Drug Therapy

To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”

While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.

I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.

To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”

While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.

I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.

To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”

While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.

I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.