Applied Evidence

CASE Charlie H, an elderly man who has been your patient for more than 10 years, is scheduled for inguinal hernia repair, and has come in for a preoperative evaluation. Based on his medical history and a physical examination, you identify several risk factors for surgical complications: a low functional capacity (<4 METS), obesity (BMI=39), advanced age (70 years), and type 2 diabetes (well controlled). What should you write in your consultation note about Charlie’s perioperative risks, and what interventions should you institute—or recommend—to mitigate his risk?

A preoperative consult, a service that family physicians are well positioned to provide, requires a thorough and systematic approach. But because of time pressures—as well as a dearth of perioperative templates, guidelines, and checklists—a cursory history and physical exam often takes the place of a comprehensive evaluation.

A thorough medical history is the most valuable tool of a physician doing a preop consult, but a comprehensive evaluation also involves the assessment of perioperative risk factors, ancillary tests to consider, and interventions to recommend to mitigate risks. Although various published guidelines address specific systems, there are few places where family physicians can find a complete toolkit. The text and tables that follow, which form the core of a comprehensive resource initially compiled to help our residents conduct clear and effective preoperative consults, will help you safeguard your patients.

A system-by-system review starts with the heart

The vast majority of perioperative problems fall into a handful of categories: cardiac, pulmonary, renal, infectious, and hematologic complications (TABLE 1). When a surgeon requests a preoperative evaluation, however, the patient’s cardiac status is generally the primary concern. This is also the portion of the preop consult with the most formally structured guidelines; those issued by the American College of Cardiology and American Heart Association (ACC/AHA) are the most widely used.¹ Initially based primarily on expert opinion, the ACC/AHA guidelines are increasingly evidence-based (http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.109.192690).^1,2 These guidelines address the evaluation of patients for noncardiac surgery. Both cardiac surgery and emergent operations are beyond the scope of the guidelines, and are not addressed here.

Patients with unstable coronary syndromes—eg, unstable angina or myocardial infarction (MI) within the past 30 days, decompensated heart failure (HF), significant arrhythmias, or severe valvular disease—face an increased risk of perioperative morbidity and mortality. To reduce the risk, such patients require optimization of the underlying condition before undergoing elective surgery.¹

Is additional cardiac testing necessary? Whether you’re assessing for cardiac status or other risks, for that matter, evidence supports the use of ancillary testing in only a small minority of surgical patients. A general rule of thumb—regardless of the system you’re assessing—is to consider adjunctive testing only if the outcome has the potential to alter patient management. Thus, exercise stress testing or resting electrocardiography (EKG), among other tests, may be considered on an individual basis (TABLE 2), but studies have failed to demonstrate improved outcomes with added testing of cardiac status on a routine basis.^5,6

Evidence is insufficient to make a firm recommendation regarding additional cardiac testing, even for patients with more than 3 clinical risk factors. Nonetheless, the ACC/AHA guidelines favor the use of adjunctive testing in such cases, especially for patients who are candidates for high-risk procedures, such as vascular surgery.¹

What’s the local standard of care? Studies to determine when further testing is beneficial and which tests would benefit which patients are ongoing. In the absence of definitive findings, it behooves primary care physicians to familiarize themselves with the practices and preferences of the cardiologists and anesthesiologists at the facility where the surgery will be performed and to follow the local standard of care.

TABLE 1
Identifying—and minimizing—perioperative risk

TABLE 2
When should you order these ancillary tests?*

Identify pulmonary risks with help from ACP
Postoperative pulmonary complications are as prevalent as cardiac complications, and contribute equally to morbidity, mortality, and length of stay. But pulmonary complications are better predictors of long-term mortality after surgery.⁷

There are several well-validated risk factors for increased perioperative pulmonary morbidity and mortality—HF, chronic obstructive pulmonary disease (COPD), advanced age, and the need for assistance with activities of daily living among them. In addition to identifying patient-specific risk factors, knowledge of the type of surgery planned will provide insight into procedure-specific risk factors (TABLE 1). The approach to the surgical pulmonary patient is addressed in an American College of Physicians (ACP) guideline published in 2006 and available at http://www.annals.org/content/144/8/575.full.pdf+html.⁷

