Drug Therapy

Experts have argued for decades about how best to manage opiate dependence, with practitioners generally subscribing to one of two strategies: either total abstinence or medication-assisted treatment (MAT).

Although MAT has proven efficacy, it has been slow to gain acceptance, and the gold standard of care since the 1930s has been abstinence-based treatment. Among elite institutional holdouts against MAT was the Hazelden Treatment Center, a leading treatment institution and publishing house that had been wedded to the abstinence model since it was founded in 1949.¹ Now, Hazelden has gone on record as embracing MAT, raising the possibility that the two predominant treatment philosophies for opiate-dependent patients may no longer be at odds.

FROM ABSTINENCE TO METHADONE MAINTENANCE

The modern day abstinence-based movement in this country started in the decade before the founding of Hazelden. In 1935, the US government opened the first of two federal drug treatment centers, known as the United States Narcotic Farm, in Lexington, KY.² The move by the government to get into the addiction treatment business largely stemmed from frustration over the growing problem of addiction at that time, coupled with a dearth of treatment options for addicts in the wake of the 1914 Harrison Narcotics Act.

The Narcotic Farm was an impressive facility—for all intents and purposes, a specialized prison—that initially housed 1,200 people. In addition to prisoners, it also accepted voluntary, nonprisoner patients. In many ways, it was ahead of its time. It offered a wide variety of services, including detoxification, group therapy, individual therapy, psychiatric and medical services, and vocational rehabilitation.² Housed on the premises was the Addiction Research Center at Lexington, the first intramural research branch of the National Institute of Mental Health. After the “Blue Grass” mandatory commitment laws were passed in the 1940s, even the voluntary patients were ultimately committed for a 1-year sentence at Lexington. This facility, and its sister facility in Ft. Worth, TX, would have been the envy of any modern-day abstinence-based treatment center in terms of the services offered and the long lengths of stay.

The quality of the program, as evidenced by the impressive array of services and long stays, would lead one to expect that its treatment outcomes over nearly 40 years of operation were equally stellar. However, in terms of outcomes the Farm was an abysmal failure, as shown by numerous studies demonstrating relapse rates of more than 90% in the patients discharged from it.^2,3

Similar frustrations at other abstinence-based treatment centers from the 1940s through the 1960s led Dr. Vincent Dole, the “father of methadone maintenance,” to conclude in 1971 that after detoxification from opiates, “human addicts almost always return to use of narcotics after they leave the hospital where they have been detoxified.”⁴ That realization inspired Dr. Dole and his wife and colleague Dr. Marie Nyswander to revisit the idea of medication-assisted treatment, an approach previously used by the morphine maintenance clinics of the early 1900s. This work led to the development of government-sanctioned methadone clinics across America and to the realization that long-term recovery was possible with medication, even without a lengthy hospital stay. For this revolutionary work on opiate addiction, Dr. Dole won the prestigious Lasker Award in 1988.

The major reason for the success of methadone was that, because of its pharmacokinetic profile, it could stabilize the patient through once-daily dosing without sedation or narcosis. As noted by Dr. Dole, once patients are on a stable dosing regimen, the obsessive preoccupation with drug use fades away.⁵

Despite its success, methadone maintenance had its share of detractors. It was fraught with controversy because it was viewed as a crutch, and those who were on it were often not considered by their abstinent peers as being in true recovery. The reasons for the negative attitudes toward MAT are unclear but may reflect antiquated beliefs that addiction may be indicative of a failure of morals or will, and that patients ought to be able to simply stop using.

Whatever the reason for the animosity surrounding MAT, it should be noted that an expert consensus panel convened by the Betty Ford Center in 2007 agreed that patients on MAT met their consensus definition of sobriety.⁶ The issue of what constitutes recovery remains a very complex and hotly debated topic that is beyond the scope of this paper and that has been discussed elsewhere.^6,7

For more than 3 decades, methadone was the only medication available for MAT. Federal regulations limit the dispensing of methadone to licensed clinics, most of which are located in major metropolitan areas. Patients must go to the clinic every day to receive their dose of methadone—a major inconvenience, especially to those with transportation issues. Adding to the lack of appeal of methadone maintenance is that the clinics are typically located in the higher-crime areas of cities. Savvy drug dealers know the location of these clinics and often loiter on nearby street corners in an attempt to lure addicts away from recovery by flaunting their illicit drugs.

A final, very significant drawback of methadone is its safety profile. It is a full-agonist narcotic that can be fatal in overdose or in the induction phase, especially if taken with other drugs, such as benzodiazepines.

2003: BUPRENORPHINE-NALOXONE IS APPROVED

Such concerns led researchers to search for other medications to be used for MAT that could perhaps be prescribed in a typical outpatient physician practice. For many reasons, buprenorphine became the most promising candidate. In 2003, the US Food and Drug Administration approved the combination medication buprenorphine-naloxone (Sub-oxone) as only the second drug indicated for maintenance treatment of opioid dependence in the United States.

Buprenorphine differs from methadone in that it is a partial agonist at mu opiate receptors, and therefore has a “ceiling” or “plateau” effect in terms of dose-response and a much improved safety profile. Unlike methadone, buprenorphine can be prescribed in a doctor’s office and does not have to be dispensed at a government-approved clinic.

Unfortunately, buprenorphine-maintained patients seem to carry the same stigma in the recovery community as those maintained on methadone—that they are simply substituting one drug for another. Detractors usually fail to consider that, as with methadone, patients do not report getting “high” from taking buprenorphine. Patients will often state that when they first start taking it, they “feel something,” but after a few days of adjustment, they simply feel normal. They don’t feel high, they are no longer in withdrawal, their cravings are virtually eliminated, and their opiate receptors are effectively occupied and blocked, so there is no “high” in the event of a relapse.

What’s more, buprenorphine is not a medication that will help them deal with life’s stressors by “chemical coping.” Sober coping is a skill they must learn by actively participating in a solid 12-step-based recovery program and, in some cases, in psychotherapy. By removing the drug obsession, buprenorphine promotes and facilitates the important recovery goal of learning how to deal with life on life’s terms.

ADDICTION AS CHRONIC ILLNESS

Outcomes studies of addiction treatment have focused largely on rates of relapse after discharge from acute treatments such as residential rehabilitation, partial hospitalization, and intensive outpatient programs. With MAT, however, outcomes research has primarily looked at the duration of retention in treatment.

The change in focus between the two types of treatment coincides with a paradigm shift that views addiction as a chronic condition that requires ongoing care. Continued participation in prescribed care with demonstrated efficacy is considered to be the major indicator of success. Under the chronic illness model employed by MAT providers, if a patient reverted to briefly using a drug of abuse, this would be an issue to address in his ongoing treatment and would not necessarily indicate treatment failure as with the acute care model. Beyond retention rates, research has demonstrated that MAT with methadone results in reductions in rates of criminal activity, illicit drug use, acquisition of human immunodeficiency virus, and overall mortality.^8–10

In outcomes studies, MAT has repeatedly shown better efficacy than abstinence-based approaches. During the first 5 years of its implementation, in 4,000 patients, methadone maintenance boasted 1-year retention rates exceeding 98%.¹¹ Over the subsequent 3 years, with the number of patients approaching 35,000, the 1-year retention rates fell to around 60%—still far exceeding results of abstinence-based treatment and approximating the number cited in most modern studies.¹¹

The retention rates in buprenorphine programs are similarly promising. Studies of 12 to 13 weeks duration have shown retention rates of 52% to 79%.^12–15 Six-month studies have demonstrated retention rates of 43% to 100%.^16–19 Another study showed that 38% of opiate-dependent patients remained in treatment with buprenorphine at 5 years.²⁰ Surprisingly, most of the buprenorphine studies have been conducted in office-based practices, which are less structured than outpatient methadone programs.

MEDICATION-ASSISTED TREATMENT IS GAINING ACCEPTANCE

Data from decades of experience with MAT strongly support the conclusion that it is superior to abstinence-based approaches.

The importance of a patient staying in treatment cannot be overemphasized, as the consequence of failing in recovery may well be an early death. On average, heroin addicts lose about 18 years of life expectancy, and the mortality rate for injection users is roughly 2% per year.²¹ The mortality rate for heroin users is 6 to 20 times greater than for age-matched peers who are not drug users.²²

As high as these numbers are, they are even higher for abusers of prescription narcotics. The annual death rate associated with opioid pain relievers (4.8 per 100,000) is nearly double that associated with illicit drugs (2.8 per 100,000).²³

The recent and rather radical change in treatment philosophy by Hazelden came as a shock to some, a disappointment to others, and a welcome change to many who saw this as a move by one of the more respected treatment centers in the country to fall in line with the body of evidence that supports MAT for those suffering from opiate dependence. It remains a mystery why so many, if not most, addiction treatment centers in the United States cling to the abstinence-based philosophy despite the overwhelming data from decades of research and experience that show that abstinence does not work for the majority of opiate addicts.

Complete abstinence from opiate drugs of abuse and potentially addictive medications is a noble but perhaps unreachable goal for many sufferers. Hazelden’s announced acceptance of MAT gives credence to the value of recovery goals that are not entirely drug-free.

Dr. Dole was correct in stating that opiate addicts usually return to drugs if not provided with MAT. Treatment programs need to inform opiate-dependent patients that abstinence-based treatment offers only a 1 in 10 chance of success. Perhaps some patients, armed with the daunting statistics regarding abstinence, will be inspired to devote themselves wholeheartedly to their recovery in an effort to make it into that elite 10% group that achieves long-lasting recovery without the aid of medications. But for the other 90%, it is encouraging to hear that Hazelden, the model treatment center for most abstinence-based programs in this country, may now lead other abstinence-based centers to reconsider their treatment philosophies.

Historically, US doctors were not allowed by federal law to prescribe opiates for addiction treatment. With the passage of DATA 2000, buprenorphine (alone or in combination with naloxone) can be prescribed for addiction treatment only by providers who obtain a waiver from the US Drug Enforcement Administration (DEA). Any doctor can become qualified to prescribe buprenorphine or buprenorphinenaloxone after completing an 8-hour online training course (available at www.buppractice.com and at www.aaap.org/buprenorphine) and by obtaining a DATA 2000 waiver and a new prescribing number from the DEA. Doctors are initially limited to treating only 30 patients with buprenorphine-naloxone at any given time, but can apply for an extension to 100 patients after having had their waiver for 1 year.

As MAT continues to gain favor, demand will grow for more providers to obtain their waivers to prescribe buprenorphine and buprenorphine-naloxone. Historically, there have always been too few methadone clinics to meet the demand. One can hope that the growing number of waivered providers will greatly improve access to care by opiate addicts, no matter where they reside. Qualified prescribers of buprenorphine and buprenorphine-naloxone are limited by the federal restrictions on the numbers of patients they can treat. If the chronic disease of addiction is to be integrated into the continuing-care approach of modern medicine and managed alongside other chronic diseases, primary care providers who are not specialized in treating addiction will need to be become comfortable with maintaining patients on buprenorphine-naloxone.⁷ Presumably, such patients will have already been stabilized through participation in addiction treatment programs in their respective geographic areas. Primary care providers will need to develop relationships with local addictionologists and treatment programs so that they will be able to refer those in active addiction for induction and stabilization on MAT and will be able to refer those already stabilized on MAT back to such specialists when relapses occur.

We may finally be approaching a time when structured residential treatment and MAT are not mutually exclusive options for our patients. These treatment options must work together for optimal outcomes. Based on our experience with hundreds of patients at Cleveland Clinic’s Alcohol and Drug Recovery Center, we believe this change of treatment philosophy is long overdue. In clinical settings, patients do not fit cleanly into one treatment arm or another and often require a blended approach to effect long-lasting change. Hazelden’s shift of treatment philosophy is an indication that this research-supported viewpoint is gaining acceptance in the traditionally drug-free halls of addiction treatment programs.

Experts have argued for decades about how best to manage opiate dependence, with practitioners generally subscribing to one of two strategies: either total abstinence or medication-assisted treatment (MAT).

Although MAT has proven efficacy, it has been slow to gain acceptance, and the gold standard of care since the 1930s has been abstinence-based treatment. Among elite institutional holdouts against MAT was the Hazelden Treatment Center, a leading treatment institution and publishing house that had been wedded to the abstinence model since it was founded in 1949.¹ Now, Hazelden has gone on record as embracing MAT, raising the possibility that the two predominant treatment philosophies for opiate-dependent patients may no longer be at odds.

FROM ABSTINENCE TO METHADONE MAINTENANCE

The modern day abstinence-based movement in this country started in the decade before the founding of Hazelden. In 1935, the US government opened the first of two federal drug treatment centers, known as the United States Narcotic Farm, in Lexington, KY.² The move by the government to get into the addiction treatment business largely stemmed from frustration over the growing problem of addiction at that time, coupled with a dearth of treatment options for addicts in the wake of the 1914 Harrison Narcotics Act.

The Narcotic Farm was an impressive facility—for all intents and purposes, a specialized prison—that initially housed 1,200 people. In addition to prisoners, it also accepted voluntary, nonprisoner patients. In many ways, it was ahead of its time. It offered a wide variety of services, including detoxification, group therapy, individual therapy, psychiatric and medical services, and vocational rehabilitation.² Housed on the premises was the Addiction Research Center at Lexington, the first intramural research branch of the National Institute of Mental Health. After the “Blue Grass” mandatory commitment laws were passed in the 1940s, even the voluntary patients were ultimately committed for a 1-year sentence at Lexington. This facility, and its sister facility in Ft. Worth, TX, would have been the envy of any modern-day abstinence-based treatment center in terms of the services offered and the long lengths of stay.

The quality of the program, as evidenced by the impressive array of services and long stays, would lead one to expect that its treatment outcomes over nearly 40 years of operation were equally stellar. However, in terms of outcomes the Farm was an abysmal failure, as shown by numerous studies demonstrating relapse rates of more than 90% in the patients discharged from it.^2,3

Similar frustrations at other abstinence-based treatment centers from the 1940s through the 1960s led Dr. Vincent Dole, the “father of methadone maintenance,” to conclude in 1971 that after detoxification from opiates, “human addicts almost always return to use of narcotics after they leave the hospital where they have been detoxified.”⁴ That realization inspired Dr. Dole and his wife and colleague Dr. Marie Nyswander to revisit the idea of medication-assisted treatment, an approach previously used by the morphine maintenance clinics of the early 1900s. This work led to the development of government-sanctioned methadone clinics across America and to the realization that long-term recovery was possible with medication, even without a lengthy hospital stay. For this revolutionary work on opiate addiction, Dr. Dole won the prestigious Lasker Award in 1988.

The major reason for the success of methadone was that, because of its pharmacokinetic profile, it could stabilize the patient through once-daily dosing without sedation or narcosis. As noted by Dr. Dole, once patients are on a stable dosing regimen, the obsessive preoccupation with drug use fades away.⁵

Despite its success, methadone maintenance had its share of detractors. It was fraught with controversy because it was viewed as a crutch, and those who were on it were often not considered by their abstinent peers as being in true recovery. The reasons for the negative attitudes toward MAT are unclear but may reflect antiquated beliefs that addiction may be indicative of a failure of morals or will, and that patients ought to be able to simply stop using.

Whatever the reason for the animosity surrounding MAT, it should be noted that an expert consensus panel convened by the Betty Ford Center in 2007 agreed that patients on MAT met their consensus definition of sobriety.⁶ The issue of what constitutes recovery remains a very complex and hotly debated topic that is beyond the scope of this paper and that has been discussed elsewhere.^6,7

For more than 3 decades, methadone was the only medication available for MAT. Federal regulations limit the dispensing of methadone to licensed clinics, most of which are located in major metropolitan areas. Patients must go to the clinic every day to receive their dose of methadone—a major inconvenience, especially to those with transportation issues. Adding to the lack of appeal of methadone maintenance is that the clinics are typically located in the higher-crime areas of cities. Savvy drug dealers know the location of these clinics and often loiter on nearby street corners in an attempt to lure addicts away from recovery by flaunting their illicit drugs.

A final, very significant drawback of methadone is its safety profile. It is a full-agonist narcotic that can be fatal in overdose or in the induction phase, especially if taken with other drugs, such as benzodiazepines.

2003: BUPRENORPHINE-NALOXONE IS APPROVED

Such concerns led researchers to search for other medications to be used for MAT that could perhaps be prescribed in a typical outpatient physician practice. For many reasons, buprenorphine became the most promising candidate. In 2003, the US Food and Drug Administration approved the combination medication buprenorphine-naloxone (Sub-oxone) as only the second drug indicated for maintenance treatment of opioid dependence in the United States.

Buprenorphine differs from methadone in that it is a partial agonist at mu opiate receptors, and therefore has a “ceiling” or “plateau” effect in terms of dose-response and a much improved safety profile. Unlike methadone, buprenorphine can be prescribed in a doctor’s office and does not have to be dispensed at a government-approved clinic.

Unfortunately, buprenorphine-maintained patients seem to carry the same stigma in the recovery community as those maintained on methadone—that they are simply substituting one drug for another. Detractors usually fail to consider that, as with methadone, patients do not report getting “high” from taking buprenorphine. Patients will often state that when they first start taking it, they “feel something,” but after a few days of adjustment, they simply feel normal. They don’t feel high, they are no longer in withdrawal, their cravings are virtually eliminated, and their opiate receptors are effectively occupied and blocked, so there is no “high” in the event of a relapse.

What’s more, buprenorphine is not a medication that will help them deal with life’s stressors by “chemical coping.” Sober coping is a skill they must learn by actively participating in a solid 12-step-based recovery program and, in some cases, in psychotherapy. By removing the drug obsession, buprenorphine promotes and facilitates the important recovery goal of learning how to deal with life on life’s terms.

ADDICTION AS CHRONIC ILLNESS

Outcomes studies of addiction treatment have focused largely on rates of relapse after discharge from acute treatments such as residential rehabilitation, partial hospitalization, and intensive outpatient programs. With MAT, however, outcomes research has primarily looked at the duration of retention in treatment.

The change in focus between the two types of treatment coincides with a paradigm shift that views addiction as a chronic condition that requires ongoing care. Continued participation in prescribed care with demonstrated efficacy is considered to be the major indicator of success. Under the chronic illness model employed by MAT providers, if a patient reverted to briefly using a drug of abuse, this would be an issue to address in his ongoing treatment and would not necessarily indicate treatment failure as with the acute care model. Beyond retention rates, research has demonstrated that MAT with methadone results in reductions in rates of criminal activity, illicit drug use, acquisition of human immunodeficiency virus, and overall mortality.^8–10

In outcomes studies, MAT has repeatedly shown better efficacy than abstinence-based approaches. During the first 5 years of its implementation, in 4,000 patients, methadone maintenance boasted 1-year retention rates exceeding 98%.¹¹ Over the subsequent 3 years, with the number of patients approaching 35,000, the 1-year retention rates fell to around 60%—still far exceeding results of abstinence-based treatment and approximating the number cited in most modern studies.¹¹

The retention rates in buprenorphine programs are similarly promising. Studies of 12 to 13 weeks duration have shown retention rates of 52% to 79%.^12–15 Six-month studies have demonstrated retention rates of 43% to 100%.^16–19 Another study showed that 38% of opiate-dependent patients remained in treatment with buprenorphine at 5 years.²⁰ Surprisingly, most of the buprenorphine studies have been conducted in office-based practices, which are less structured than outpatient methadone programs.

