outside the office

Adverse effects are a primary reason older adults discontinue an analgesic trial.³⁷ Make certain the patient (or caregiver, as appropriate) understands what adverse effects might occur, and create a plan to address them if they do.

Recommendations. Because many older people are reluctant to communicate with their physicians outside of an office visit, establish how often and when communication should occur. Telephone calls and/or e-mail are practical tools for patients to communicate questions or concerns to you, and you can enhance treatment outcomes with timely replies. In the near future, mobile health technologies may play a key role in monitoring for adverse effects and communicating positive treatment outcomes.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams & Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams &amp; Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams &amp; Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.