What tests to consider? The ACP guideline is notable not only for its recommendations, but for the things that are not recommended but may nevertheless be considered the standard of care in some locales. Chest radiography and spirometry are 2 such examples. Although these tests may be appropriate on an individual basis for patients with a previous diagnosis of COPD or asthma, their routine use is of little value—and the ACP does not recommend them as part of a standard preop evaluation.⁷ Some laboratory tests may aid in risk stratification, however.

A serum albumin level <35 g/L is strongly associated with postop pulmonary complications.⁸ Checking levels in all patients suspected of hypoalbuminemia, including any patient with 1 or more pulmonary risk factors, is reasonable for a physician performing a preoperative evaluation. Consider checking blood urea nitrogen (BUN) levels, as well. Uremia (BUN >21 mg/dL) is also associated with increased pulmonary complications, although not as strongly as hypoalbuminemia.

Postpone or proceed? Acute conditions are another key consideration. An upper respiratory infection (URI) increases the risk of postoperative pulmonary complications, especially in children.^9,10 A simple algorithm offers guidance in deciding when to postpone surgery in pediatric patients with a URI:⁹

Recommend that it be delayed if the procedure involves general anesthesia and 1 or more of the following risk factors is present: asthma, a history of prematurity, copious secretions, a parent who smokes, planned use of an endotracheal tube, or a procedure involving the airway.

Surgery can proceed if symptoms of the infection are mild, general anesthesia is not required, or a risk/benefit analysis supports it. Considerations include the urgency of the procedure, whether the surgery has previously been postponed, the comfort level of the clinicians involved, and the distance the family must travel for the procedure.¹¹

If you recommend that surgery proceed as planned, suggest perioperative interventions to mitigate risk. Recommend that a laryngeal mask airway be used, if needed, in place of an endotracheal tube; that pulse oximetry monitoring occur; that good hydration and humidification of air be provided; and that the patient receive anticholinergic agents for secretions.

Other measures that have been shown to be effective in reducing perioperative pulmonary complications include deep breathing exercises (incentive spirometry) and the use of a nasogastric tube for those with postoperative emesis, intolerance of oral intake, or symptomatic abdominal distension.⁷ If your patient has risk factors for pulmonary complications, include a recommendation for a postop nasogastric tube in your preop consultation note. However, newer data indicating that patients had fewer pulmonary complications, a more rapid return of normal bowel function, no increased discomfort, and no increase in anastomotic leaks without a nasogastric tube^12,13 may lead to guideline revision.

A scoring system helps evaluate renal risk
Patients with CRF face increased risk of perioperative morbidity and mortality. But as long as the glomerular filtration rate (GFR) is >25 mL/min—which is only 25% of normal—surgery is generally well tolerated. As GFR drops to 10 to 15 mL/min, the rate of surgical complications rises rapidly, reaching 55% to 60%. For such patients, preoperative dialysis is worth considering.¹⁴

Postoperative acute kidney injury (AKI), as acute renal failure is now known,¹⁵ is associated with a 58% mortality rate.¹⁶ Fortunately, this complication develops in only about 1% of surgical patients.¹⁷ Both patient-specific risk factors (CRF, with creatinine >2.1 mg/dL; HF; diabetes, particularly being insulin dependent; age >60 years; jaundice) and procedure-specific risks (aortic, cardiovascular, or liver transplant surgery) help predict which surgical candidates face the highest risk.^16,18,19 Thakar et al have developed a scoring system to identify those at greatest risk for AKI.²⁰ (See “Cardiovascular surgery and acute kidney injury: Scoring the risk” at www.jfponline.com by clicking on “Before surgery: Have you done enough to mitigate risk?” and scrolling to the end.)