MEDICATION-ASSISTED TREATMENT IS GAINING ACCEPTANCE

Data from decades of experience with MAT strongly support the conclusion that it is superior to abstinence-based approaches.

The importance of a patient staying in treatment cannot be overemphasized, as the consequence of failing in recovery may well be an early death. On average, heroin addicts lose about 18 years of life expectancy, and the mortality rate for injection users is roughly 2% per year.²¹ The mortality rate for heroin users is 6 to 20 times greater than for age-matched peers who are not drug users.²²

As high as these numbers are, they are even higher for abusers of prescription narcotics. The annual death rate associated with opioid pain relievers (4.8 per 100,000) is nearly double that associated with illicit drugs (2.8 per 100,000).²³

The recent and rather radical change in treatment philosophy by Hazelden came as a shock to some, a disappointment to others, and a welcome change to many who saw this as a move by one of the more respected treatment centers in the country to fall in line with the body of evidence that supports MAT for those suffering from opiate dependence. It remains a mystery why so many, if not most, addiction treatment centers in the United States cling to the abstinence-based philosophy despite the overwhelming data from decades of research and experience that show that abstinence does not work for the majority of opiate addicts.

Complete abstinence from opiate drugs of abuse and potentially addictive medications is a noble but perhaps unreachable goal for many sufferers. Hazelden’s announced acceptance of MAT gives credence to the value of recovery goals that are not entirely drug-free.

Dr. Dole was correct in stating that opiate addicts usually return to drugs if not provided with MAT. Treatment programs need to inform opiate-dependent patients that abstinence-based treatment offers only a 1 in 10 chance of success. Perhaps some patients, armed with the daunting statistics regarding abstinence, will be inspired to devote themselves wholeheartedly to their recovery in an effort to make it into that elite 10% group that achieves long-lasting recovery without the aid of medications. But for the other 90%, it is encouraging to hear that Hazelden, the model treatment center for most abstinence-based programs in this country, may now lead other abstinence-based centers to reconsider their treatment philosophies.

Historically, US doctors were not allowed by federal law to prescribe opiates for addiction treatment. With the passage of DATA 2000, buprenorphine (alone or in combination with naloxone) can be prescribed for addiction treatment only by providers who obtain a waiver from the US Drug Enforcement Administration (DEA). Any doctor can become qualified to prescribe buprenorphine or buprenorphinenaloxone after completing an 8-hour online training course (available at www.buppractice.com and at www.aaap.org/buprenorphine) and by obtaining a DATA 2000 waiver and a new prescribing number from the DEA. Doctors are initially limited to treating only 30 patients with buprenorphine-naloxone at any given time, but can apply for an extension to 100 patients after having had their waiver for 1 year.

As MAT continues to gain favor, demand will grow for more providers to obtain their waivers to prescribe buprenorphine and buprenorphine-naloxone. Historically, there have always been too few methadone clinics to meet the demand. One can hope that the growing number of waivered providers will greatly improve access to care by opiate addicts, no matter where they reside. Qualified prescribers of buprenorphine and buprenorphine-naloxone are limited by the federal restrictions on the numbers of patients they can treat. If the chronic disease of addiction is to be integrated into the continuing-care approach of modern medicine and managed alongside other chronic diseases, primary care providers who are not specialized in treating addiction will need to be become comfortable with maintaining patients on buprenorphine-naloxone.⁷ Presumably, such patients will have already been stabilized through participation in addiction treatment programs in their respective geographic areas. Primary care providers will need to develop relationships with local addictionologists and treatment programs so that they will be able to refer those in active addiction for induction and stabilization on MAT and will be able to refer those already stabilized on MAT back to such specialists when relapses occur.

We may finally be approaching a time when structured residential treatment and MAT are not mutually exclusive options for our patients. These treatment options must work together for optimal outcomes. Based on our experience with hundreds of patients at Cleveland Clinic’s Alcohol and Drug Recovery Center, we believe this change of treatment philosophy is long overdue. In clinical settings, patients do not fit cleanly into one treatment arm or another and often require a blended approach to effect long-lasting change. Hazelden’s shift of treatment philosophy is an indication that this research-supported viewpoint is gaining acceptance in the traditionally drug-free halls of addiction treatment programs.

Experts have argued for decades about how best to manage opiate dependence, with practitioners generally subscribing to one of two strategies: either total abstinence or medication-assisted treatment (MAT).

Although MAT has proven efficacy, it has been slow to gain acceptance, and the gold standard of care since the 1930s has been abstinence-based treatment. Among elite institutional holdouts against MAT was the Hazelden Treatment Center, a leading treatment institution and publishing house that had been wedded to the abstinence model since it was founded in 1949.¹ Now, Hazelden has gone on record as embracing MAT, raising the possibility that the two predominant treatment philosophies for opiate-dependent patients may no longer be at odds.

FROM ABSTINENCE TO METHADONE MAINTENANCE

The modern day abstinence-based movement in this country started in the decade before the founding of Hazelden. In 1935, the US government opened the first of two federal drug treatment centers, known as the United States Narcotic Farm, in Lexington, KY.² The move by the government to get into the addiction treatment business largely stemmed from frustration over the growing problem of addiction at that time, coupled with a dearth of treatment options for addicts in the wake of the 1914 Harrison Narcotics Act.

The Narcotic Farm was an impressive facility—for all intents and purposes, a specialized prison—that initially housed 1,200 people. In addition to prisoners, it also accepted voluntary, nonprisoner patients. In many ways, it was ahead of its time. It offered a wide variety of services, including detoxification, group therapy, individual therapy, psychiatric and medical services, and vocational rehabilitation.² Housed on the premises was the Addiction Research Center at Lexington, the first intramural research branch of the National Institute of Mental Health. After the “Blue Grass” mandatory commitment laws were passed in the 1940s, even the voluntary patients were ultimately committed for a 1-year sentence at Lexington. This facility, and its sister facility in Ft. Worth, TX, would have been the envy of any modern-day abstinence-based treatment center in terms of the services offered and the long lengths of stay.

The quality of the program, as evidenced by the impressive array of services and long stays, would lead one to expect that its treatment outcomes over nearly 40 years of operation were equally stellar. However, in terms of outcomes the Farm was an abysmal failure, as shown by numerous studies demonstrating relapse rates of more than 90% in the patients discharged from it.^2,3

Similar frustrations at other abstinence-based treatment centers from the 1940s through the 1960s led Dr. Vincent Dole, the “father of methadone maintenance,” to conclude in 1971 that after detoxification from opiates, “human addicts almost always return to use of narcotics after they leave the hospital where they have been detoxified.”⁴ That realization inspired Dr. Dole and his wife and colleague Dr. Marie Nyswander to revisit the idea of medication-assisted treatment, an approach previously used by the morphine maintenance clinics of the early 1900s. This work led to the development of government-sanctioned methadone clinics across America and to the realization that long-term recovery was possible with medication, even without a lengthy hospital stay. For this revolutionary work on opiate addiction, Dr. Dole won the prestigious Lasker Award in 1988.

The major reason for the success of methadone was that, because of its pharmacokinetic profile, it could stabilize the patient through once-daily dosing without sedation or narcosis. As noted by Dr. Dole, once patients are on a stable dosing regimen, the obsessive preoccupation with drug use fades away.⁵

Despite its success, methadone maintenance had its share of detractors. It was fraught with controversy because it was viewed as a crutch, and those who were on it were often not considered by their abstinent peers as being in true recovery. The reasons for the negative attitudes toward MAT are unclear but may reflect antiquated beliefs that addiction may be indicative of a failure of morals or will, and that patients ought to be able to simply stop using.

Whatever the reason for the animosity surrounding MAT, it should be noted that an expert consensus panel convened by the Betty Ford Center in 2007 agreed that patients on MAT met their consensus definition of sobriety.⁶ The issue of what constitutes recovery remains a very complex and hotly debated topic that is beyond the scope of this paper and that has been discussed elsewhere.^6,7

For more than 3 decades, methadone was the only medication available for MAT. Federal regulations limit the dispensing of methadone to licensed clinics, most of which are located in major metropolitan areas. Patients must go to the clinic every day to receive their dose of methadone—a major inconvenience, especially to those with transportation issues. Adding to the lack of appeal of methadone maintenance is that the clinics are typically located in the higher-crime areas of cities. Savvy drug dealers know the location of these clinics and often loiter on nearby street corners in an attempt to lure addicts away from recovery by flaunting their illicit drugs.

A final, very significant drawback of methadone is its safety profile. It is a full-agonist narcotic that can be fatal in overdose or in the induction phase, especially if taken with other drugs, such as benzodiazepines.

2003: BUPRENORPHINE-NALOXONE IS APPROVED

Such concerns led researchers to search for other medications to be used for MAT that could perhaps be prescribed in a typical outpatient physician practice. For many reasons, buprenorphine became the most promising candidate. In 2003, the US Food and Drug Administration approved the combination medication buprenorphine-naloxone (Sub-oxone) as only the second drug indicated for maintenance treatment of opioid dependence in the United States.

Buprenorphine differs from methadone in that it is a partial agonist at mu opiate receptors, and therefore has a “ceiling” or “plateau” effect in terms of dose-response and a much improved safety profile. Unlike methadone, buprenorphine can be prescribed in a doctor’s office and does not have to be dispensed at a government-approved clinic.

Unfortunately, buprenorphine-maintained patients seem to carry the same stigma in the recovery community as those maintained on methadone—that they are simply substituting one drug for another. Detractors usually fail to consider that, as with methadone, patients do not report getting “high” from taking buprenorphine. Patients will often state that when they first start taking it, they “feel something,” but after a few days of adjustment, they simply feel normal. They don’t feel high, they are no longer in withdrawal, their cravings are virtually eliminated, and their opiate receptors are effectively occupied and blocked, so there is no “high” in the event of a relapse.

What’s more, buprenorphine is not a medication that will help them deal with life’s stressors by “chemical coping.” Sober coping is a skill they must learn by actively participating in a solid 12-step-based recovery program and, in some cases, in psychotherapy. By removing the drug obsession, buprenorphine promotes and facilitates the important recovery goal of learning how to deal with life on life’s terms.

ADDICTION AS CHRONIC ILLNESS

Outcomes studies of addiction treatment have focused largely on rates of relapse after discharge from acute treatments such as residential rehabilitation, partial hospitalization, and intensive outpatient programs. With MAT, however, outcomes research has primarily looked at the duration of retention in treatment.

The change in focus between the two types of treatment coincides with a paradigm shift that views addiction as a chronic condition that requires ongoing care. Continued participation in prescribed care with demonstrated efficacy is considered to be the major indicator of success. Under the chronic illness model employed by MAT providers, if a patient reverted to briefly using a drug of abuse, this would be an issue to address in his ongoing treatment and would not necessarily indicate treatment failure as with the acute care model. Beyond retention rates, research has demonstrated that MAT with methadone results in reductions in rates of criminal activity, illicit drug use, acquisition of human immunodeficiency virus, and overall mortality.^8–10

In outcomes studies, MAT has repeatedly shown better efficacy than abstinence-based approaches. During the first 5 years of its implementation, in 4,000 patients, methadone maintenance boasted 1-year retention rates exceeding 98%.¹¹ Over the subsequent 3 years, with the number of patients approaching 35,000, the 1-year retention rates fell to around 60%—still far exceeding results of abstinence-based treatment and approximating the number cited in most modern studies.¹¹

The retention rates in buprenorphine programs are similarly promising. Studies of 12 to 13 weeks duration have shown retention rates of 52% to 79%.^12–15 Six-month studies have demonstrated retention rates of 43% to 100%.^16–19 Another study showed that 38% of opiate-dependent patients remained in treatment with buprenorphine at 5 years.²⁰ Surprisingly, most of the buprenorphine studies have been conducted in office-based practices, which are less structured than outpatient methadone programs.

MEDICATION-ASSISTED TREATMENT IS GAINING ACCEPTANCE

Data from decades of experience with MAT strongly support the conclusion that it is superior to abstinence-based approaches.

The importance of a patient staying in treatment cannot be overemphasized, as the consequence of failing in recovery may well be an early death. On average, heroin addicts lose about 18 years of life expectancy, and the mortality rate for injection users is roughly 2% per year.²¹ The mortality rate for heroin users is 6 to 20 times greater than for age-matched peers who are not drug users.²²

As high as these numbers are, they are even higher for abusers of prescription narcotics. The annual death rate associated with opioid pain relievers (4.8 per 100,000) is nearly double that associated with illicit drugs (2.8 per 100,000).²³

The recent and rather radical change in treatment philosophy by Hazelden came as a shock to some, a disappointment to others, and a welcome change to many who saw this as a move by one of the more respected treatment centers in the country to fall in line with the body of evidence that supports MAT for those suffering from opiate dependence. It remains a mystery why so many, if not most, addiction treatment centers in the United States cling to the abstinence-based philosophy despite the overwhelming data from decades of research and experience that show that abstinence does not work for the majority of opiate addicts.

Complete abstinence from opiate drugs of abuse and potentially addictive medications is a noble but perhaps unreachable goal for many sufferers. Hazelden’s announced acceptance of MAT gives credence to the value of recovery goals that are not entirely drug-free.

Dr. Dole was correct in stating that opiate addicts usually return to drugs if not provided with MAT. Treatment programs need to inform opiate-dependent patients that abstinence-based treatment offers only a 1 in 10 chance of success. Perhaps some patients, armed with the daunting statistics regarding abstinence, will be inspired to devote themselves wholeheartedly to their recovery in an effort to make it into that elite 10% group that achieves long-lasting recovery without the aid of medications. But for the other 90%, it is encouraging to hear that Hazelden, the model treatment center for most abstinence-based programs in this country, may now lead other abstinence-based centers to reconsider their treatment philosophies.

Historically, US doctors were not allowed by federal law to prescribe opiates for addiction treatment. With the passage of DATA 2000, buprenorphine (alone or in combination with naloxone) can be prescribed for addiction treatment only by providers who obtain a waiver from the US Drug Enforcement Administration (DEA). Any doctor can become qualified to prescribe buprenorphine or buprenorphinenaloxone after completing an 8-hour online training course (available at www.buppractice.com and at www.aaap.org/buprenorphine) and by obtaining a DATA 2000 waiver and a new prescribing number from the DEA. Doctors are initially limited to treating only 30 patients with buprenorphine-naloxone at any given time, but can apply for an extension to 100 patients after having had their waiver for 1 year.

As MAT continues to gain favor, demand will grow for more providers to obtain their waivers to prescribe buprenorphine and buprenorphine-naloxone. Historically, there have always been too few methadone clinics to meet the demand. One can hope that the growing number of waivered providers will greatly improve access to care by opiate addicts, no matter where they reside. Qualified prescribers of buprenorphine and buprenorphine-naloxone are limited by the federal restrictions on the numbers of patients they can treat. If the chronic disease of addiction is to be integrated into the continuing-care approach of modern medicine and managed alongside other chronic diseases, primary care providers who are not specialized in treating addiction will need to be become comfortable with maintaining patients on buprenorphine-naloxone.⁷ Presumably, such patients will have already been stabilized through participation in addiction treatment programs in their respective geographic areas. Primary care providers will need to develop relationships with local addictionologists and treatment programs so that they will be able to refer those in active addiction for induction and stabilization on MAT and will be able to refer those already stabilized on MAT back to such specialists when relapses occur.

We may finally be approaching a time when structured residential treatment and MAT are not mutually exclusive options for our patients. These treatment options must work together for optimal outcomes. Based on our experience with hundreds of patients at Cleveland Clinic’s Alcohol and Drug Recovery Center, we believe this change of treatment philosophy is long overdue. In clinical settings, patients do not fit cleanly into one treatment arm or another and often require a blended approach to effect long-lasting change. Hazelden’s shift of treatment philosophy is an indication that this research-supported viewpoint is gaining acceptance in the traditionally drug-free halls of addiction treatment programs.

A 57-year-old woman with no history of cardiovascular disease comes to the clinic for her annual evaluation. She does not have diabetes mellitus, but she does have hypertension and chronic osteoarthritis, currently treated with acetaminophen. Additionally, she admits to active tobacco use. Her systolic blood pressure is 130 mm Hg on therapy with hydrochlorothiazide. Her electrocardiogram demonstrates left ventricular hypertrophy. Her low-density lipoprotein (LDL) cholesterol level is 140 mg/dL, and her high-density lipoprotein (HDL) cholesterol level is 50 mg/dL. Should this patient be started on aspirin therapy?

Acetylsalicylic acid (aspirin) is an analgesic, antipyretic, and anti-inflammatory agent, but its more prominent use today is as an antithrombotic agent to treat or prevent cardiovascular events. Its antithrombotic properties are due to its effects on the enzyme cyclooxygenase. However, cyclooxygenase is also involved in regulation of the gastric mucosa, and so aspirin increases the risk of gastrointestinal bleeding.

Approximately 50 million people take aspirin on a daily basis to treat or prevent cardiovascular disease.¹ Of these, at least half are taking more than 100 mg per day,² reflecting the general belief that, for aspirin dosage, “more is better”—which is not true.

Additionally, recommendations about the use of aspirin were based on studies that included relatively few members of several important subgroups, such as people with diabetes without known cardiovascular disease, women, and the elderly, and thus may not reflect appropriate indications and dosages for these groups.

Here, we examine the literature, outline an individualized approach to aspirin therapy, and highlight areas for future study.

HISTORY OF ASPIRIN USE IN CARDIOVASCULAR DISEASE

• 1700s—Willow bark is used as an analgesic.
• 1897—Synthetic aspirin is developed as an antipyretic and anti-inflammatory agent.
• 1974—First landmark trial of aspirin for secondary prevention of myocardial infarction.³
• 1982—Nobel Prize awarded for discovery of aspirin mechanism.
• 1985—US Food and Drug Administration approves aspirin for the treatment and secondary prevention of acute myocardial infarction.
• 1998—The Second International Study of Infarct Survival (ISIS-2) finds that giving aspirin to patients with myocardial infarction within 24 hours of presentation leads to a significant reduction in vascular deaths.⁴

Ongoing uncertainties

Aspirin now carries a class I indication for all patients with suspected myocardial infarction. Since there are an estimated 600,000 new coronary events and 325,000 recurrent ischemic events per year in the United States,⁵ the need for aspirin will continue to remain great. It is also approved to prevent and treat stroke and in patients with unstable angina.

However, questions continue to emerge about aspirin’s dosing and appropriate use in specific populations. The initial prevention trials used a wide range of doses and, as mentioned, included few women, few people with diabetes, and few elderly people. The uncertainties are especially pertinent for patients without known vascular disease, in whom the absolute risk reduction is much less, making the assessment of bleeding risk particularly important. Furthermore, the absolute risk-to-benefit assessment may be different in certain populations.

Guidelines on the use of aspirin to prevent cardiovascular disease (Table 1)^6–10 have evolved to take into account these possible disparities, and studies are taking place to further investigate aspirin use in these groups.