Minimize renal complications. Helping patients achieve good intravascular volume and osmolar status preoperatively will reduce their risk of renal complications. Other prophylactic measures: Minimize exposure to nephrotoxins (eg, nonsteroidal anti-inflammatory drugs or contrast media) to the extent possible. Consider evaluating the serum electrolyte and creatinine levels of patients with multiple risk factors to determine whether they can safely undergo surgery; some experts suggest preoperative urinalysis, as well.¹⁸

Patients with end-stage renal disease have very high perioperative morbidity.²¹ They are at increased risk for hyperkalemia, infection, hyper- and hypotension, bleeding, arrhythmias, and clotted fistulas, in descending order of incidence.¹⁸ Preoperative planning, including the need for dialysis before surgery, is necessary to manage these risks.

Risk of postop infection: Focusing on the foreseeable
Postoperative infections, both at the surgical site and remote from the incision, are a significant cause of morbidity and mortality. Pneumonia is among the most prominent remote infections associated with surgery,²² and early ambulation, deep breathing exercises, and tight glycemic control can greatly decrease the risk.

Surgical site infection (SSI) remains an important concern, occurring in 37% of cases.²³ Risk factors include hyperglycemia, malnutrition, perioperative steroid use, preexisting infections, tobacco smoking, peripheral vascular disease, advanced age, radiation therapy, blood transfusions, prolonged preoperative stay, preoperative shaving, hypothermia, hypoxia, length of operation, and postoperative incontinence.²⁴ While many of these risk factors are dependent on interventions in the operating room and recovery room or during subsequent hospitalization, it is important to address foreseeable risks as part of the preoperative evaluation.

Glycemic control is crucial. Perhaps the most well-documented risk for SSI is hyperglycemia—a common problem among hospitalized patients.¹⁶ Hyperglycemia impairs leukocyte and complement function,^25,26 thereby increasing risk of infectious complications. Tight glycemic control in the surgical patient, especially on the surgical intensive care unit, has been associated with improved outcomes.²⁷

Identify the presence of diabetes in the preoperative consult note, and adjust the patient’s medication regimen as needed, to help him or her achieve optimal glycemic control. In some cases, it may be necessary to delay nonurgent surgery until the patient achieves adequate control.

Malnutrition is another risk factor for SSI. For patients who are undernourished or morbidly obese, checking serum albumin levels may be beneficial. Supplementation for 1 to 2 weeks prior to surgery may decrease the risk of infection for patients who are undernourished;²⁸ for obese patients, weight loss is beneficial. Although significant preoperative weight loss may not be possible, it is important to list an elevated body mass index as a risk factor in the consultation note.

Corticosteroids, used to treat conditions such as COPD, inflammatory bowel disease, allergies, and autoimmune disorders, are another risk factor for perioperative infection. In addition to their effect on glycemic control, corticosteroids directly suppress the immune system. Whenever possible, they should be discontinued preoperatively. If this is not possible, call attention to the patient’s use of corticosteroids in the consultation note.

Preexisting infection presents the possibility of the spread of organisms to the surgical site and, whenever possible, surgery should be postponed until the infection resolves. If the patient has a history of prior infection or colonization with methicillin-resistant Staphylococcus aureus, be sure to include that in the consultation note, as well.

Leukocyte-containing blood product transfusions are associated with a 2-fold increase in some postop infectious complications.^29-31 This is in addition to the well-known risk of bloodborne pathogens associated with transfusions, and is yet another reason to avoid perioperative transfusions whenever possible.

Smoking impairs tissue oxygenation, which delays healing and increases risk of infection. Smoking cessation should be strongly encouraged at every preoperative consultation. Recommend nicotine replacement therapy even for patients who aren’t willing to quit altogether; point out that giving up cigarettes for just 30 days (or more) before surgery can decrease the likelihood of complications.²⁸

In addition to these identified risk factors, anything that compromises the immune status increases the risk of infection. Alcohol or drug abusers, chronic pain patients, transplant recipients, cancer patients taking immunosuppressants, postsplenectomy patients, and patients with HIV are all at increased risk. Identify any such conditions during your preoperative evaluation, and be sure to include them in your communication with the surgical team.