ASPIRIN AND GASTROINTESTINAL BLEEDING

Aspirin’s association with bleeding, particularly gastrointestinal bleeding, was recognized early as a use-limiting side effect. With or without aspirin, gastrointestinal bleeding is a common cause of morbidity and death, with an incidence of approximately 100 per 100,000 bleeding episodes in adults per year for upper gastrointestinal bleeding and 20 to 30 per 100,000 per year for lower gastrointestinal bleeding.^11,12

The standard dosage (ie, 325 mg/day) is associated with a significantly higher risk of gastrointestinal bleeding (including fatal bleeds) than is 75 mg.¹³ However, even with lower doses, the risk of gastrointestinal bleeding is estimated to be twice as high as with no aspirin.¹⁴

And here is the irony: studies have shown that higher doses of aspirin offer no advantage in preventing thrombotic events compared with lower doses.¹⁵ For example, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Stroke Syndromes study reported a higher rate of gastrointestinal bleeding with standard-dose aspirin therapy than with low-dose aspirin, with no additional cardiovascular benefit with the higher dose.¹⁶

Furthermore, several other risk factors increase the risk of gastrointestinal bleeding with aspirin use (Table 2). These risk factors are common in the general population but were not necessarily represented in participants in clinical trials. Thus, estimates of risk based on trial data most likely underestimate actual risk in the general population, and therefore, the individual patient’s risk of gastrointestinal bleeding, based on these and other factors, needs to be taken into consideration.

ASPIRIN IN PATIENTS WITH CORONARY ARTERY DISEASE

Randomized clinical trials have validated the benefits of aspirin in secondary prevention of cardiovascular events in patients who have had a myocardial infarction. Patients with coronary disease who withdraw from aspirin therapy or otherwise do not adhere to it have a risk of cardiovascular events three times higher than those who stay with it.¹⁷

Despite the strong data, however, several issues and questions remain about the use of aspirin for secondary prevention.

Bleeding risk must be considered, since gastrointestinal bleeding is associated with a higher risk of death and myocardial infarction in patients with cardiovascular disease.¹⁸ Many patients with coronary disease are on more than one antiplatelet or anticoagulant therapy for concomitant conditions such as atrial fibrillation or because they underwent a percutaneous intervention, which further increases the risk of bleeding.

This bleeding risk is reflected in changes in the most recent recommendations for aspirin dosing after percutaneous coronary intervention. Earlier guidelines advocated use of either 162 or 325 mg after the procedure. However, the most recent update (in 2011) now supports 81 mg for maintenance dosing after intervention.⁷

Patients with coronary disease but without prior myocardial infarction or intervention. Current guidelines recommend 75 to 162 mg of aspirin in all patients with coronary artery disease.⁶ However, this group is diverse and includes patients who have undergone percutaneous coronary intervention, patients with chronic stable angina, and patients with asymptomatic coronary artery disease found on imaging studies. The magnitude of benefit is not clear for those who have no symptoms or who have stable angina.

Most of the evidence supporting aspirin use in chronic angina came from a single trial in Sweden, in which 2,000 patients with chronic stable angina were given either 75 mg daily or placebo. Those who received aspirin had a 34% lower rate of myocardial infarction and sudden death.¹⁹

A substudy of the Physicians’ Health Study, with fewer patients, also noted a significant reduction in the rate of first myocardial infarction. The dose of aspirin in this study was 325 mg every other day.²⁰

In the Women’s Health Initiative Observational Study, 70% of women with stable cardiovascular disease taking aspirin were taking 325 mg daily.²¹ This study demonstrated a significant reduction in the cardiovascular mortality rate, which supports current guidelines, and found no difference in outcomes with doses of 81 mg compared with 325 mg.²¹ This again corroborates that low-dose aspirin is preferential to standard-dose aspirin in women with cardiovascular disease.

These findings have not been validated in larger prospective trials. Thus, current guidelines for aspirin use may reflect extrapolation of aspirin benefit from higher-risk patients to lower-risk patients.

Nevertheless, although the debate continues, it has generally been accepted that in patients who are at high risk of vascular disease or who have had a myocardial infarction, the benefits of aspirin—a 20% relative reduction in vascular events²²—clearly outweigh the risks.

ASPIRIN FOR PRIMARY PREVENTION

Assessing risk vs benefit is more complex when considering populations without known cardiovascular disease.

Only a few studies have specifically evaluated the use of aspirin for primary prevention (Table 3).^23–31 The initial trials were in male physicians in the United Kingdom and the United States in the late 1980s and had somewhat conflicting results. A British study did not find a significant reduction in myocardial infarction,²³ but the US Physician’s Health Study study did: the relative risk was 0.56 (95% confidence interval 0.45–0.70, P < .00001).²⁴ The US study had more than four times the number of participants, used different dosing (325 mg every other day compared with 500 or 300 mg daily in the British study), and had a higher rate of compliance.

Several studies over the next decade demonstrated variable but significant reductions in cardiovascular events as well.^25–27

A meta-analysis of primary prevention trials of aspirin was published in 2009.²² Although the relative risk reduction was similar in primary and secondary prevention, the absolute risk reduction in primary prevention was not nearly as great as in secondary prevention.

These findings are somewhat difficult to interpret, as the component trials included a wide spectrum of patients, ranging from healthy people with no symptoms and no known risk factors to those with limited risk factors. The trials were also performed over several decades during which primary prevention strategies were evolving. Additionally, most of the participants were middle-aged, nondiabetic men, so the results may not necessarily apply to people with diabetes, to women, or to the elderly. Thus, the pooled data in favor of aspirin for primary prevention may not be as broadly applicable to the general population as was once thought.

Aspirin for primary prevention in women

Guidelines for aspirin use in primary prevention were initially thought to be equally applicable to both sexes. However, concerns about the relatively low number of women participating in the studies and the possible mechanistic differences in aspirin efficacy in men vs women prompted further study.

A meta-analysis of randomized controlled trials found that aspirin was associated with a 12% relative reduction in the incidence of cardiovascular events in women and 14% in men. On the other hand, for stroke, the relative risk reduction was 17% in women, while men had no benefit.³²

Most of the women in this meta-analysis were participants in the Women’s Health Study, and they were at low baseline risk.²⁸ Although only about 10% of patients in this study were over age 65, this older group accounted for most of the benefit: these older women had a 26% risk reduction in major adverse cardiovascular events and 30% reduction in stroke.

Thus, for women, aspirin seems to become effective for primary prevention at an older age than in men, and the guidelines have been changed accordingly (Figure 1).

More women should be taking aspirin than actually are. For example, Rivera et al³³ found that only 41% of eligible women were receiving aspirin for primary prevention and 48% of eligible women were receiving it for secondary prevention.

People with diabetes

People with diabetes without overt cardiovascular disease are at higher risk of cardiovascular events than age- and sex-matched controls.³⁴ On the other hand, people with diabetes may be more prone to aspirin resistance and may not derive as much cardiovascular benefit from aspirin.

Early primary prevention studies included few people with diabetes. Subsequent meta-analyses of trials that used a wide range of aspirin doses found a relative risk reduction of 9%, which was not statistically significant.^9,35,36

But there is some evidence that people with diabetes, with³⁷ and without²² coronary disease, may be at higher inherent risk of bleeding than people without diabetes. Although aspirin may not necessarily increase the risk of bleeding in diabetic patients, recent data suggest no benefit in terms of a reduction in vascular events.³⁸

The balance of risk vs benefit for aspirin in this special population is not clear, although some argue that these patients should be treated somewhere on the spectrum of risk between primary and secondary prevention.

The US Preventive Services Task Force did not differentiate between people with or without diabetes in its 2009 guidelines for aspirin for primary prevention.⁸ However, the debate is reflected in a change in 2010 American College of Cardiology/American Diabetes Association guidelines regarding aspirin use in people with diabetes without known cardiovascular disease.³⁹ As opposed to earlier recommendations from these organizations in favor of aspirin for all people with diabetes regardless of 10-year risk, current recommendations advise low-dose aspirin (81–162 mg) for diabetic patients without known vascular disease who have a greater than 10% risk of a cardiovascular event and are not at increased risk of bleeding.

These changes were based on the findings of two trials: the Prevention and Progression of Arterial Disease and Diabetes Trial (POPADAD) and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study. These did not show a statistically significant benefit in prevention of cardiovascular events with aspirin.^29,30

After the new guidelines came out, a meta-analysis further bolstered its recommendations. ⁴⁰ In seven randomized clinical trials in 11,000 patients, the relative risk reduction was 9% with aspirin, which did not reach statistical significance.

The use of statins has been increasing, and this trend may have played a role in the marginal benefit of aspirin therapy in these recent studies. In the Japanese trial, approximately 25% of the patients were known to be using a statin; the percentage of statin use was not reported specifically in POPADAD, but both of these studies were published in 2008, when the proportion of diabetic patients taking a statin would be expected to be higher than in earlier primary prevention trials, which were performed primarily in the 1990s. Thus, the beneficial effects of statins may have somewhat diluted the risk reduction attributable to aspirin.

Trials under way in patients with diabetes

The evolving and somewhat conflicting guidelines highlight the need for further study in patients with diabetes. To address this area, two trials are in progress: the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND).^41,42

ACCEPT-D is testing low-dose aspirin (100 mg daily) in diabetic patients who are also on simvastatin. This study also includes prespecified subgroups stratified by sex, age, and baseline lipid levels.

The ASCEND trial will use the same aspirin dose as ACCEPT-D, with a target enrollment of 10,000 patients with diabetes without known vascular disease.

More frequent dosing for people with diabetes?

Although not supported by current guidelines, recent work has suggested that people with diabetes may need more-frequent dosing of aspirin.⁴³ This topic warrants further investigation.

Aspirin as primary prevention in elderly patients

The incidence of cardiovascular events increases with age³⁷—but so does the incidence of gastrointestinal bleeding.⁴⁴ Upper gastrointestinal bleeding is especially worrisome in the elderly, in whom the estimated case-fatality rate is high.¹² Assessment of risk and benefit is particularly important in patients over age 65 without known coronary disease.

Uncertainty about aspirin use in this population is reflected in the most recent US Preventive Services Task Force guidelines, which do not advocate either for or against regular aspirin use for primary prevention in those over the age of 80.

Data on this topic from clinical trials are limited. The Antithrombotic Trialists’ Collaboration (2009) found that although age is associated with a risk of major coronary events similar to that of other traditional risk factors such as diabetes, hypertension, and tobacco use, older age is also associated with the highest risk of major extracranial bleeding.²²

Because of the lack of data in this population, several studies are currently under way. The Aspirin in Reducing Events in the Elderly (ASPREE) trial is studying 100 mg daily in nondiabetic patients without known cardiovascular disease who are age 70 and older.⁴⁵ An additional trial will study patients age 60 to 85 with concurrent diagnoses of hypertension, hyperlipidemia, or diabetes and will test the same aspirin dose as in ASPREE.⁴⁶ These trials should provide further insight into the safety and efficacy of aspirin for primary prevention in the elderly.

FUTURE DIRECTIONS

Aspirin remains a cornerstone of therapy in patients with cardiovascular disease and in secondary prevention of adverse cardiovascular events, but its role in primary prevention remains under scrutiny. Recommendations have evolved to reflect emerging data in special populations, and an algorithm based on Framingham risk assessment in men for myocardial infarction and ischemic stroke assessment in women for assessing appropriateness of aspirin therapy based on currently available guidelines is presented in Figure 1.^6,8,47–49 Targeted studies have advanced our understanding of aspirin use in women, and future studies in people with diabetes and in the elderly should provide further insight into the role of aspirin for primary prevention in these specific groups as well.

Additionally, the range of doses used in clinical studies has propagated the general misperception that higher doses of aspirin are more efficacious. Future studies should continue to use lower doses of aspirin to minimize bleeding risk with an added focus on re-examining its net benefit in the modern era of increasing statin use, which may reduce the absolute risk reduction attributable to aspirin.

One particular area of debate is whether enteric coating can result in functional aspirin resistance. Grosser et al⁵⁰ found that sustained aspirin resistance was rare, and “pseudoresistance” was related to the use of a single enteric-coated aspirin instead of immediate-release aspirin in people who had not been taking aspirin up to then. This complements an earlier study, which found that enteric-coated aspirin had an appropriate effect when given for 7 days.⁵¹ Therefore, for patients who have not been taking aspirin, the first dose should always be immediate-release, not enteric coated.

SHOULD OUR PATIENT RECEIVE ASPIRIN?

The patient we described at the beginning of this article has several risk factors—hypertension, dyslipidemia, left ventricular hypertrophy, and smoking—but no known cardiovascular disease as yet. Her risk of an adverse cardiovascular event appears moderate. However, her 10-year risk of stroke by the Framingham risk calculation is 10%, which would qualify her for aspirin for primary prevention. Of particular note is that the significance of left ventricular hypertrophy as a risk factor for stroke in women is higher than in men and in our case accounts for half of this patient’s risk.

We should explain to the patient that the anticipated benefits of aspirin for stroke prevention outweigh bleeding risks, and thus aspirin therapy would be recommended. However, with her elevated LDL-cholesterol, she may benefit from a statin, which could lessen the relative risk reduction from additional aspirin use.

A 57-year-old woman with no history of cardiovascular disease comes to the clinic for her annual evaluation. She does not have diabetes mellitus, but she does have hypertension and chronic osteoarthritis, currently treated with acetaminophen. Additionally, she admits to active tobacco use. Her systolic blood pressure is 130 mm Hg on therapy with hydrochlorothiazide. Her electrocardiogram demonstrates left ventricular hypertrophy. Her low-density lipoprotein (LDL) cholesterol level is 140 mg/dL, and her high-density lipoprotein (HDL) cholesterol level is 50 mg/dL. Should this patient be started on aspirin therapy?

Acetylsalicylic acid (aspirin) is an analgesic, antipyretic, and anti-inflammatory agent, but its more prominent use today is as an antithrombotic agent to treat or prevent cardiovascular events. Its antithrombotic properties are due to its effects on the enzyme cyclooxygenase. However, cyclooxygenase is also involved in regulation of the gastric mucosa, and so aspirin increases the risk of gastrointestinal bleeding.

Approximately 50 million people take aspirin on a daily basis to treat or prevent cardiovascular disease.¹ Of these, at least half are taking more than 100 mg per day,² reflecting the general belief that, for aspirin dosage, “more is better”—which is not true.

Additionally, recommendations about the use of aspirin were based on studies that included relatively few members of several important subgroups, such as people with diabetes without known cardiovascular disease, women, and the elderly, and thus may not reflect appropriate indications and dosages for these groups.

Here, we examine the literature, outline an individualized approach to aspirin therapy, and highlight areas for future study.

HISTORY OF ASPIRIN USE IN CARDIOVASCULAR DISEASE

• 1700s—Willow bark is used as an analgesic.
• 1897—Synthetic aspirin is developed as an antipyretic and anti-inflammatory agent.
• 1974—First landmark trial of aspirin for secondary prevention of myocardial infarction.³
• 1982—Nobel Prize awarded for discovery of aspirin mechanism.
• 1985—US Food and Drug Administration approves aspirin for the treatment and secondary prevention of acute myocardial infarction.
• 1998—The Second International Study of Infarct Survival (ISIS-2) finds that giving aspirin to patients with myocardial infarction within 24 hours of presentation leads to a significant reduction in vascular deaths.⁴

Ongoing uncertainties

Aspirin now carries a class I indication for all patients with suspected myocardial infarction. Since there are an estimated 600,000 new coronary events and 325,000 recurrent ischemic events per year in the United States,⁵ the need for aspirin will continue to remain great. It is also approved to prevent and treat stroke and in patients with unstable angina.

However, questions continue to emerge about aspirin’s dosing and appropriate use in specific populations. The initial prevention trials used a wide range of doses and, as mentioned, included few women, few people with diabetes, and few elderly people. The uncertainties are especially pertinent for patients without known vascular disease, in whom the absolute risk reduction is much less, making the assessment of bleeding risk particularly important. Furthermore, the absolute risk-to-benefit assessment may be different in certain populations.

Guidelines on the use of aspirin to prevent cardiovascular disease (Table 1)^6–10 have evolved to take into account these possible disparities, and studies are taking place to further investigate aspirin use in these groups.

ASPIRIN AND GASTROINTESTINAL BLEEDING

Aspirin’s association with bleeding, particularly gastrointestinal bleeding, was recognized early as a use-limiting side effect. With or without aspirin, gastrointestinal bleeding is a common cause of morbidity and death, with an incidence of approximately 100 per 100,000 bleeding episodes in adults per year for upper gastrointestinal bleeding and 20 to 30 per 100,000 per year for lower gastrointestinal bleeding.^11,12

The standard dosage (ie, 325 mg/day) is associated with a significantly higher risk of gastrointestinal bleeding (including fatal bleeds) than is 75 mg.¹³ However, even with lower doses, the risk of gastrointestinal bleeding is estimated to be twice as high as with no aspirin.¹⁴

And here is the irony: studies have shown that higher doses of aspirin offer no advantage in preventing thrombotic events compared with lower doses.¹⁵ For example, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Stroke Syndromes study reported a higher rate of gastrointestinal bleeding with standard-dose aspirin therapy than with low-dose aspirin, with no additional cardiovascular benefit with the higher dose.¹⁶

Furthermore, several other risk factors increase the risk of gastrointestinal bleeding with aspirin use (Table 2). These risk factors are common in the general population but were not necessarily represented in participants in clinical trials. Thus, estimates of risk based on trial data most likely underestimate actual risk in the general population, and therefore, the individual patient’s risk of gastrointestinal bleeding, based on these and other factors, needs to be taken into consideration.

ASPIRIN IN PATIENTS WITH CORONARY ARTERY DISEASE

Randomized clinical trials have validated the benefits of aspirin in secondary prevention of cardiovascular events in patients who have had a myocardial infarction. Patients with coronary disease who withdraw from aspirin therapy or otherwise do not adhere to it have a risk of cardiovascular events three times higher than those who stay with it.¹⁷

Despite the strong data, however, several issues and questions remain about the use of aspirin for secondary prevention.

Bleeding risk must be considered, since gastrointestinal bleeding is associated with a higher risk of death and myocardial infarction in patients with cardiovascular disease.¹⁸ Many patients with coronary disease are on more than one antiplatelet or anticoagulant therapy for concomitant conditions such as atrial fibrillation or because they underwent a percutaneous intervention, which further increases the risk of bleeding.

This bleeding risk is reflected in changes in the most recent recommendations for aspirin dosing after percutaneous coronary intervention. Earlier guidelines advocated use of either 162 or 325 mg after the procedure. However, the most recent update (in 2011) now supports 81 mg for maintenance dosing after intervention.⁷

Patients with coronary disease but without prior myocardial infarction or intervention. Current guidelines recommend 75 to 162 mg of aspirin in all patients with coronary artery disease.⁶ However, this group is diverse and includes patients who have undergone percutaneous coronary intervention, patients with chronic stable angina, and patients with asymptomatic coronary artery disease found on imaging studies. The magnitude of benefit is not clear for those who have no symptoms or who have stable angina.