A common request in preop consults relates to bacterial endocarditis prophylaxis. Only an extremely small number of cases of infective endocarditis occur with dental procedures, however, so the benefits of antibiotic prophylaxis would be minimal, even if the prophylactic therapy were 100% effective.³² As a result, the ACC/AHA guidelines recommend prophylaxis for dental procedures only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. Administration of antibiotics solely to prevent endocarditis is not recommended for patients undergoing genitourinary or gastrointestinal tract procedures.³²

Hematologic evaluation: Address risks of bleeding, clotting
Historically, a variety of tests have been employed in an effort to identify patients at risk for bleeding complications prior to surgery—including prothrombin time, partial thromboplastin time, platelet count, and bleeding time, or platelet function. While highly reproducible, automated, and inexpensive when considered individually, the cumulative cost of routine use of these tests is high.³³

A recent review of the literature indicates that, for surgical patients without synthetic liver dysfunction or a history of oral anticoagulant use, routine testing is of little value in the assessment of bleeding risk.³⁴ Patients with a negative bleeding history do not require routine coagulation screening prior to surgery.³⁵

Instead, use the medical history to identify risk factors for bleeding. These include excessive bruising, nosebleeds, prolonged bleeding after cuts, bleeding >3 minutes after brushing teeth, and heavy or prolonged menses (TABLE 1). Patients with a past medical history of liver disease; renal failure; hypersplenism; hematologic disease; collagen vascular disease; hemophilia or other inherited hemorrhagic disorder; gastrointestinal or urogenital blood loss; and severe bleeding after dental extraction, other surgery, or childbirth are also at heightened risk, as are those who take medications that affect hemostasis. Physical findings suggestive of risk include purpura, hematoma, jaundice, and signs of cirrhosis.³⁴

While laboratory testing is only appropriate to confirm those at risk in the subpopulation selected by the history and physical, here, as with other adjunctive testing, it is important to consider local standards and the preferences of the surgeon who requested the preop consult.

Treat anemia. Preoperative anemia is linked to adverse outcomes in surgical patients,³⁶ although it is not clear whether the anemia itself or the perioperative transfusions associated with the condition are at the root of the problem.³⁷ Macrocytic anemia may require treatment with vitamin B₁₂ and folate; iron deficiency anemia is treated with iron. Some physicians also recommend the use of erythropoietin starting 3 weeks prior to surgery for patients with normocytic anemia with hemoglobin <13 g/dL.^38,39

Thromboembolism risk. Excessive clotting is responsible for more perioperative complications than excessive bleeding. There is a high prevalence of venous thromboembolism (VTE) among surgical patients, with both patient- and procedure-specific risk factors. Although a variety of coagulopathies increase the baseline risk for VTE, routine laboratory screening of the general surgical population for thrombophilia is not recommended.^34,35

When risk factors are present based on both the patient’s medical history and the type of procedure, prophylactic measures may be needed (TABLE 3). Options include mechanical prophylaxis (graduated compression stockings and intermittent pneumatic devices) and chemoprophylaxis. Recommended for high-risk cases, such as patients undergoing orthopedic surgery that precludes early mobilization, chemoprophylaxis options include low-molecular-weight heparin, low-dose unfractionated heparin, fondaparinux (a synthetic factor Xa inhibitor), and vitamin K antagonists such as warfarin.⁴⁰ Aspirin alone is not recommended, as it has not been found to be an effective prophylaxis for VTE.

CASE After following this system-by-system review of your patient, Charlie H, you identify and explicitly communicate the following risk factors in your consultation note:

• Cardiovascular: type 2 diabetes, low functional capacity
• Pulmonary: advanced age
• Renal: advanced age
• Infectious: type 2 diabetes, advanced age, BMI=39
• Hematologic: advanced age, obesity

Based on these findings, you develop the following plan for Charlie H, detailed in the consultation note you submit to the surgical team:

• Continue home diabetes medications perioperatively, supplemented with a basal-bolus insulin regimen.
• Initiate incentive spirometry postoperatively; use an NG tube if postoperative nausea and vomiting occur.
• Maintain MAP >65 mm Hg.
• Institute aggressive early ambulation and use of graduated compression stockings for DVT prophylaxis.
  Submitted by ___________ on ________.