Most of the evidence supporting aspirin use in chronic angina came from a single trial in Sweden, in which 2,000 patients with chronic stable angina were given either 75 mg daily or placebo. Those who received aspirin had a 34% lower rate of myocardial infarction and sudden death.¹⁹

A substudy of the Physicians’ Health Study, with fewer patients, also noted a significant reduction in the rate of first myocardial infarction. The dose of aspirin in this study was 325 mg every other day.²⁰

In the Women’s Health Initiative Observational Study, 70% of women with stable cardiovascular disease taking aspirin were taking 325 mg daily.²¹ This study demonstrated a significant reduction in the cardiovascular mortality rate, which supports current guidelines, and found no difference in outcomes with doses of 81 mg compared with 325 mg.²¹ This again corroborates that low-dose aspirin is preferential to standard-dose aspirin in women with cardiovascular disease.

These findings have not been validated in larger prospective trials. Thus, current guidelines for aspirin use may reflect extrapolation of aspirin benefit from higher-risk patients to lower-risk patients.

Nevertheless, although the debate continues, it has generally been accepted that in patients who are at high risk of vascular disease or who have had a myocardial infarction, the benefits of aspirin—a 20% relative reduction in vascular events²²—clearly outweigh the risks.

ASPIRIN FOR PRIMARY PREVENTION

Assessing risk vs benefit is more complex when considering populations without known cardiovascular disease.

Only a few studies have specifically evaluated the use of aspirin for primary prevention (Table 3).^23–31 The initial trials were in male physicians in the United Kingdom and the United States in the late 1980s and had somewhat conflicting results. A British study did not find a significant reduction in myocardial infarction,²³ but the US Physician’s Health Study study did: the relative risk was 0.56 (95% confidence interval 0.45–0.70, P < .00001).²⁴ The US study had more than four times the number of participants, used different dosing (325 mg every other day compared with 500 or 300 mg daily in the British study), and had a higher rate of compliance.

Several studies over the next decade demonstrated variable but significant reductions in cardiovascular events as well.^25–27

A meta-analysis of primary prevention trials of aspirin was published in 2009.²² Although the relative risk reduction was similar in primary and secondary prevention, the absolute risk reduction in primary prevention was not nearly as great as in secondary prevention.

These findings are somewhat difficult to interpret, as the component trials included a wide spectrum of patients, ranging from healthy people with no symptoms and no known risk factors to those with limited risk factors. The trials were also performed over several decades during which primary prevention strategies were evolving. Additionally, most of the participants were middle-aged, nondiabetic men, so the results may not necessarily apply to people with diabetes, to women, or to the elderly. Thus, the pooled data in favor of aspirin for primary prevention may not be as broadly applicable to the general population as was once thought.

Aspirin for primary prevention in women

Guidelines for aspirin use in primary prevention were initially thought to be equally applicable to both sexes. However, concerns about the relatively low number of women participating in the studies and the possible mechanistic differences in aspirin efficacy in men vs women prompted further study.

A meta-analysis of randomized controlled trials found that aspirin was associated with a 12% relative reduction in the incidence of cardiovascular events in women and 14% in men. On the other hand, for stroke, the relative risk reduction was 17% in women, while men had no benefit.³²

Most of the women in this meta-analysis were participants in the Women’s Health Study, and they were at low baseline risk.²⁸ Although only about 10% of patients in this study were over age 65, this older group accounted for most of the benefit: these older women had a 26% risk reduction in major adverse cardiovascular events and 30% reduction in stroke.

Thus, for women, aspirin seems to become effective for primary prevention at an older age than in men, and the guidelines have been changed accordingly (Figure 1).

More women should be taking aspirin than actually are. For example, Rivera et al³³ found that only 41% of eligible women were receiving aspirin for primary prevention and 48% of eligible women were receiving it for secondary prevention.

People with diabetes

People with diabetes without overt cardiovascular disease are at higher risk of cardiovascular events than age- and sex-matched controls.³⁴ On the other hand, people with diabetes may be more prone to aspirin resistance and may not derive as much cardiovascular benefit from aspirin.

Early primary prevention studies included few people with diabetes. Subsequent meta-analyses of trials that used a wide range of aspirin doses found a relative risk reduction of 9%, which was not statistically significant.^9,35,36

But there is some evidence that people with diabetes, with³⁷ and without²² coronary disease, may be at higher inherent risk of bleeding than people without diabetes. Although aspirin may not necessarily increase the risk of bleeding in diabetic patients, recent data suggest no benefit in terms of a reduction in vascular events.³⁸

The balance of risk vs benefit for aspirin in this special population is not clear, although some argue that these patients should be treated somewhere on the spectrum of risk between primary and secondary prevention.

The US Preventive Services Task Force did not differentiate between people with or without diabetes in its 2009 guidelines for aspirin for primary prevention.⁸ However, the debate is reflected in a change in 2010 American College of Cardiology/American Diabetes Association guidelines regarding aspirin use in people with diabetes without known cardiovascular disease.³⁹ As opposed to earlier recommendations from these organizations in favor of aspirin for all people with diabetes regardless of 10-year risk, current recommendations advise low-dose aspirin (81–162 mg) for diabetic patients without known vascular disease who have a greater than 10% risk of a cardiovascular event and are not at increased risk of bleeding.

These changes were based on the findings of two trials: the Prevention and Progression of Arterial Disease and Diabetes Trial (POPADAD) and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study. These did not show a statistically significant benefit in prevention of cardiovascular events with aspirin.^29,30

After the new guidelines came out, a meta-analysis further bolstered its recommendations. ⁴⁰ In seven randomized clinical trials in 11,000 patients, the relative risk reduction was 9% with aspirin, which did not reach statistical significance.

The use of statins has been increasing, and this trend may have played a role in the marginal benefit of aspirin therapy in these recent studies. In the Japanese trial, approximately 25% of the patients were known to be using a statin; the percentage of statin use was not reported specifically in POPADAD, but both of these studies were published in 2008, when the proportion of diabetic patients taking a statin would be expected to be higher than in earlier primary prevention trials, which were performed primarily in the 1990s. Thus, the beneficial effects of statins may have somewhat diluted the risk reduction attributable to aspirin.

Trials under way in patients with diabetes

The evolving and somewhat conflicting guidelines highlight the need for further study in patients with diabetes. To address this area, two trials are in progress: the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND).^41,42

ACCEPT-D is testing low-dose aspirin (100 mg daily) in diabetic patients who are also on simvastatin. This study also includes prespecified subgroups stratified by sex, age, and baseline lipid levels.

The ASCEND trial will use the same aspirin dose as ACCEPT-D, with a target enrollment of 10,000 patients with diabetes without known vascular disease.

More frequent dosing for people with diabetes?

Although not supported by current guidelines, recent work has suggested that people with diabetes may need more-frequent dosing of aspirin.⁴³ This topic warrants further investigation.

Aspirin as primary prevention in elderly patients

The incidence of cardiovascular events increases with age³⁷—but so does the incidence of gastrointestinal bleeding.⁴⁴ Upper gastrointestinal bleeding is especially worrisome in the elderly, in whom the estimated case-fatality rate is high.¹² Assessment of risk and benefit is particularly important in patients over age 65 without known coronary disease.

Uncertainty about aspirin use in this population is reflected in the most recent US Preventive Services Task Force guidelines, which do not advocate either for or against regular aspirin use for primary prevention in those over the age of 80.

Data on this topic from clinical trials are limited. The Antithrombotic Trialists’ Collaboration (2009) found that although age is associated with a risk of major coronary events similar to that of other traditional risk factors such as diabetes, hypertension, and tobacco use, older age is also associated with the highest risk of major extracranial bleeding.²²

Because of the lack of data in this population, several studies are currently under way. The Aspirin in Reducing Events in the Elderly (ASPREE) trial is studying 100 mg daily in nondiabetic patients without known cardiovascular disease who are age 70 and older.⁴⁵ An additional trial will study patients age 60 to 85 with concurrent diagnoses of hypertension, hyperlipidemia, or diabetes and will test the same aspirin dose as in ASPREE.⁴⁶ These trials should provide further insight into the safety and efficacy of aspirin for primary prevention in the elderly.

FUTURE DIRECTIONS

Aspirin remains a cornerstone of therapy in patients with cardiovascular disease and in secondary prevention of adverse cardiovascular events, but its role in primary prevention remains under scrutiny. Recommendations have evolved to reflect emerging data in special populations, and an algorithm based on Framingham risk assessment in men for myocardial infarction and ischemic stroke assessment in women for assessing appropriateness of aspirin therapy based on currently available guidelines is presented in Figure 1.^6,8,47–49 Targeted studies have advanced our understanding of aspirin use in women, and future studies in people with diabetes and in the elderly should provide further insight into the role of aspirin for primary prevention in these specific groups as well.

Additionally, the range of doses used in clinical studies has propagated the general misperception that higher doses of aspirin are more efficacious. Future studies should continue to use lower doses of aspirin to minimize bleeding risk with an added focus on re-examining its net benefit in the modern era of increasing statin use, which may reduce the absolute risk reduction attributable to aspirin.

One particular area of debate is whether enteric coating can result in functional aspirin resistance. Grosser et al⁵⁰ found that sustained aspirin resistance was rare, and “pseudoresistance” was related to the use of a single enteric-coated aspirin instead of immediate-release aspirin in people who had not been taking aspirin up to then. This complements an earlier study, which found that enteric-coated aspirin had an appropriate effect when given for 7 days.⁵¹ Therefore, for patients who have not been taking aspirin, the first dose should always be immediate-release, not enteric coated.

SHOULD OUR PATIENT RECEIVE ASPIRIN?

The patient we described at the beginning of this article has several risk factors—hypertension, dyslipidemia, left ventricular hypertrophy, and smoking—but no known cardiovascular disease as yet. Her risk of an adverse cardiovascular event appears moderate. However, her 10-year risk of stroke by the Framingham risk calculation is 10%, which would qualify her for aspirin for primary prevention. Of particular note is that the significance of left ventricular hypertrophy as a risk factor for stroke in women is higher than in men and in our case accounts for half of this patient’s risk.

We should explain to the patient that the anticipated benefits of aspirin for stroke prevention outweigh bleeding risks, and thus aspirin therapy would be recommended. However, with her elevated LDL-cholesterol, she may benefit from a statin, which could lessen the relative risk reduction from additional aspirin use.

A 57-year-old woman with no history of cardiovascular disease comes to the clinic for her annual evaluation. She does not have diabetes mellitus, but she does have hypertension and chronic osteoarthritis, currently treated with acetaminophen. Additionally, she admits to active tobacco use. Her systolic blood pressure is 130 mm Hg on therapy with hydrochlorothiazide. Her electrocardiogram demonstrates left ventricular hypertrophy. Her low-density lipoprotein (LDL) cholesterol level is 140 mg/dL, and her high-density lipoprotein (HDL) cholesterol level is 50 mg/dL. Should this patient be started on aspirin therapy?

Acetylsalicylic acid (aspirin) is an analgesic, antipyretic, and anti-inflammatory agent, but its more prominent use today is as an antithrombotic agent to treat or prevent cardiovascular events. Its antithrombotic properties are due to its effects on the enzyme cyclooxygenase. However, cyclooxygenase is also involved in regulation of the gastric mucosa, and so aspirin increases the risk of gastrointestinal bleeding.

Approximately 50 million people take aspirin on a daily basis to treat or prevent cardiovascular disease.¹ Of these, at least half are taking more than 100 mg per day,² reflecting the general belief that, for aspirin dosage, “more is better”—which is not true.

Additionally, recommendations about the use of aspirin were based on studies that included relatively few members of several important subgroups, such as people with diabetes without known cardiovascular disease, women, and the elderly, and thus may not reflect appropriate indications and dosages for these groups.

Here, we examine the literature, outline an individualized approach to aspirin therapy, and highlight areas for future study.

HISTORY OF ASPIRIN USE IN CARDIOVASCULAR DISEASE

• 1700s—Willow bark is used as an analgesic.
• 1897—Synthetic aspirin is developed as an antipyretic and anti-inflammatory agent.
• 1974—First landmark trial of aspirin for secondary prevention of myocardial infarction.³
• 1982—Nobel Prize awarded for discovery of aspirin mechanism.
• 1985—US Food and Drug Administration approves aspirin for the treatment and secondary prevention of acute myocardial infarction.
• 1998—The Second International Study of Infarct Survival (ISIS-2) finds that giving aspirin to patients with myocardial infarction within 24 hours of presentation leads to a significant reduction in vascular deaths.⁴

Ongoing uncertainties

Aspirin now carries a class I indication for all patients with suspected myocardial infarction. Since there are an estimated 600,000 new coronary events and 325,000 recurrent ischemic events per year in the United States,⁵ the need for aspirin will continue to remain great. It is also approved to prevent and treat stroke and in patients with unstable angina.

However, questions continue to emerge about aspirin’s dosing and appropriate use in specific populations. The initial prevention trials used a wide range of doses and, as mentioned, included few women, few people with diabetes, and few elderly people. The uncertainties are especially pertinent for patients without known vascular disease, in whom the absolute risk reduction is much less, making the assessment of bleeding risk particularly important. Furthermore, the absolute risk-to-benefit assessment may be different in certain populations.

Guidelines on the use of aspirin to prevent cardiovascular disease (Table 1)^6–10 have evolved to take into account these possible disparities, and studies are taking place to further investigate aspirin use in these groups.

ASPIRIN AND GASTROINTESTINAL BLEEDING

Aspirin’s association with bleeding, particularly gastrointestinal bleeding, was recognized early as a use-limiting side effect. With or without aspirin, gastrointestinal bleeding is a common cause of morbidity and death, with an incidence of approximately 100 per 100,000 bleeding episodes in adults per year for upper gastrointestinal bleeding and 20 to 30 per 100,000 per year for lower gastrointestinal bleeding.^11,12

The standard dosage (ie, 325 mg/day) is associated with a significantly higher risk of gastrointestinal bleeding (including fatal bleeds) than is 75 mg.¹³ However, even with lower doses, the risk of gastrointestinal bleeding is estimated to be twice as high as with no aspirin.¹⁴

And here is the irony: studies have shown that higher doses of aspirin offer no advantage in preventing thrombotic events compared with lower doses.¹⁵ For example, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Stroke Syndromes study reported a higher rate of gastrointestinal bleeding with standard-dose aspirin therapy than with low-dose aspirin, with no additional cardiovascular benefit with the higher dose.¹⁶

Furthermore, several other risk factors increase the risk of gastrointestinal bleeding with aspirin use (Table 2). These risk factors are common in the general population but were not necessarily represented in participants in clinical trials. Thus, estimates of risk based on trial data most likely underestimate actual risk in the general population, and therefore, the individual patient’s risk of gastrointestinal bleeding, based on these and other factors, needs to be taken into consideration.

ASPIRIN IN PATIENTS WITH CORONARY ARTERY DISEASE

Randomized clinical trials have validated the benefits of aspirin in secondary prevention of cardiovascular events in patients who have had a myocardial infarction. Patients with coronary disease who withdraw from aspirin therapy or otherwise do not adhere to it have a risk of cardiovascular events three times higher than those who stay with it.¹⁷

Despite the strong data, however, several issues and questions remain about the use of aspirin for secondary prevention.

Bleeding risk must be considered, since gastrointestinal bleeding is associated with a higher risk of death and myocardial infarction in patients with cardiovascular disease.¹⁸ Many patients with coronary disease are on more than one antiplatelet or anticoagulant therapy for concomitant conditions such as atrial fibrillation or because they underwent a percutaneous intervention, which further increases the risk of bleeding.

This bleeding risk is reflected in changes in the most recent recommendations for aspirin dosing after percutaneous coronary intervention. Earlier guidelines advocated use of either 162 or 325 mg after the procedure. However, the most recent update (in 2011) now supports 81 mg for maintenance dosing after intervention.⁷

Patients with coronary disease but without prior myocardial infarction or intervention. Current guidelines recommend 75 to 162 mg of aspirin in all patients with coronary artery disease.⁶ However, this group is diverse and includes patients who have undergone percutaneous coronary intervention, patients with chronic stable angina, and patients with asymptomatic coronary artery disease found on imaging studies. The magnitude of benefit is not clear for those who have no symptoms or who have stable angina.

Most of the evidence supporting aspirin use in chronic angina came from a single trial in Sweden, in which 2,000 patients with chronic stable angina were given either 75 mg daily or placebo. Those who received aspirin had a 34% lower rate of myocardial infarction and sudden death.¹⁹

A substudy of the Physicians’ Health Study, with fewer patients, also noted a significant reduction in the rate of first myocardial infarction. The dose of aspirin in this study was 325 mg every other day.²⁰

In the Women’s Health Initiative Observational Study, 70% of women with stable cardiovascular disease taking aspirin were taking 325 mg daily.²¹ This study demonstrated a significant reduction in the cardiovascular mortality rate, which supports current guidelines, and found no difference in outcomes with doses of 81 mg compared with 325 mg.²¹ This again corroborates that low-dose aspirin is preferential to standard-dose aspirin in women with cardiovascular disease.

These findings have not been validated in larger prospective trials. Thus, current guidelines for aspirin use may reflect extrapolation of aspirin benefit from higher-risk patients to lower-risk patients.

Nevertheless, although the debate continues, it has generally been accepted that in patients who are at high risk of vascular disease or who have had a myocardial infarction, the benefits of aspirin—a 20% relative reduction in vascular events²²—clearly outweigh the risks.

ASPIRIN FOR PRIMARY PREVENTION

Assessing risk vs benefit is more complex when considering populations without known cardiovascular disease.

Only a few studies have specifically evaluated the use of aspirin for primary prevention (Table 3).^23–31 The initial trials were in male physicians in the United Kingdom and the United States in the late 1980s and had somewhat conflicting results. A British study did not find a significant reduction in myocardial infarction,²³ but the US Physician’s Health Study study did: the relative risk was 0.56 (95% confidence interval 0.45–0.70, P < .00001).²⁴ The US study had more than four times the number of participants, used different dosing (325 mg every other day compared with 500 or 300 mg daily in the British study), and had a higher rate of compliance.

Several studies over the next decade demonstrated variable but significant reductions in cardiovascular events as well.^25–27

A meta-analysis of primary prevention trials of aspirin was published in 2009.²² Although the relative risk reduction was similar in primary and secondary prevention, the absolute risk reduction in primary prevention was not nearly as great as in secondary prevention.

These findings are somewhat difficult to interpret, as the component trials included a wide spectrum of patients, ranging from healthy people with no symptoms and no known risk factors to those with limited risk factors. The trials were also performed over several decades during which primary prevention strategies were evolving. Additionally, most of the participants were middle-aged, nondiabetic men, so the results may not necessarily apply to people with diabetes, to women, or to the elderly. Thus, the pooled data in favor of aspirin for primary prevention may not be as broadly applicable to the general population as was once thought.

Aspirin for primary prevention in women

Guidelines for aspirin use in primary prevention were initially thought to be equally applicable to both sexes. However, concerns about the relatively low number of women participating in the studies and the possible mechanistic differences in aspirin efficacy in men vs women prompted further study.

A meta-analysis of randomized controlled trials found that aspirin was associated with a 12% relative reduction in the incidence of cardiovascular events in women and 14% in men. On the other hand, for stroke, the relative risk reduction was 17% in women, while men had no benefit.³²

Most of the women in this meta-analysis were participants in the Women’s Health Study, and they were at low baseline risk.²⁸ Although only about 10% of patients in this study were over age 65, this older group accounted for most of the benefit: these older women had a 26% risk reduction in major adverse cardiovascular events and 30% reduction in stroke.

Thus, for women, aspirin seems to become effective for primary prevention at an older age than in men, and the guidelines have been changed accordingly (Figure 1).

More women should be taking aspirin than actually are. For example, Rivera et al³³ found that only 41% of eligible women were receiving aspirin for primary prevention and 48% of eligible women were receiving it for secondary prevention.

People with diabetes

People with diabetes without overt cardiovascular disease are at higher risk of cardiovascular events than age- and sex-matched controls.³⁴ On the other hand, people with diabetes may be more prone to aspirin resistance and may not derive as much cardiovascular benefit from aspirin.

Early primary prevention studies included few people with diabetes. Subsequent meta-analyses of trials that used a wide range of aspirin doses found a relative risk reduction of 9%, which was not statistically significant.^9,35,36

But there is some evidence that people with diabetes, with³⁷ and without²² coronary disease, may be at higher inherent risk of bleeding than people without diabetes. Although aspirin may not necessarily increase the risk of bleeding in diabetic patients, recent data suggest no benefit in terms of a reduction in vascular events.³⁸

The balance of risk vs benefit for aspirin in this special population is not clear, although some argue that these patients should be treated somewhere on the spectrum of risk between primary and secondary prevention.

The US Preventive Services Task Force did not differentiate between people with or without diabetes in its 2009 guidelines for aspirin for primary prevention.⁸ However, the debate is reflected in a change in 2010 American College of Cardiology/American Diabetes Association guidelines regarding aspirin use in people with diabetes without known cardiovascular disease.³⁹ As opposed to earlier recommendations from these organizations in favor of aspirin for all people with diabetes regardless of 10-year risk, current recommendations advise low-dose aspirin (81–162 mg) for diabetic patients without known vascular disease who have a greater than 10% risk of a cardiovascular event and are not at increased risk of bleeding.

These changes were based on the findings of two trials: the Prevention and Progression of Arterial Disease and Diabetes Trial (POPADAD) and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study. These did not show a statistically significant benefit in prevention of cardiovascular events with aspirin.^29,30

After the new guidelines came out, a meta-analysis further bolstered its recommendations. ⁴⁰ In seven randomized clinical trials in 11,000 patients, the relative risk reduction was 9% with aspirin, which did not reach statistical significance.

The use of statins has been increasing, and this trend may have played a role in the marginal benefit of aspirin therapy in these recent studies. In the Japanese trial, approximately 25% of the patients were known to be using a statin; the percentage of statin use was not reported specifically in POPADAD, but both of these studies were published in 2008, when the proportion of diabetic patients taking a statin would be expected to be higher than in earlier primary prevention trials, which were performed primarily in the 1990s. Thus, the beneficial effects of statins may have somewhat diluted the risk reduction attributable to aspirin.

Trials under way in patients with diabetes

The evolving and somewhat conflicting guidelines highlight the need for further study in patients with diabetes. To address this area, two trials are in progress: the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND).^41,42

ACCEPT-D is testing low-dose aspirin (100 mg daily) in diabetic patients who are also on simvastatin. This study also includes prespecified subgroups stratified by sex, age, and baseline lipid levels.

The ASCEND trial will use the same aspirin dose as ACCEPT-D, with a target enrollment of 10,000 patients with diabetes without known vascular disease.

More frequent dosing for people with diabetes?

Although not supported by current guidelines, recent work has suggested that people with diabetes may need more-frequent dosing of aspirin.⁴³ This topic warrants further investigation.

Aspirin as primary prevention in elderly patients

The incidence of cardiovascular events increases with age³⁷—but so does the incidence of gastrointestinal bleeding.⁴⁴ Upper gastrointestinal bleeding is especially worrisome in the elderly, in whom the estimated case-fatality rate is high.¹² Assessment of risk and benefit is particularly important in patients over age 65 without known coronary disease.

Uncertainty about aspirin use in this population is reflected in the most recent US Preventive Services Task Force guidelines, which do not advocate either for or against regular aspirin use for primary prevention in those over the age of 80.

Data on this topic from clinical trials are limited. The Antithrombotic Trialists’ Collaboration (2009) found that although age is associated with a risk of major coronary events similar to that of other traditional risk factors such as diabetes, hypertension, and tobacco use, older age is also associated with the highest risk of major extracranial bleeding.²²

Because of the lack of data in this population, several studies are currently under way. The Aspirin in Reducing Events in the Elderly (ASPREE) trial is studying 100 mg daily in nondiabetic patients without known cardiovascular disease who are age 70 and older.⁴⁵ An additional trial will study patients age 60 to 85 with concurrent diagnoses of hypertension, hyperlipidemia, or diabetes and will test the same aspirin dose as in ASPREE.⁴⁶ These trials should provide further insight into the safety and efficacy of aspirin for primary prevention in the elderly.

FUTURE DIRECTIONS

Aspirin remains a cornerstone of therapy in patients with cardiovascular disease and in secondary prevention of adverse cardiovascular events, but its role in primary prevention remains under scrutiny. Recommendations have evolved to reflect emerging data in special populations, and an algorithm based on Framingham risk assessment in men for myocardial infarction and ischemic stroke assessment in women for assessing appropriateness of aspirin therapy based on currently available guidelines is presented in Figure 1.^6,8,47–49 Targeted studies have advanced our understanding of aspirin use in women, and future studies in people with diabetes and in the elderly should provide further insight into the role of aspirin for primary prevention in these specific groups as well.

Additionally, the range of doses used in clinical studies has propagated the general misperception that higher doses of aspirin are more efficacious. Future studies should continue to use lower doses of aspirin to minimize bleeding risk with an added focus on re-examining its net benefit in the modern era of increasing statin use, which may reduce the absolute risk reduction attributable to aspirin.

One particular area of debate is whether enteric coating can result in functional aspirin resistance. Grosser et al⁵⁰ found that sustained aspirin resistance was rare, and “pseudoresistance” was related to the use of a single enteric-coated aspirin instead of immediate-release aspirin in people who had not been taking aspirin up to then. This complements an earlier study, which found that enteric-coated aspirin had an appropriate effect when given for 7 days.⁵¹ Therefore, for patients who have not been taking aspirin, the first dose should always be immediate-release, not enteric coated.

SHOULD OUR PATIENT RECEIVE ASPIRIN?

The patient we described at the beginning of this article has several risk factors—hypertension, dyslipidemia, left ventricular hypertrophy, and smoking—but no known cardiovascular disease as yet. Her risk of an adverse cardiovascular event appears moderate. However, her 10-year risk of stroke by the Framingham risk calculation is 10%, which would qualify her for aspirin for primary prevention. Of particular note is that the significance of left ventricular hypertrophy as a risk factor for stroke in women is higher than in men and in our case accounts for half of this patient’s risk.

We should explain to the patient that the anticipated benefits of aspirin for stroke prevention outweigh bleeding risks, and thus aspirin therapy would be recommended. However, with her elevated LDL-cholesterol, she may benefit from a statin, which could lessen the relative risk reduction from additional aspirin use.

Why individual clinicians make specific decisions usually can be sorted out. But our behavior as a group is more difficult to understand and, even when there are pressing and convincing reasons to change, behavior is difficult to alter.

In this issue, Drs. Federico Perez and David Van Duin discuss the emergence of carbapenem-resistant bacteria, dubbed “superbugs” by the media. Antibiotic resistance is not new; it was reported in Staphylococcus species within several years of the introduction of penicillin.¹ However, it has been increasing in prevalence and molecular complexity after years of relatively promiscuous antibiotic use. As the percentage of inpatients with immunosuppression and frailty increases in this environment of known antibiotic resistance, initial empiric antibiotic choices will by necessity include drugs likely to further promote development of resistant strains. But why do physicians still prescribe antibiotics for uncomplicated upper respiratory tract infections and asymptomatic bacteriuria, despite numerous studies and guidelines suggesting this practice has little benefit? Is it because patients expect a prescription in return for their copayment? Is it the path of least resistance? Or do physicians not accept the data showing that it is unnecessary?

Dr. Gerald Appel discusses diabetic nephropathy, an area that involves resistance of another kind, ie, the apparent resistance of physicians and patients to achieving evidence-based treatment targets. We hold controlled trials as the Holy Grail of evidence-based medicine, yet we seem to have an aversion to following guidelines based on trial-derived evidence. (I do not refer here to blind guideline adherence, ignoring individual patient characteristics.)

So how can physicians’ behavior be altered and our resistance to change be reduced? Experiments are under way, such as paying physicians based on their performance, linking patients’ insurance rates to achieving selected outcomes, and linking physician practice self-review to certification. Perhaps naively, I continue to believe that the most effective impetus to changing personal practice is the dissemination of data from high-quality trials (tempered by our accumulated experience and keeping our eyes wide open), coupled with our desire to do the best for our patients.

Why individual clinicians make specific decisions usually can be sorted out. But our behavior as a group is more difficult to understand and, even when there are pressing and convincing reasons to change, behavior is difficult to alter.

In this issue, Drs. Federico Perez and David Van Duin discuss the emergence of carbapenem-resistant bacteria, dubbed “superbugs” by the media. Antibiotic resistance is not new; it was reported in Staphylococcus species within several years of the introduction of penicillin.¹ However, it has been increasing in prevalence and molecular complexity after years of relatively promiscuous antibiotic use. As the percentage of inpatients with immunosuppression and frailty increases in this environment of known antibiotic resistance, initial empiric antibiotic choices will by necessity include drugs likely to further promote development of resistant strains. But why do physicians still prescribe antibiotics for uncomplicated upper respiratory tract infections and asymptomatic bacteriuria, despite numerous studies and guidelines suggesting this practice has little benefit? Is it because patients expect a prescription in return for their copayment? Is it the path of least resistance? Or do physicians not accept the data showing that it is unnecessary?

Dr. Gerald Appel discusses diabetic nephropathy, an area that involves resistance of another kind, ie, the apparent resistance of physicians and patients to achieving evidence-based treatment targets. We hold controlled trials as the Holy Grail of evidence-based medicine, yet we seem to have an aversion to following guidelines based on trial-derived evidence. (I do not refer here to blind guideline adherence, ignoring individual patient characteristics.)

So how can physicians’ behavior be altered and our resistance to change be reduced? Experiments are under way, such as paying physicians based on their performance, linking patients’ insurance rates to achieving selected outcomes, and linking physician practice self-review to certification. Perhaps naively, I continue to believe that the most effective impetus to changing personal practice is the dissemination of data from high-quality trials (tempered by our accumulated experience and keeping our eyes wide open), coupled with our desire to do the best for our patients.

Why individual clinicians make specific decisions usually can be sorted out. But our behavior as a group is more difficult to understand and, even when there are pressing and convincing reasons to change, behavior is difficult to alter.

In this issue, Drs. Federico Perez and David Van Duin discuss the emergence of carbapenem-resistant bacteria, dubbed “superbugs” by the media. Antibiotic resistance is not new; it was reported in Staphylococcus species within several years of the introduction of penicillin.¹ However, it has been increasing in prevalence and molecular complexity after years of relatively promiscuous antibiotic use. As the percentage of inpatients with immunosuppression and frailty increases in this environment of known antibiotic resistance, initial empiric antibiotic choices will by necessity include drugs likely to further promote development of resistant strains. But why do physicians still prescribe antibiotics for uncomplicated upper respiratory tract infections and asymptomatic bacteriuria, despite numerous studies and guidelines suggesting this practice has little benefit? Is it because patients expect a prescription in return for their copayment? Is it the path of least resistance? Or do physicians not accept the data showing that it is unnecessary?

Dr. Gerald Appel discusses diabetic nephropathy, an area that involves resistance of another kind, ie, the apparent resistance of physicians and patients to achieving evidence-based treatment targets. We hold controlled trials as the Holy Grail of evidence-based medicine, yet we seem to have an aversion to following guidelines based on trial-derived evidence. (I do not refer here to blind guideline adherence, ignoring individual patient characteristics.)

So how can physicians’ behavior be altered and our resistance to change be reduced? Experiments are under way, such as paying physicians based on their performance, linking patients’ insurance rates to achieving selected outcomes, and linking physician practice self-review to certification. Perhaps naively, I continue to believe that the most effective impetus to changing personal practice is the dissemination of data from high-quality trials (tempered by our accumulated experience and keeping our eyes wide open), coupled with our desire to do the best for our patients.

Diabetes is on the rise, and so is diabetic nephropathy. In view of this epidemic, physicians should consider strategies to detect and control kidney disease in their diabetic patients.

This article will focus on kidney disease in adult-onset type 2 diabetes. Although it has different pathogenetic mechanisms than type 1 diabetes, the clinical course of the two conditions is very similar in terms of the prevalence of proteinuria after diagnosis, the progression to renal failure after the onset of proteinuria, and treatment options.¹

DIABETES AND DIABETIC KIDNEY DISEASE ARE ON THE RISE

The incidence of diabetes increases with age, and with the aging of the baby boomers, its prevalence is growing dramatically. The 2005– 2008 National Health and Nutrition Examination Survey estimated the prevalence as 3.7% in adults age 20 to 44, 13.7% at age 45 to 64, and 26.9% in people age 65 and older. The obesity epidemic is also contributing to the increase in diabetes in all age groups.

Diabetic kidney disease has increased in the United States from about 4 million cases 20 years ago to about 7 million in 2005–2008.² Diabetes is the major cause of end-stage renal disease in the developed world, accounting for 40% to 50% of cases. Other major causes are hypertension (27%) and glomerulonephritis (13%).³

Physicians in nearly every field of medicine now care for patients with diabetic nephropathy. The classic presentation—a patient who has impaired vision, fluid retention with edema, and hypertension—is commonly seen in dialysis units and ophthalmology and cardiovascular clinics.

CLINICAL PROGRESSION

Early in the course of diabetic nephropathy, blood pressure is normal and microalbuminuria is not evident, but many patients have a high glomerular filtration rate (GFR), indicating temporarily “enhanced” renal function or hyperfiltration. The next stage is characterized by microalbuminuria, correlating with glomerular mesangial expansion: the GFR falls back into the normal range and blood pressure starts to increase. Finally, macroalbuminuria occurs, accompanied by rising blood pressure and a declining GFR, correlating with the histologic appearance of glomerulosclerosis and Kimmelstiel-Wilson nodules.⁴

Hypertension develops in 5% of patients by 10 years after type 1 diabetes is diagnosed, 33% by 20 years, and 70% by 40 years. In contrast, 40% of patients with type 2 diabetes have high blood pressure at diagnosis.

Unfortunately, in most cases, this progression is a one-way street, so it is critical to intervene to try to slow the progression early in the course of the disease process.

SCREENING FOR DIABETIC NEPHROPATHY

Nephropathy screening guidelines for patients with diabetes are provided in Table 1.⁵

Blood pressure should be monitored at each office visit (Table 1). The goal for adults with diabetes should be to reduce blood pressure to 130/80 mm Hg. Reduction beyond this level may be associated with an increased mortality rate.⁶ Very high blood pressure (> 180 mm Hg systolic) should be lowered slowly. Lowering blood pressure delays the progression from microalbuminuria (30–299 mg/day or 20–199 μg/min) to macroalbuminuria (> 300 mg/day or > 200 μg/min) and slows the progression to renal failure.

Urinary albumin. Proteinuria takes 5 to 10 years to develop after the onset of diabetes. Because it is possible for patients with type 2 diabetes to have had the disease for some time before being diagnosed, urinary albumin screening should be performed at diagnosis and annually thereafter. Patients with type 1 are usually diagnosed with diabetes at or near onset of disease; therefore, annual screening for urinary albumin can begin 5 years after diagnosis.⁵

Proteinuria can be measured in different ways (Table 2). The basic screening test for clinical proteinuria is the urine dipstick, which is very sensitive to albumin and relatively insensitive to other proteins. “Trace-positive” results are common in healthy people, so proteinuria is not confirmed unless a patient has repeatedly positive results.

Microalbuminuria is important to measure, especially if it helps determine therapy. It is not detectable by the urinary dipstick, but can be measured in the following ways:

• Measurement of the albumin-creatinine ratio in a random spot collection
• 24-hour collection (creatinine should simultaneously be measured and creatinine clearance calculated)
• Timed collection (4 hours or overnight).

The first method is preferred, and any positive test result must be confirmed by repeat analyses of urinary albumin before a patient is diagnosed with microalbuminuria.

Occasionally a patient presenting with proteinuria but normal blood sugar and hemoglobin A_1c will have a biopsy that reveals morphologic changes of classic diabetic nephropathy. Most such patients have a history of hyperglycemia, indicating that they actually have been diabetic.

Proteinuria is the strongest predictor of renal outcomes. The Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled trial in more than 1,500 patients with type 2 diabetes to test the effects of losartan on renal outcome. Those with high albuminuria (> 3.0 g albumin/g creatinine) at baseline were five times more likely to reach a renal end point and were eight times more likely to have progression to end-stage renal disease than patients with low albuminuria (< 1.5 g/g).⁷ The degree of albuminuria after 6 months of treatment showed similar predictive trends, indicating that monitoring and treating proteinuria are extremely important goals.

STRATEGY 1 TO LIMIT RENAL INJURY: REDUCE BLOOD PRESSURE

Blood pressure control improves renal and cardiovascular function.

As early as 1983, Parving et al,⁸ in a study of only 10 insulin-dependent diabetic patients, showed strong evidence that early aggressive antihypertensive treatment improved the course of diabetic nephropathy. During the mean pretreatment period of 29 months, the GFR decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the mean 39-month period of antihypertensive treatment with metoprolol, hydralazine, and furosemide or a thiazide, mean arterial blood pressure fell from 144/97 to 128/84 mm Hg and urinary albumin excretion from 977 to 433 μg/ min. The rate of decline in GFR slowed from 0.91 mL/min/month before treatment to 0.39 mL/min/month during treatment.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial⁹ enrolled more than 11,000 patients internationally with type 2 diabetes at high risk for cardiovascular events. In addition to standard therapy, blood pressure was intensively controlled in one group with a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic indapamide. The intensive-therapy group achieved blood pressures less than 140/80 mm Hg and had a mean reduction of systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg vs controls. Despite these apparently modest reductions, the intensively controlled group had a significant 9% reduction of the primary outcome of combined macrovascular events (cardiovascular death, myocardial infarction, and stroke) and microvascular events (new or worsening nephropathy, or retinopathy).¹⁰

A meta-analysis of studies of patients with type 2 diabetes found reduced nephropathy with systolic blood pressure control to less than 130 mm Hg.¹¹

The United Kingdom Prospective Diabetes Study (UKPDS) is a series of studies of diabetes. The original study in 1998 enrolled 5,102 patients with newly diagnosed type 2 diabetes.¹² The more than 1,000 patients with hypertension were randomized to either tight blood pressure control or regular care. The intensive treatment group had a mean blood pressure reduction of 9 mm Hg systolic and 3 mm Hg diastolic, along with major reductions in all diabetes end points, diabetes deaths, microvascular disease, and stroke over a median follow-up of 8.4 years.

Continuous blood pressure control is critical

Tight blood pressure control must be maintained to have continued benefit. During the 10 years following the UKPDS, no attempts were made to maintain the previously assigned therapies. A follow-up study¹³ of 884 UKPDS patients found that blood pressures were the same again between the two groups 2 years after the trial was stopped, and no beneficial legacy effect from previous blood pressure control was evident on end points.