TABLE 3
Perioperative thromboembolism: Risk and prophylaxis

CORRESPONDENCE Mark K. Huntington, MD, PhD, FAAFP, Center for Family Medicine, 1115 East Twentieth Street, Sioux Falls, SD 57105; [email protected]

CASE Charlie H, an elderly man who has been your patient for more than 10 years, is scheduled for inguinal hernia repair, and has come in for a preoperative evaluation. Based on his medical history and a physical examination, you identify several risk factors for surgical complications: a low functional capacity (<4 METS), obesity (BMI=39), advanced age (70 years), and type 2 diabetes (well controlled). What should you write in your consultation note about Charlie’s perioperative risks, and what interventions should you institute—or recommend—to mitigate his risk?

A preoperative consult, a service that family physicians are well positioned to provide, requires a thorough and systematic approach. But because of time pressures—as well as a dearth of perioperative templates, guidelines, and checklists—a cursory history and physical exam often takes the place of a comprehensive evaluation.

A thorough medical history is the most valuable tool of a physician doing a preop consult, but a comprehensive evaluation also involves the assessment of perioperative risk factors, ancillary tests to consider, and interventions to recommend to mitigate risks. Although various published guidelines address specific systems, there are few places where family physicians can find a complete toolkit. The text and tables that follow, which form the core of a comprehensive resource initially compiled to help our residents conduct clear and effective preoperative consults, will help you safeguard your patients.

A system-by-system review starts with the heart

The vast majority of perioperative problems fall into a handful of categories: cardiac, pulmonary, renal, infectious, and hematologic complications (TABLE 1). When a surgeon requests a preoperative evaluation, however, the patient’s cardiac status is generally the primary concern. This is also the portion of the preop consult with the most formally structured guidelines; those issued by the American College of Cardiology and American Heart Association (ACC/AHA) are the most widely used.¹ Initially based primarily on expert opinion, the ACC/AHA guidelines are increasingly evidence-based (http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.109.192690).^1,2 These guidelines address the evaluation of patients for noncardiac surgery. Both cardiac surgery and emergent operations are beyond the scope of the guidelines, and are not addressed here.

Patients with unstable coronary syndromes—eg, unstable angina or myocardial infarction (MI) within the past 30 days, decompensated heart failure (HF), significant arrhythmias, or severe valvular disease—face an increased risk of perioperative morbidity and mortality. To reduce the risk, such patients require optimization of the underlying condition before undergoing elective surgery.¹

Is additional cardiac testing necessary? Whether you’re assessing for cardiac status or other risks, for that matter, evidence supports the use of ancillary testing in only a small minority of surgical patients. A general rule of thumb—regardless of the system you’re assessing—is to consider adjunctive testing only if the outcome has the potential to alter patient management. Thus, exercise stress testing or resting electrocardiography (EKG), among other tests, may be considered on an individual basis (TABLE 2), but studies have failed to demonstrate improved outcomes with added testing of cardiac status on a routine basis.^5,6

Evidence is insufficient to make a firm recommendation regarding additional cardiac testing, even for patients with more than 3 clinical risk factors. Nonetheless, the ACC/AHA guidelines favor the use of adjunctive testing in such cases, especially for patients who are candidates for high-risk procedures, such as vascular surgery.¹

What’s the local standard of care? Studies to determine when further testing is beneficial and which tests would benefit which patients are ongoing. In the absence of definitive findings, it behooves primary care physicians to familiarize themselves with the practices and preferences of the cardiologists and anesthesiologists at the facility where the surgery will be performed and to follow the local standard of care.