Control below 120 mm Hg systolic not needed

Blood pressure control slows kidney disease and prevents major macrovascular disease, but there is no evidence that lowering systolic blood pressure below 120 mm Hg provides additional benefit. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹⁴ more than 10,000 patients with type 2 diabetes and existing cardiovascular disease or additional cardiovascular risk factors were randomized to a goal of systolic blood pressure less than 120 mm Hg or less than 140 mm Hg (actual mean systolic pressures were 119 vs 134 mm Hg, respectively). Over nearly 5 years, there was no difference in cardiovascular events or deaths between the two groups.¹⁵

Since 1997, six international organizations have revised their recommended blood pressure goals in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 125/75 to 140/80 mm Hg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to less than 130/80 mm Hg.^16–21 Table 3 summarizes blood pressure goals for patients with diabetes.

STRATEGY 2: CONTROL BLOOD SUGAR

Recommendations for blood sugar goals are more controversial.

The Diabetes Control and Complications Trial²² provided early evidence that tight blood sugar control slows the development of microalbuminuria and macroalbuminuria. The study randomized more than 1,400 patients with type 1 diabetes to either standard therapy (1 or 2 daily insulin injections) or intensive therapy (an external insulin pump or 3 or more insulin injections guided by frequent blood glucose monitoring) to keep blood glucose levels close to normal. About half the patients had mild retinopathy at baseline and the others had no retinopathy. After 6.5 years, intensive therapy was found to significantly delay the onset and slow the progression of diabetic retinopathy and nephropathy.

The Kumamoto Study²³ randomized 110 patients with type 2 diabetes and either no retinopathy (primary prevention cohort) or simple retinopathy (secondary prevention cohort) to receive either multiple insulin injections or conventional insulin therapy over 8 years. Intensive therapy led to lower rates of retinopathy (7.7% vs 32% in primary prevention and 19% vs 44% in secondary prevention) and progressive nephropathy (7% vs 28% in primary prevention at 6 years and 11% vs 32% in secondary prevention).

In addition to studying the effects of blood pressure control, the UKPDS also studied the effects of intensive blood glucose control.^24,25 Nearly 4,000 patients with newly diagnosed type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin, or to conventional treatment with diet. Over 10 years, the mean hemoglobin A_1c was reduced to 7.0% in the intensive group and 7.9% in the conventional group. The risk of any diabetes-related end point was 12% lower in the intensive group, 10% lower for diabetes-related death, and 6% lower for all-cause mortality. There was also a 25% reduction in microvascular disease (retinopathy and nephropathy). However, the intensive group had more hypoglycemic episodes than the conventional group and a tendency to some increase in macrovascular events. A legacy effect was evident: patients who had intensive treatment had less microvascular disease progression years after stopping therapy.

Earlier trials provided strong evidence that blood glucose control prevents or slows retinopathy and nephropathy. The critical question is, “At what expense?” Although diabetes is the most common cause of kidney failure in the United States, most people with diabetes do not die of kidney failure, but of cardiovascular disease. Two recent large trials had different results regarding glycemic control below hemoglobin A_1c of 7.0% and macrovascular risk, creating a controversy about what recommendations are best.

The ADVANCE trial, enrolling 11,140 patients with type 2 diabetes, was largely conducted in Australia and used the sulfonylurea glipizide for glycemic control. Compared with the group that received standard therapy (n=5,569), the intensive-treatment group (n=5,571) achieved mean hemoglobin A_1c levels of 6.5% compared with 7.3% in the standard group, and had less nephropathy, less microalbuminuria, less doubling of creatinine, and a lower rate of end-stage renal disease (4% vs 5% in the standard therapy group). No difference between the two groups was found in retinopathy. Rates of all-cause mortality did not differ between the groups.⁹

The ACCORD trial had more than 10,000 subjects with type 2 diabetes and took place mostly in the United States. Using mainly rosiglitazone for intensive therapy, the intensive group achieved hemoglobin A_1c levels of 6.4% vs 7.5% in the standard-therapy group. The trial was stopped early, at 3.7 years, because of a higher risk of death and cardiovascular events in the group with intensive glycemic control. However, the intensive-therapy group did have a significant decrease in microvascular renal outcomes and a reduction in the progression of retinopathy.^14,26

In summary, tighter glycemic control improves microvascular complications—both retinopathy and nephropathy—in patients with type 2 diabetes. The benefit of intensive therapy on macrovascular complications (stroke, myocardial infarction) in long-standing diabetes has not been convincingly demonstrated in randomized trials. The UKPDS suggested that maintaining a hemoglobin A_1c of 7% in patients newly diagnosed with type 2 diabetes confers long-term cardiovascular benefits. The target hemoglobin A_1c for type 2 diabetes should be tailored to the patient: 7% is a reasonable goal for most patients, but the goal should be higher for the elderly and frail. Reducing the risk of cardiovascular death is still best done by controlling blood pressure, reducing lipids, quitting smoking, and losing weight.

STRATEGY 3: INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

Components of the renin-angiotensin-aldo-sterone system are present not only in the circulation but also in many tissues, including the heart, brain, kidney, blood vessels, and adrenal glands. The role of renin-angiotensin-aldosterone system blockers in treating and preventing diabetic nephropathy has become controversial in recent years with findings from new studies.

The renin-angiotensin-aldosterone system is important in the development or maintenance of high blood pressure and the resultant damage to the brain, heart, and kidney. Drug development has focused on inhibiting steps in the biochemical pathway. ACE inhibitors block the formation of angiotensin II—the most biologically potent angiotensin peptide—and are among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure. Angiotensin receptor blockers (ARBs) interact with the angiotensin AT1 receptor and block most of its actions. They are approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and they help prevent left ventricular hypertrophy and mesangial sclerosis. Large studies have shown that ACE inhibitors and ARBs offer similar cardiovascular benefit.

The glomerulus has the only capillary bed with a blood supply that drains into an efferent arteriole instead of a venule, providing high resistance to aid filtration. Efferent arterioles are rich in AT1 receptors. In the presence of angiotensin II they constrict, increasing pressure in the glomerulus, which can lead to proteinuria and glomerulosclerosis. ACE inhibitors and ARBs relax the efferent arteriole, allowing increased blood flow through the glomerulus. This reduction in intraglomerular pressure is associated with less proteinuria and less glomerulosclerosis.

Diabetes promotes renal disease in many ways. Glucose and advanced glycation end products can lead to increased blood flow and increased pressure in the glomerulus. Through a variety of pathways, hyperglycemia, acting on angiotensin II, leads to NF-kapa beta production, profibrotic cytokines, increased matrix, and eventual fibrosis. ACE inhibitors and ARBs counteract many of these.

ACE inhibitors and ARBs slow nephropathy progression beyond blood pressure control

Several major clinical trials^27–32 examined the effects of either ACE inhibitors or ARBs in slowing the progression of diabetic nephropathy and have had consistently positive results.

The Collaborative Study Group³⁰ was a 3-year randomized trial in 419 patients with type 1 diabetes, using the ACE inhibitor captopril vs placebo. Captopril was associated with less decline in kidney function and a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small difference in blood pressures between the two groups.

The Irbesartan Diabetic Nephropathy Trial (IDNT)³¹ studied the effect of the ARB irbesartan vs the calcium channel blocker amlodipine vs placebo over 2.6 years in 1,715 patients with type 2 diabetes. Irbesartan was found to be significantly more effective in protecting against the progression of nephropathy, independent of reduction in blood pressure.

The RENAAL trial,³² published in 2001, was a 3-year, randomized, double-blind study comparing the ARB losartan at increasing dosages with placebo (both taken in addition to conventional antihypertensive treatment) in 1,513 patients with type 2 diabetes and nephropathy. The blood pressure goal was 140/90 mm Hg in both groups, but the losartan group had a lower rate of doubling of serum creatinine, end-stage renal disease, and combined end-stage renal disease or death.

‘Aldosterone escape’ motivates the search for new therapies

An important reason for developing more ways to block the renin-angiotensin-aldosterone system is because of “aldosterone escape,” the phenomenon of angiotensin II or aldosterone returning to pretreatment levels despite continued ACE inhibition.

Biollaz et al,³³ in a 1982 study of 19 patients with hypertension, showed that despite reducing blood pressure and keeping the blood level of ACE very low with twice-daily enalapril 20 mg, blood and urine levels of angiotensin II steadily rose back to baseline levels within a few months.

A growing body of evidence suggests that despite effective inhibition of angiotensin II activity, non-ACE synthetic pathways still permit angiotensin II generation via serine proteases such as chymase, cathepsin G, and tissue plasminogen activator.

Thus, efforts have been made to block the renin-angiotensin system in other places. In addition to ACE inhibitors and ARBs, two aldosterone receptor antagonists are available, spironolactone and eplerenone, both used to treat heart failure. A direct renin inhibitor, aliskiren, is also available.

A number of studies have shown that combination treatment with agents having different targets in the renin-angiotensin-aldosterone system leads to larger reductions in albuminuria than does single-agent therapy.

Mogensen et al³⁴ studied the effect of the ACE inhibitor lisinopril (20 mg per day) plus the ARB candesartan (16 mg per day) in subjects with microalbuminuria, hypertension, and type 2 diabetes. Combined treatment was more effective in reducing proteinuria.

Epstein et al³⁵ studied the effects of the ACE inhibitor enalapril (20 mg/day) combined with either of two doses of the selective aldosterone receptor antagonist eplerenone (50 or 100 mg/day) or placebo. Both eplerenone dosages, when added to the enalapril treatment, significantly reduced albuminuria from baseline as early as week 4 (P < .001), but placebo treatment added to the enalapril did not result in any significant decrease in urinary albumin excretion. Systolic blood pressure decreased significantly in all treatment groups and by about the same amount.

The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) trial³⁶ randomized more than 600 patients with type 2 diabetes and nephropathy to aliskiren (a renin inhibitor) or placebo added to the ARB losartan. Again, combination treatment was more renoprotective, independent of blood pressure lowering.

Worse outcomes with combination therapy?

More recent studies have indicated that although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal and cardiovascular outcomes. The multicenter Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)³⁷ randomized more than 25,000 patients age 55 and older with established atherosclerotic vascular disease or with diabetes and end-organ damage to receive either the ARB telmisartan 80 mg daily, the ACE inhibitor ramipril 10 mg daily, or both. Mean follow-up was 56 months. The combination-treatment group had higher rates of death and renal disease than the single-therapy groups (which did not differ from one another).

Why the combination therapy had poorer outcomes is under debate. Patients may get sudden drops in blood pressure that are not detected with only periodic monitoring. Renal failure was mostly acute rather than chronic, and the estimated GFR declined more in the combined therapy group than in the single-therapy groups.

The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) was designed to test the effect of the direct renin inhibitor aliskiren or placebo, both arms combined with either an ACE inhibitor or an ARB in patients with type 2 diabetes at high risk for cardiovascular and renal events. The trial was terminated early because of more strokes and deaths in the combination therapy arms. The results led the FDA to issue black box warnings against using aliskiren with these other classes of agents, and all studies testing similar combinations have been stopped. (In one study that was stopped and has not yet been published, 100 patients with proteinuria were treated with either aliskiren, the ARB losartan, or both, to evaluate the effects of aldosterone escape. Results showed no differences: about one-third of each group had this phenomenon.)

My personal recommendation is as follows: for younger patients with proteinuria, at lower risk for cardiovascular events and with disease due not to diabetes but to immunoglobulin A nephropathy or another proteinuric kidney disease, treat with both an ACE inhibitor and ARB. But the combination should not be used for patients at high risk of cardiovascular disease, which includes almost all patients with diabetes.

If more aggressive renin-angiotensin system blockade is needed against diabetic nephropathy, adding a diuretic increases the impact of blocking the renin-angiotensin-aldosterone system on both proteinuria and progression of renal disease. The aldosterone blocker spironolactone 25 mg can be added if potassium levels are carefully monitored.

ACE inhibitor plus calcium channel blocker is safer than ACE inhibitor plus diuretic

The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial³⁸ randomized more than 11,000 high-risk patients with hypertension to receive an ACE inhibitor (benazepril) plus either a calcium channel blocker (amlodipine) or thiazide diuretic (hydrochlorothiazide). Blood pressures were identical between the two groups, but the trial was terminated early, at 36 months, because of a higher risk of the combined end point of cardiovascular death, myocardial infarction, stroke, and other major cardiac events in the ACE inhibitor-thiazide group.

Although some experts believe this study is definitive and indicates that high blood pressure should never be treated with an ACE inhibitor-thiazide combination, I believe that caution is needed in interpreting these findings. This regimen should be avoided in older patients with diabetes at high risk for cardiovascular disease, but otherwise, getting blood pressure under control is critical, and this combination can be used if it works and the patient is tolerating it well.

In summary, the choice of blood pressure-lowering medications is based on reducing cardiovascular events and slowing the progression of kidney disease. Either an ACE inhibitor or an ARB is the first choice for patients with diabetes, hypertension, and any degree of proteinuria. Many experts recommend beginning one of these agents even if proteinuria is not present. However, the combination of an ACE inhibitor and ARB should not be used in diabetic patients, especially if they have cardiovascular disease, until further data clarify the results of the ONTARGET and ALTITUDE trials.

STRATEGY 4: METABOLIC MANIPULATION WITH NOVEL AGENTS

Several new agents have recently been studied for the treatment of diabetic nephropathy, including aminoguanidine, which reduces levels of advanced glycation end-products, and sulodexide, which blocks basement membrane permeability. Neither agent has been shown to be safe and effective in diabetic nephropathy. The newest agent is bardoxolone methyl. It induces the Keap1–Nrf2 pathway, which up-regulates cytoprotective factors, suppressing inflammatory and other cytokines that are major mediators of progression of chronic kidney disease.³⁹

Pergola et al,⁴⁰ in a phase 2, double-blind trial, randomized 227 adults with diabetic kidney disease and a low estimated GFR (20–45 mL/min/1.73 m²) to receive placebo or bardoxolone 25, 75, or 150 mg daily. Drug treatment was associated with improvement in the estimated GFR, a finding that persisted throughout the 52 weeks of treatment. Surprisingly, proteinuria did not decrease with drug treatment.

As of this writing, a large multicenter controlled randomized trial has been halted because of concerns by the data safety monitoring board, which found increased rates of death and fluid retention with the drug. A number of recent trials have shown a beneficial effect of sodium bicarbonate therapy in patients with late-stage chronic kidney disease. They have shown slowing of the progression of GFR decline in a number of renal diseases, including diabetes.

Diabetes is on the rise, and so is diabetic nephropathy. In view of this epidemic, physicians should consider strategies to detect and control kidney disease in their diabetic patients.

This article will focus on kidney disease in adult-onset type 2 diabetes. Although it has different pathogenetic mechanisms than type 1 diabetes, the clinical course of the two conditions is very similar in terms of the prevalence of proteinuria after diagnosis, the progression to renal failure after the onset of proteinuria, and treatment options.¹

DIABETES AND DIABETIC KIDNEY DISEASE ARE ON THE RISE

The incidence of diabetes increases with age, and with the aging of the baby boomers, its prevalence is growing dramatically. The 2005– 2008 National Health and Nutrition Examination Survey estimated the prevalence as 3.7% in adults age 20 to 44, 13.7% at age 45 to 64, and 26.9% in people age 65 and older. The obesity epidemic is also contributing to the increase in diabetes in all age groups.

Diabetic kidney disease has increased in the United States from about 4 million cases 20 years ago to about 7 million in 2005–2008.² Diabetes is the major cause of end-stage renal disease in the developed world, accounting for 40% to 50% of cases. Other major causes are hypertension (27%) and glomerulonephritis (13%).³

Physicians in nearly every field of medicine now care for patients with diabetic nephropathy. The classic presentation—a patient who has impaired vision, fluid retention with edema, and hypertension—is commonly seen in dialysis units and ophthalmology and cardiovascular clinics.

CLINICAL PROGRESSION

Early in the course of diabetic nephropathy, blood pressure is normal and microalbuminuria is not evident, but many patients have a high glomerular filtration rate (GFR), indicating temporarily “enhanced” renal function or hyperfiltration. The next stage is characterized by microalbuminuria, correlating with glomerular mesangial expansion: the GFR falls back into the normal range and blood pressure starts to increase. Finally, macroalbuminuria occurs, accompanied by rising blood pressure and a declining GFR, correlating with the histologic appearance of glomerulosclerosis and Kimmelstiel-Wilson nodules.⁴

Hypertension develops in 5% of patients by 10 years after type 1 diabetes is diagnosed, 33% by 20 years, and 70% by 40 years. In contrast, 40% of patients with type 2 diabetes have high blood pressure at diagnosis.

Unfortunately, in most cases, this progression is a one-way street, so it is critical to intervene to try to slow the progression early in the course of the disease process.

SCREENING FOR DIABETIC NEPHROPATHY

Nephropathy screening guidelines for patients with diabetes are provided in Table 1.⁵

Blood pressure should be monitored at each office visit (Table 1). The goal for adults with diabetes should be to reduce blood pressure to 130/80 mm Hg. Reduction beyond this level may be associated with an increased mortality rate.⁶ Very high blood pressure (> 180 mm Hg systolic) should be lowered slowly. Lowering blood pressure delays the progression from microalbuminuria (30–299 mg/day or 20–199 μg/min) to macroalbuminuria (> 300 mg/day or > 200 μg/min) and slows the progression to renal failure.

Urinary albumin. Proteinuria takes 5 to 10 years to develop after the onset of diabetes. Because it is possible for patients with type 2 diabetes to have had the disease for some time before being diagnosed, urinary albumin screening should be performed at diagnosis and annually thereafter. Patients with type 1 are usually diagnosed with diabetes at or near onset of disease; therefore, annual screening for urinary albumin can begin 5 years after diagnosis.⁵

Proteinuria can be measured in different ways (Table 2). The basic screening test for clinical proteinuria is the urine dipstick, which is very sensitive to albumin and relatively insensitive to other proteins. “Trace-positive” results are common in healthy people, so proteinuria is not confirmed unless a patient has repeatedly positive results.

Microalbuminuria is important to measure, especially if it helps determine therapy. It is not detectable by the urinary dipstick, but can be measured in the following ways:

• Measurement of the albumin-creatinine ratio in a random spot collection
• 24-hour collection (creatinine should simultaneously be measured and creatinine clearance calculated)
• Timed collection (4 hours or overnight).

The first method is preferred, and any positive test result must be confirmed by repeat analyses of urinary albumin before a patient is diagnosed with microalbuminuria.

Occasionally a patient presenting with proteinuria but normal blood sugar and hemoglobin A_1c will have a biopsy that reveals morphologic changes of classic diabetic nephropathy. Most such patients have a history of hyperglycemia, indicating that they actually have been diabetic.

Proteinuria is the strongest predictor of renal outcomes. The Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled trial in more than 1,500 patients with type 2 diabetes to test the effects of losartan on renal outcome. Those with high albuminuria (> 3.0 g albumin/g creatinine) at baseline were five times more likely to reach a renal end point and were eight times more likely to have progression to end-stage renal disease than patients with low albuminuria (< 1.5 g/g).⁷ The degree of albuminuria after 6 months of treatment showed similar predictive trends, indicating that monitoring and treating proteinuria are extremely important goals.

STRATEGY 1 TO LIMIT RENAL INJURY: REDUCE BLOOD PRESSURE

Blood pressure control improves renal and cardiovascular function.

As early as 1983, Parving et al,⁸ in a study of only 10 insulin-dependent diabetic patients, showed strong evidence that early aggressive antihypertensive treatment improved the course of diabetic nephropathy. During the mean pretreatment period of 29 months, the GFR decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the mean 39-month period of antihypertensive treatment with metoprolol, hydralazine, and furosemide or a thiazide, mean arterial blood pressure fell from 144/97 to 128/84 mm Hg and urinary albumin excretion from 977 to 433 μg/ min. The rate of decline in GFR slowed from 0.91 mL/min/month before treatment to 0.39 mL/min/month during treatment.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial⁹ enrolled more than 11,000 patients internationally with type 2 diabetes at high risk for cardiovascular events. In addition to standard therapy, blood pressure was intensively controlled in one group with a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic indapamide. The intensive-therapy group achieved blood pressures less than 140/80 mm Hg and had a mean reduction of systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg vs controls. Despite these apparently modest reductions, the intensively controlled group had a significant 9% reduction of the primary outcome of combined macrovascular events (cardiovascular death, myocardial infarction, and stroke) and microvascular events (new or worsening nephropathy, or retinopathy).¹⁰

A meta-analysis of studies of patients with type 2 diabetes found reduced nephropathy with systolic blood pressure control to less than 130 mm Hg.¹¹

The United Kingdom Prospective Diabetes Study (UKPDS) is a series of studies of diabetes. The original study in 1998 enrolled 5,102 patients with newly diagnosed type 2 diabetes.¹² The more than 1,000 patients with hypertension were randomized to either tight blood pressure control or regular care. The intensive treatment group had a mean blood pressure reduction of 9 mm Hg systolic and 3 mm Hg diastolic, along with major reductions in all diabetes end points, diabetes deaths, microvascular disease, and stroke over a median follow-up of 8.4 years.

Continuous blood pressure control is critical

Tight blood pressure control must be maintained to have continued benefit. During the 10 years following the UKPDS, no attempts were made to maintain the previously assigned therapies. A follow-up study¹³ of 884 UKPDS patients found that blood pressures were the same again between the two groups 2 years after the trial was stopped, and no beneficial legacy effect from previous blood pressure control was evident on end points.

Control below 120 mm Hg systolic not needed

Blood pressure control slows kidney disease and prevents major macrovascular disease, but there is no evidence that lowering systolic blood pressure below 120 mm Hg provides additional benefit. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹⁴ more than 10,000 patients with type 2 diabetes and existing cardiovascular disease or additional cardiovascular risk factors were randomized to a goal of systolic blood pressure less than 120 mm Hg or less than 140 mm Hg (actual mean systolic pressures were 119 vs 134 mm Hg, respectively). Over nearly 5 years, there was no difference in cardiovascular events or deaths between the two groups.¹⁵

Since 1997, six international organizations have revised their recommended blood pressure goals in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 125/75 to 140/80 mm Hg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to less than 130/80 mm Hg.^16–21 Table 3 summarizes blood pressure goals for patients with diabetes.

STRATEGY 2: CONTROL BLOOD SUGAR

Recommendations for blood sugar goals are more controversial.

The Diabetes Control and Complications Trial²² provided early evidence that tight blood sugar control slows the development of microalbuminuria and macroalbuminuria. The study randomized more than 1,400 patients with type 1 diabetes to either standard therapy (1 or 2 daily insulin injections) or intensive therapy (an external insulin pump or 3 or more insulin injections guided by frequent blood glucose monitoring) to keep blood glucose levels close to normal. About half the patients had mild retinopathy at baseline and the others had no retinopathy. After 6.5 years, intensive therapy was found to significantly delay the onset and slow the progression of diabetic retinopathy and nephropathy.

The Kumamoto Study²³ randomized 110 patients with type 2 diabetes and either no retinopathy (primary prevention cohort) or simple retinopathy (secondary prevention cohort) to receive either multiple insulin injections or conventional insulin therapy over 8 years. Intensive therapy led to lower rates of retinopathy (7.7% vs 32% in primary prevention and 19% vs 44% in secondary prevention) and progressive nephropathy (7% vs 28% in primary prevention at 6 years and 11% vs 32% in secondary prevention).

In addition to studying the effects of blood pressure control, the UKPDS also studied the effects of intensive blood glucose control.^24,25 Nearly 4,000 patients with newly diagnosed type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin, or to conventional treatment with diet. Over 10 years, the mean hemoglobin A_1c was reduced to 7.0% in the intensive group and 7.9% in the conventional group. The risk of any diabetes-related end point was 12% lower in the intensive group, 10% lower for diabetes-related death, and 6% lower for all-cause mortality. There was also a 25% reduction in microvascular disease (retinopathy and nephropathy). However, the intensive group had more hypoglycemic episodes than the conventional group and a tendency to some increase in macrovascular events. A legacy effect was evident: patients who had intensive treatment had less microvascular disease progression years after stopping therapy.

Earlier trials provided strong evidence that blood glucose control prevents or slows retinopathy and nephropathy. The critical question is, “At what expense?” Although diabetes is the most common cause of kidney failure in the United States, most people with diabetes do not die of kidney failure, but of cardiovascular disease. Two recent large trials had different results regarding glycemic control below hemoglobin A_1c of 7.0% and macrovascular risk, creating a controversy about what recommendations are best.

The ADVANCE trial, enrolling 11,140 patients with type 2 diabetes, was largely conducted in Australia and used the sulfonylurea glipizide for glycemic control. Compared with the group that received standard therapy (n=5,569), the intensive-treatment group (n=5,571) achieved mean hemoglobin A_1c levels of 6.5% compared with 7.3% in the standard group, and had less nephropathy, less microalbuminuria, less doubling of creatinine, and a lower rate of end-stage renal disease (4% vs 5% in the standard therapy group). No difference between the two groups was found in retinopathy. Rates of all-cause mortality did not differ between the groups.⁹

The ACCORD trial had more than 10,000 subjects with type 2 diabetes and took place mostly in the United States. Using mainly rosiglitazone for intensive therapy, the intensive group achieved hemoglobin A_1c levels of 6.4% vs 7.5% in the standard-therapy group. The trial was stopped early, at 3.7 years, because of a higher risk of death and cardiovascular events in the group with intensive glycemic control. However, the intensive-therapy group did have a significant decrease in microvascular renal outcomes and a reduction in the progression of retinopathy.^14,26

In summary, tighter glycemic control improves microvascular complications—both retinopathy and nephropathy—in patients with type 2 diabetes. The benefit of intensive therapy on macrovascular complications (stroke, myocardial infarction) in long-standing diabetes has not been convincingly demonstrated in randomized trials. The UKPDS suggested that maintaining a hemoglobin A_1c of 7% in patients newly diagnosed with type 2 diabetes confers long-term cardiovascular benefits. The target hemoglobin A_1c for type 2 diabetes should be tailored to the patient: 7% is a reasonable goal for most patients, but the goal should be higher for the elderly and frail. Reducing the risk of cardiovascular death is still best done by controlling blood pressure, reducing lipids, quitting smoking, and losing weight.

STRATEGY 3: INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

Components of the renin-angiotensin-aldo-sterone system are present not only in the circulation but also in many tissues, including the heart, brain, kidney, blood vessels, and adrenal glands. The role of renin-angiotensin-aldosterone system blockers in treating and preventing diabetic nephropathy has become controversial in recent years with findings from new studies.

The renin-angiotensin-aldosterone system is important in the development or maintenance of high blood pressure and the resultant damage to the brain, heart, and kidney. Drug development has focused on inhibiting steps in the biochemical pathway. ACE inhibitors block the formation of angiotensin II—the most biologically potent angiotensin peptide—and are among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure. Angiotensin receptor blockers (ARBs) interact with the angiotensin AT1 receptor and block most of its actions. They are approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and they help prevent left ventricular hypertrophy and mesangial sclerosis. Large studies have shown that ACE inhibitors and ARBs offer similar cardiovascular benefit.

The glomerulus has the only capillary bed with a blood supply that drains into an efferent arteriole instead of a venule, providing high resistance to aid filtration. Efferent arterioles are rich in AT1 receptors. In the presence of angiotensin II they constrict, increasing pressure in the glomerulus, which can lead to proteinuria and glomerulosclerosis. ACE inhibitors and ARBs relax the efferent arteriole, allowing increased blood flow through the glomerulus. This reduction in intraglomerular pressure is associated with less proteinuria and less glomerulosclerosis.

Diabetes promotes renal disease in many ways. Glucose and advanced glycation end products can lead to increased blood flow and increased pressure in the glomerulus. Through a variety of pathways, hyperglycemia, acting on angiotensin II, leads to NF-kapa beta production, profibrotic cytokines, increased matrix, and eventual fibrosis. ACE inhibitors and ARBs counteract many of these.

ACE inhibitors and ARBs slow nephropathy progression beyond blood pressure control

Several major clinical trials^27–32 examined the effects of either ACE inhibitors or ARBs in slowing the progression of diabetic nephropathy and have had consistently positive results.

The Collaborative Study Group³⁰ was a 3-year randomized trial in 419 patients with type 1 diabetes, using the ACE inhibitor captopril vs placebo. Captopril was associated with less decline in kidney function and a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small difference in blood pressures between the two groups.

The Irbesartan Diabetic Nephropathy Trial (IDNT)³¹ studied the effect of the ARB irbesartan vs the calcium channel blocker amlodipine vs placebo over 2.6 years in 1,715 patients with type 2 diabetes. Irbesartan was found to be significantly more effective in protecting against the progression of nephropathy, independent of reduction in blood pressure.

The RENAAL trial,³² published in 2001, was a 3-year, randomized, double-blind study comparing the ARB losartan at increasing dosages with placebo (both taken in addition to conventional antihypertensive treatment) in 1,513 patients with type 2 diabetes and nephropathy. The blood pressure goal was 140/90 mm Hg in both groups, but the losartan group had a lower rate of doubling of serum creatinine, end-stage renal disease, and combined end-stage renal disease or death.

‘Aldosterone escape’ motivates the search for new therapies

An important reason for developing more ways to block the renin-angiotensin-aldosterone system is because of “aldosterone escape,” the phenomenon of angiotensin II or aldosterone returning to pretreatment levels despite continued ACE inhibition.

Biollaz et al,³³ in a 1982 study of 19 patients with hypertension, showed that despite reducing blood pressure and keeping the blood level of ACE very low with twice-daily enalapril 20 mg, blood and urine levels of angiotensin II steadily rose back to baseline levels within a few months.

A growing body of evidence suggests that despite effective inhibition of angiotensin II activity, non-ACE synthetic pathways still permit angiotensin II generation via serine proteases such as chymase, cathepsin G, and tissue plasminogen activator.

Thus, efforts have been made to block the renin-angiotensin system in other places. In addition to ACE inhibitors and ARBs, two aldosterone receptor antagonists are available, spironolactone and eplerenone, both used to treat heart failure. A direct renin inhibitor, aliskiren, is also available.

A number of studies have shown that combination treatment with agents having different targets in the renin-angiotensin-aldosterone system leads to larger reductions in albuminuria than does single-agent therapy.

Mogensen et al³⁴ studied the effect of the ACE inhibitor lisinopril (20 mg per day) plus the ARB candesartan (16 mg per day) in subjects with microalbuminuria, hypertension, and type 2 diabetes. Combined treatment was more effective in reducing proteinuria.

Epstein et al³⁵ studied the effects of the ACE inhibitor enalapril (20 mg/day) combined with either of two doses of the selective aldosterone receptor antagonist eplerenone (50 or 100 mg/day) or placebo. Both eplerenone dosages, when added to the enalapril treatment, significantly reduced albuminuria from baseline as early as week 4 (P < .001), but placebo treatment added to the enalapril did not result in any significant decrease in urinary albumin excretion. Systolic blood pressure decreased significantly in all treatment groups and by about the same amount.

The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) trial³⁶ randomized more than 600 patients with type 2 diabetes and nephropathy to aliskiren (a renin inhibitor) or placebo added to the ARB losartan. Again, combination treatment was more renoprotective, independent of blood pressure lowering.

Worse outcomes with combination therapy?

More recent studies have indicated that although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal and cardiovascular outcomes. The multicenter Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)³⁷ randomized more than 25,000 patients age 55 and older with established atherosclerotic vascular disease or with diabetes and end-organ damage to receive either the ARB telmisartan 80 mg daily, the ACE inhibitor ramipril 10 mg daily, or both. Mean follow-up was 56 months. The combination-treatment group had higher rates of death and renal disease than the single-therapy groups (which did not differ from one another).

Why the combination therapy had poorer outcomes is under debate. Patients may get sudden drops in blood pressure that are not detected with only periodic monitoring. Renal failure was mostly acute rather than chronic, and the estimated GFR declined more in the combined therapy group than in the single-therapy groups.

The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) was designed to test the effect of the direct renin inhibitor aliskiren or placebo, both arms combined with either an ACE inhibitor or an ARB in patients with type 2 diabetes at high risk for cardiovascular and renal events. The trial was terminated early because of more strokes and deaths in the combination therapy arms. The results led the FDA to issue black box warnings against using aliskiren with these other classes of agents, and all studies testing similar combinations have been stopped. (In one study that was stopped and has not yet been published, 100 patients with proteinuria were treated with either aliskiren, the ARB losartan, or both, to evaluate the effects of aldosterone escape. Results showed no differences: about one-third of each group had this phenomenon.)

My personal recommendation is as follows: for younger patients with proteinuria, at lower risk for cardiovascular events and with disease due not to diabetes but to immunoglobulin A nephropathy or another proteinuric kidney disease, treat with both an ACE inhibitor and ARB. But the combination should not be used for patients at high risk of cardiovascular disease, which includes almost all patients with diabetes.

If more aggressive renin-angiotensin system blockade is needed against diabetic nephropathy, adding a diuretic increases the impact of blocking the renin-angiotensin-aldosterone system on both proteinuria and progression of renal disease. The aldosterone blocker spironolactone 25 mg can be added if potassium levels are carefully monitored.

ACE inhibitor plus calcium channel blocker is safer than ACE inhibitor plus diuretic

The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial³⁸ randomized more than 11,000 high-risk patients with hypertension to receive an ACE inhibitor (benazepril) plus either a calcium channel blocker (amlodipine) or thiazide diuretic (hydrochlorothiazide). Blood pressures were identical between the two groups, but the trial was terminated early, at 36 months, because of a higher risk of the combined end point of cardiovascular death, myocardial infarction, stroke, and other major cardiac events in the ACE inhibitor-thiazide group.

Although some experts believe this study is definitive and indicates that high blood pressure should never be treated with an ACE inhibitor-thiazide combination, I believe that caution is needed in interpreting these findings. This regimen should be avoided in older patients with diabetes at high risk for cardiovascular disease, but otherwise, getting blood pressure under control is critical, and this combination can be used if it works and the patient is tolerating it well.

In summary, the choice of blood pressure-lowering medications is based on reducing cardiovascular events and slowing the progression of kidney disease. Either an ACE inhibitor or an ARB is the first choice for patients with diabetes, hypertension, and any degree of proteinuria. Many experts recommend beginning one of these agents even if proteinuria is not present. However, the combination of an ACE inhibitor and ARB should not be used in diabetic patients, especially if they have cardiovascular disease, until further data clarify the results of the ONTARGET and ALTITUDE trials.

STRATEGY 4: METABOLIC MANIPULATION WITH NOVEL AGENTS

Several new agents have recently been studied for the treatment of diabetic nephropathy, including aminoguanidine, which reduces levels of advanced glycation end-products, and sulodexide, which blocks basement membrane permeability. Neither agent has been shown to be safe and effective in diabetic nephropathy. The newest agent is bardoxolone methyl. It induces the Keap1–Nrf2 pathway, which up-regulates cytoprotective factors, suppressing inflammatory and other cytokines that are major mediators of progression of chronic kidney disease.³⁹

Pergola et al,⁴⁰ in a phase 2, double-blind trial, randomized 227 adults with diabetic kidney disease and a low estimated GFR (20–45 mL/min/1.73 m²) to receive placebo or bardoxolone 25, 75, or 150 mg daily. Drug treatment was associated with improvement in the estimated GFR, a finding that persisted throughout the 52 weeks of treatment. Surprisingly, proteinuria did not decrease with drug treatment.

As of this writing, a large multicenter controlled randomized trial has been halted because of concerns by the data safety monitoring board, which found increased rates of death and fluid retention with the drug. A number of recent trials have shown a beneficial effect of sodium bicarbonate therapy in patients with late-stage chronic kidney disease. They have shown slowing of the progression of GFR decline in a number of renal diseases, including diabetes.

Diabetes is on the rise, and so is diabetic nephropathy. In view of this epidemic, physicians should consider strategies to detect and control kidney disease in their diabetic patients.

This article will focus on kidney disease in adult-onset type 2 diabetes. Although it has different pathogenetic mechanisms than type 1 diabetes, the clinical course of the two conditions is very similar in terms of the prevalence of proteinuria after diagnosis, the progression to renal failure after the onset of proteinuria, and treatment options.¹

DIABETES AND DIABETIC KIDNEY DISEASE ARE ON THE RISE

The incidence of diabetes increases with age, and with the aging of the baby boomers, its prevalence is growing dramatically. The 2005– 2008 National Health and Nutrition Examination Survey estimated the prevalence as 3.7% in adults age 20 to 44, 13.7% at age 45 to 64, and 26.9% in people age 65 and older. The obesity epidemic is also contributing to the increase in diabetes in all age groups.

Diabetic kidney disease has increased in the United States from about 4 million cases 20 years ago to about 7 million in 2005–2008.² Diabetes is the major cause of end-stage renal disease in the developed world, accounting for 40% to 50% of cases. Other major causes are hypertension (27%) and glomerulonephritis (13%).³

Physicians in nearly every field of medicine now care for patients with diabetic nephropathy. The classic presentation—a patient who has impaired vision, fluid retention with edema, and hypertension—is commonly seen in dialysis units and ophthalmology and cardiovascular clinics.

CLINICAL PROGRESSION

Early in the course of diabetic nephropathy, blood pressure is normal and microalbuminuria is not evident, but many patients have a high glomerular filtration rate (GFR), indicating temporarily “enhanced” renal function or hyperfiltration. The next stage is characterized by microalbuminuria, correlating with glomerular mesangial expansion: the GFR falls back into the normal range and blood pressure starts to increase. Finally, macroalbuminuria occurs, accompanied by rising blood pressure and a declining GFR, correlating with the histologic appearance of glomerulosclerosis and Kimmelstiel-Wilson nodules.⁴

Hypertension develops in 5% of patients by 10 years after type 1 diabetes is diagnosed, 33% by 20 years, and 70% by 40 years. In contrast, 40% of patients with type 2 diabetes have high blood pressure at diagnosis.

Unfortunately, in most cases, this progression is a one-way street, so it is critical to intervene to try to slow the progression early in the course of the disease process.

SCREENING FOR DIABETIC NEPHROPATHY

Nephropathy screening guidelines for patients with diabetes are provided in Table 1.⁵

Blood pressure should be monitored at each office visit (Table 1). The goal for adults with diabetes should be to reduce blood pressure to 130/80 mm Hg. Reduction beyond this level may be associated with an increased mortality rate.⁶ Very high blood pressure (> 180 mm Hg systolic) should be lowered slowly. Lowering blood pressure delays the progression from microalbuminuria (30–299 mg/day or 20–199 μg/min) to macroalbuminuria (> 300 mg/day or > 200 μg/min) and slows the progression to renal failure.

Urinary albumin. Proteinuria takes 5 to 10 years to develop after the onset of diabetes. Because it is possible for patients with type 2 diabetes to have had the disease for some time before being diagnosed, urinary albumin screening should be performed at diagnosis and annually thereafter. Patients with type 1 are usually diagnosed with diabetes at or near onset of disease; therefore, annual screening for urinary albumin can begin 5 years after diagnosis.⁵

Proteinuria can be measured in different ways (Table 2). The basic screening test for clinical proteinuria is the urine dipstick, which is very sensitive to albumin and relatively insensitive to other proteins. “Trace-positive” results are common in healthy people, so proteinuria is not confirmed unless a patient has repeatedly positive results.

Microalbuminuria is important to measure, especially if it helps determine therapy. It is not detectable by the urinary dipstick, but can be measured in the following ways:

• Measurement of the albumin-creatinine ratio in a random spot collection
• 24-hour collection (creatinine should simultaneously be measured and creatinine clearance calculated)
• Timed collection (4 hours or overnight).

The first method is preferred, and any positive test result must be confirmed by repeat analyses of urinary albumin before a patient is diagnosed with microalbuminuria.

Occasionally a patient presenting with proteinuria but normal blood sugar and hemoglobin A_1c will have a biopsy that reveals morphologic changes of classic diabetic nephropathy. Most such patients have a history of hyperglycemia, indicating that they actually have been diabetic.

Proteinuria is the strongest predictor of renal outcomes. The Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled trial in more than 1,500 patients with type 2 diabetes to test the effects of losartan on renal outcome. Those with high albuminuria (> 3.0 g albumin/g creatinine) at baseline were five times more likely to reach a renal end point and were eight times more likely to have progression to end-stage renal disease than patients with low albuminuria (< 1.5 g/g).⁷ The degree of albuminuria after 6 months of treatment showed similar predictive trends, indicating that monitoring and treating proteinuria are extremely important goals.

STRATEGY 1 TO LIMIT RENAL INJURY: REDUCE BLOOD PRESSURE

Blood pressure control improves renal and cardiovascular function.

As early as 1983, Parving et al,⁸ in a study of only 10 insulin-dependent diabetic patients, showed strong evidence that early aggressive antihypertensive treatment improved the course of diabetic nephropathy. During the mean pretreatment period of 29 months, the GFR decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the mean 39-month period of antihypertensive treatment with metoprolol, hydralazine, and furosemide or a thiazide, mean arterial blood pressure fell from 144/97 to 128/84 mm Hg and urinary albumin excretion from 977 to 433 μg/ min. The rate of decline in GFR slowed from 0.91 mL/min/month before treatment to 0.39 mL/min/month during treatment.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial⁹ enrolled more than 11,000 patients internationally with type 2 diabetes at high risk for cardiovascular events. In addition to standard therapy, blood pressure was intensively controlled in one group with a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic indapamide. The intensive-therapy group achieved blood pressures less than 140/80 mm Hg and had a mean reduction of systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg vs controls. Despite these apparently modest reductions, the intensively controlled group had a significant 9% reduction of the primary outcome of combined macrovascular events (cardiovascular death, myocardial infarction, and stroke) and microvascular events (new or worsening nephropathy, or retinopathy).¹⁰

A meta-analysis of studies of patients with type 2 diabetes found reduced nephropathy with systolic blood pressure control to less than 130 mm Hg.¹¹

The United Kingdom Prospective Diabetes Study (UKPDS) is a series of studies of diabetes. The original study in 1998 enrolled 5,102 patients with newly diagnosed type 2 diabetes.¹² The more than 1,000 patients with hypertension were randomized to either tight blood pressure control or regular care. The intensive treatment group had a mean blood pressure reduction of 9 mm Hg systolic and 3 mm Hg diastolic, along with major reductions in all diabetes end points, diabetes deaths, microvascular disease, and stroke over a median follow-up of 8.4 years.

Continuous blood pressure control is critical

Tight blood pressure control must be maintained to have continued benefit. During the 10 years following the UKPDS, no attempts were made to maintain the previously assigned therapies. A follow-up study¹³ of 884 UKPDS patients found that blood pressures were the same again between the two groups 2 years after the trial was stopped, and no beneficial legacy effect from previous blood pressure control was evident on end points.

Control below 120 mm Hg systolic not needed

Blood pressure control slows kidney disease and prevents major macrovascular disease, but there is no evidence that lowering systolic blood pressure below 120 mm Hg provides additional benefit. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹⁴ more than 10,000 patients with type 2 diabetes and existing cardiovascular disease or additional cardiovascular risk factors were randomized to a goal of systolic blood pressure less than 120 mm Hg or less than 140 mm Hg (actual mean systolic pressures were 119 vs 134 mm Hg, respectively). Over nearly 5 years, there was no difference in cardiovascular events or deaths between the two groups.¹⁵

Since 1997, six international organizations have revised their recommended blood pressure goals in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 125/75 to 140/80 mm Hg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to less than 130/80 mm Hg.^16–21 Table 3 summarizes blood pressure goals for patients with diabetes.

STRATEGY 2: CONTROL BLOOD SUGAR

Recommendations for blood sugar goals are more controversial.

The Diabetes Control and Complications Trial²² provided early evidence that tight blood sugar control slows the development of microalbuminuria and macroalbuminuria. The study randomized more than 1,400 patients with type 1 diabetes to either standard therapy (1 or 2 daily insulin injections) or intensive therapy (an external insulin pump or 3 or more insulin injections guided by frequent blood glucose monitoring) to keep blood glucose levels close to normal. About half the patients had mild retinopathy at baseline and the others had no retinopathy. After 6.5 years, intensive therapy was found to significantly delay the onset and slow the progression of diabetic retinopathy and nephropathy.

The Kumamoto Study²³ randomized 110 patients with type 2 diabetes and either no retinopathy (primary prevention cohort) or simple retinopathy (secondary prevention cohort) to receive either multiple insulin injections or conventional insulin therapy over 8 years. Intensive therapy led to lower rates of retinopathy (7.7% vs 32% in primary prevention and 19% vs 44% in secondary prevention) and progressive nephropathy (7% vs 28% in primary prevention at 6 years and 11% vs 32% in secondary prevention).

In addition to studying the effects of blood pressure control, the UKPDS also studied the effects of intensive blood glucose control.^24,25 Nearly 4,000 patients with newly diagnosed type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin, or to conventional treatment with diet. Over 10 years, the mean hemoglobin A_1c was reduced to 7.0% in the intensive group and 7.9% in the conventional group. The risk of any diabetes-related end point was 12% lower in the intensive group, 10% lower for diabetes-related death, and 6% lower for all-cause mortality. There was also a 25% reduction in microvascular disease (retinopathy and nephropathy). However, the intensive group had more hypoglycemic episodes than the conventional group and a tendency to some increase in macrovascular events. A legacy effect was evident: patients who had intensive treatment had less microvascular disease progression years after stopping therapy.

Earlier trials provided strong evidence that blood glucose control prevents or slows retinopathy and nephropathy. The critical question is, “At what expense?” Although diabetes is the most common cause of kidney failure in the United States, most people with diabetes do not die of kidney failure, but of cardiovascular disease. Two recent large trials had different results regarding glycemic control below hemoglobin A_1c of 7.0% and macrovascular risk, creating a controversy about what recommendations are best.

The ADVANCE trial, enrolling 11,140 patients with type 2 diabetes, was largely conducted in Australia and used the sulfonylurea glipizide for glycemic control. Compared with the group that received standard therapy (n=5,569), the intensive-treatment group (n=5,571) achieved mean hemoglobin A_1c levels of 6.5% compared with 7.3% in the standard group, and had less nephropathy, less microalbuminuria, less doubling of creatinine, and a lower rate of end-stage renal disease (4% vs 5% in the standard therapy group). No difference between the two groups was found in retinopathy. Rates of all-cause mortality did not differ between the groups.⁹

The ACCORD trial had more than 10,000 subjects with type 2 diabetes and took place mostly in the United States. Using mainly rosiglitazone for intensive therapy, the intensive group achieved hemoglobin A_1c levels of 6.4% vs 7.5% in the standard-therapy group. The trial was stopped early, at 3.7 years, because of a higher risk of death and cardiovascular events in the group with intensive glycemic control. However, the intensive-therapy group did have a significant decrease in microvascular renal outcomes and a reduction in the progression of retinopathy.^14,26

In summary, tighter glycemic control improves microvascular complications—both retinopathy and nephropathy—in patients with type 2 diabetes. The benefit of intensive therapy on macrovascular complications (stroke, myocardial infarction) in long-standing diabetes has not been convincingly demonstrated in randomized trials. The UKPDS suggested that maintaining a hemoglobin A_1c of 7% in patients newly diagnosed with type 2 diabetes confers long-term cardiovascular benefits. The target hemoglobin A_1c for type 2 diabetes should be tailored to the patient: 7% is a reasonable goal for most patients, but the goal should be higher for the elderly and frail. Reducing the risk of cardiovascular death is still best done by controlling blood pressure, reducing lipids, quitting smoking, and losing weight.

STRATEGY 3: INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

Components of the renin-angiotensin-aldo-sterone system are present not only in the circulation but also in many tissues, including the heart, brain, kidney, blood vessels, and adrenal glands. The role of renin-angiotensin-aldosterone system blockers in treating and preventing diabetic nephropathy has become controversial in recent years with findings from new studies.

The renin-angiotensin-aldosterone system is important in the development or maintenance of high blood pressure and the resultant damage to the brain, heart, and kidney. Drug development has focused on inhibiting steps in the biochemical pathway. ACE inhibitors block the formation of angiotensin II—the most biologically potent angiotensin peptide—and are among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure. Angiotensin receptor blockers (ARBs) interact with the angiotensin AT1 receptor and block most of its actions. They are approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and they help prevent left ventricular hypertrophy and mesangial sclerosis. Large studies have shown that ACE inhibitors and ARBs offer similar cardiovascular benefit.

The glomerulus has the only capillary bed with a blood supply that drains into an efferent arteriole instead of a venule, providing high resistance to aid filtration. Efferent arterioles are rich in AT1 receptors. In the presence of angiotensin II they constrict, increasing pressure in the glomerulus, which can lead to proteinuria and glomerulosclerosis. ACE inhibitors and ARBs relax the efferent arteriole, allowing increased blood flow through the glomerulus. This reduction in intraglomerular pressure is associated with less proteinuria and less glomerulosclerosis.

Diabetes promotes renal disease in many ways. Glucose and advanced glycation end products can lead to increased blood flow and increased pressure in the glomerulus. Through a variety of pathways, hyperglycemia, acting on angiotensin II, leads to NF-kapa beta production, profibrotic cytokines, increased matrix, and eventual fibrosis. ACE inhibitors and ARBs counteract many of these.

ACE inhibitors and ARBs slow nephropathy progression beyond blood pressure control

Several major clinical trials^27–32 examined the effects of either ACE inhibitors or ARBs in slowing the progression of diabetic nephropathy and have had consistently positive results.

The Collaborative Study Group³⁰ was a 3-year randomized trial in 419 patients with type 1 diabetes, using the ACE inhibitor captopril vs placebo. Captopril was associated with less decline in kidney function and a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small difference in blood pressures between the two groups.

The Irbesartan Diabetic Nephropathy Trial (IDNT)³¹ studied the effect of the ARB irbesartan vs the calcium channel blocker amlodipine vs placebo over 2.6 years in 1,715 patients with type 2 diabetes. Irbesartan was found to be significantly more effective in protecting against the progression of nephropathy, independent of reduction in blood pressure.

The RENAAL trial,³² published in 2001, was a 3-year, randomized, double-blind study comparing the ARB losartan at increasing dosages with placebo (both taken in addition to conventional antihypertensive treatment) in 1,513 patients with type 2 diabetes and nephropathy. The blood pressure goal was 140/90 mm Hg in both groups, but the losartan group had a lower rate of doubling of serum creatinine, end-stage renal disease, and combined end-stage renal disease or death.

‘Aldosterone escape’ motivates the search for new therapies

An important reason for developing more ways to block the renin-angiotensin-aldosterone system is because of “aldosterone escape,” the phenomenon of angiotensin II or aldosterone returning to pretreatment levels despite continued ACE inhibition.

Biollaz et al,³³ in a 1982 study of 19 patients with hypertension, showed that despite reducing blood pressure and keeping the blood level of ACE very low with twice-daily enalapril 20 mg, blood and urine levels of angiotensin II steadily rose back to baseline levels within a few months.

A growing body of evidence suggests that despite effective inhibition of angiotensin II activity, non-ACE synthetic pathways still permit angiotensin II generation via serine proteases such as chymase, cathepsin G, and tissue plasminogen activator.

Thus, efforts have been made to block the renin-angiotensin system in other places. In addition to ACE inhibitors and ARBs, two aldosterone receptor antagonists are available, spironolactone and eplerenone, both used to treat heart failure. A direct renin inhibitor, aliskiren, is also available.

A number of studies have shown that combination treatment with agents having different targets in the renin-angiotensin-aldosterone system leads to larger reductions in albuminuria than does single-agent therapy.

Mogensen et al³⁴ studied the effect of the ACE inhibitor lisinopril (20 mg per day) plus the ARB candesartan (16 mg per day) in subjects with microalbuminuria, hypertension, and type 2 diabetes. Combined treatment was more effective in reducing proteinuria.

Epstein et al³⁵ studied the effects of the ACE inhibitor enalapril (20 mg/day) combined with either of two doses of the selective aldosterone receptor antagonist eplerenone (50 or 100 mg/day) or placebo. Both eplerenone dosages, when added to the enalapril treatment, significantly reduced albuminuria from baseline as early as week 4 (P < .001), but placebo treatment added to the enalapril did not result in any significant decrease in urinary albumin excretion. Systolic blood pressure decreased significantly in all treatment groups and by about the same amount.

The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) trial³⁶ randomized more than 600 patients with type 2 diabetes and nephropathy to aliskiren (a renin inhibitor) or placebo added to the ARB losartan. Again, combination treatment was more renoprotective, independent of blood pressure lowering.

Worse outcomes with combination therapy?

More recent studies have indicated that although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal and cardiovascular outcomes. The multicenter Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)³⁷ randomized more than 25,000 patients age 55 and older with established atherosclerotic vascular disease or with diabetes and end-organ damage to receive either the ARB telmisartan 80 mg daily, the ACE inhibitor ramipril 10 mg daily, or both. Mean follow-up was 56 months. The combination-treatment group had higher rates of death and renal disease than the single-therapy groups (which did not differ from one another).

Why the combination therapy had poorer outcomes is under debate. Patients may get sudden drops in blood pressure that are not detected with only periodic monitoring. Renal failure was mostly acute rather than chronic, and the estimated GFR declined more in the combined therapy group than in the single-therapy groups.

The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) was designed to test the effect of the direct renin inhibitor aliskiren or placebo, both arms combined with either an ACE inhibitor or an ARB in patients with type 2 diabetes at high risk for cardiovascular and renal events. The trial was terminated early because of more strokes and deaths in the combination therapy arms. The results led the FDA to issue black box warnings against using aliskiren with these other classes of agents, and all studies testing similar combinations have been stopped. (In one study that was stopped and has not yet been published, 100 patients with proteinuria were treated with either aliskiren, the ARB losartan, or both, to evaluate the effects of aldosterone escape. Results showed no differences: about one-third of each group had this phenomenon.)

My personal recommendation is as follows: for younger patients with proteinuria, at lower risk for cardiovascular events and with disease due not to diabetes but to immunoglobulin A nephropathy or another proteinuric kidney disease, treat with both an ACE inhibitor and ARB. But the combination should not be used for patients at high risk of cardiovascular disease, which includes almost all patients with diabetes.

If more aggressive renin-angiotensin system blockade is needed against diabetic nephropathy, adding a diuretic increases the impact of blocking the renin-angiotensin-aldosterone system on both proteinuria and progression of renal disease. The aldosterone blocker spironolactone 25 mg can be added if potassium levels are carefully monitored.

ACE inhibitor plus calcium channel blocker is safer than ACE inhibitor plus diuretic

The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial³⁸ randomized more than 11,000 high-risk patients with hypertension to receive an ACE inhibitor (benazepril) plus either a calcium channel blocker (amlodipine) or thiazide diuretic (hydrochlorothiazide). Blood pressures were identical between the two groups, but the trial was terminated early, at 36 months, because of a higher risk of the combined end point of cardiovascular death, myocardial infarction, stroke, and other major cardiac events in the ACE inhibitor-thiazide group.

Although some experts believe this study is definitive and indicates that high blood pressure should never be treated with an ACE inhibitor-thiazide combination, I believe that caution is needed in interpreting these findings. This regimen should be avoided in older patients with diabetes at high risk for cardiovascular disease, but otherwise, getting blood pressure under control is critical, and this combination can be used if it works and the patient is tolerating it well.

In summary, the choice of blood pressure-lowering medications is based on reducing cardiovascular events and slowing the progression of kidney disease. Either an ACE inhibitor or an ARB is the first choice for patients with diabetes, hypertension, and any degree of proteinuria. Many experts recommend beginning one of these agents even if proteinuria is not present. However, the combination of an ACE inhibitor and ARB should not be used in diabetic patients, especially if they have cardiovascular disease, until further data clarify the results of the ONTARGET and ALTITUDE trials.

STRATEGY 4: METABOLIC MANIPULATION WITH NOVEL AGENTS

Several new agents have recently been studied for the treatment of diabetic nephropathy, including aminoguanidine, which reduces levels of advanced glycation end-products, and sulodexide, which blocks basement membrane permeability. Neither agent has been shown to be safe and effective in diabetic nephropathy. The newest agent is bardoxolone methyl. It induces the Keap1–Nrf2 pathway, which up-regulates cytoprotective factors, suppressing inflammatory and other cytokines that are major mediators of progression of chronic kidney disease.³⁹

Pergola et al,⁴⁰ in a phase 2, double-blind trial, randomized 227 adults with diabetic kidney disease and a low estimated GFR (20–45 mL/min/1.73 m²) to receive placebo or bardoxolone 25, 75, or 150 mg daily. Drug treatment was associated with improvement in the estimated GFR, a finding that persisted throughout the 52 weeks of treatment. Surprisingly, proteinuria did not decrease with drug treatment.

As of this writing, a large multicenter controlled randomized trial has been halted because of concerns by the data safety monitoring board, which found increased rates of death and fluid retention with the drug. A number of recent trials have shown a beneficial effect of sodium bicarbonate therapy in patients with late-stage chronic kidney disease. They have shown slowing of the progression of GFR decline in a number of renal diseases, including diabetes.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.