TABLE 1
Identifying—and minimizing—perioperative risk

TABLE 2
When should you order these ancillary tests?*

Identify pulmonary risks with help from ACP
Postoperative pulmonary complications are as prevalent as cardiac complications, and contribute equally to morbidity, mortality, and length of stay. But pulmonary complications are better predictors of long-term mortality after surgery.⁷

There are several well-validated risk factors for increased perioperative pulmonary morbidity and mortality—HF, chronic obstructive pulmonary disease (COPD), advanced age, and the need for assistance with activities of daily living among them. In addition to identifying patient-specific risk factors, knowledge of the type of surgery planned will provide insight into procedure-specific risk factors (TABLE 1). The approach to the surgical pulmonary patient is addressed in an American College of Physicians (ACP) guideline published in 2006 and available at http://www.annals.org/content/144/8/575.full.pdf+html.⁷

What tests to consider? The ACP guideline is notable not only for its recommendations, but for the things that are not recommended but may nevertheless be considered the standard of care in some locales. Chest radiography and spirometry are 2 such examples. Although these tests may be appropriate on an individual basis for patients with a previous diagnosis of COPD or asthma, their routine use is of little value—and the ACP does not recommend them as part of a standard preop evaluation.⁷ Some laboratory tests may aid in risk stratification, however.

A serum albumin level <35 g/L is strongly associated with postop pulmonary complications.⁸ Checking levels in all patients suspected of hypoalbuminemia, including any patient with 1 or more pulmonary risk factors, is reasonable for a physician performing a preoperative evaluation. Consider checking blood urea nitrogen (BUN) levels, as well. Uremia (BUN >21 mg/dL) is also associated with increased pulmonary complications, although not as strongly as hypoalbuminemia.

Postpone or proceed? Acute conditions are another key consideration. An upper respiratory infection (URI) increases the risk of postoperative pulmonary complications, especially in children.^9,10 A simple algorithm offers guidance in deciding when to postpone surgery in pediatric patients with a URI:⁹

Recommend that it be delayed if the procedure involves general anesthesia and 1 or more of the following risk factors is present: asthma, a history of prematurity, copious secretions, a parent who smokes, planned use of an endotracheal tube, or a procedure involving the airway.

Surgery can proceed if symptoms of the infection are mild, general anesthesia is not required, or a risk/benefit analysis supports it. Considerations include the urgency of the procedure, whether the surgery has previously been postponed, the comfort level of the clinicians involved, and the distance the family must travel for the procedure.¹¹

If you recommend that surgery proceed as planned, suggest perioperative interventions to mitigate risk. Recommend that a laryngeal mask airway be used, if needed, in place of an endotracheal tube; that pulse oximetry monitoring occur; that good hydration and humidification of air be provided; and that the patient receive anticholinergic agents for secretions.

Other measures that have been shown to be effective in reducing perioperative pulmonary complications include deep breathing exercises (incentive spirometry) and the use of a nasogastric tube for those with postoperative emesis, intolerance of oral intake, or symptomatic abdominal distension.⁷ If your patient has risk factors for pulmonary complications, include a recommendation for a postop nasogastric tube in your preop consultation note. However, newer data indicating that patients had fewer pulmonary complications, a more rapid return of normal bowel function, no increased discomfort, and no increase in anastomotic leaks without a nasogastric tube^12,13 may lead to guideline revision.

A scoring system helps evaluate renal risk
Patients with CRF face increased risk of perioperative morbidity and mortality. But as long as the glomerular filtration rate (GFR) is >25 mL/min—which is only 25% of normal—surgery is generally well tolerated. As GFR drops to 10 to 15 mL/min, the rate of surgical complications rises rapidly, reaching 55% to 60%. For such patients, preoperative dialysis is worth considering.¹⁴

Postoperative acute kidney injury (AKI), as acute renal failure is now known,¹⁵ is associated with a 58% mortality rate.¹⁶ Fortunately, this complication develops in only about 1% of surgical patients.¹⁷ Both patient-specific risk factors (CRF, with creatinine >2.1 mg/dL; HF; diabetes, particularly being insulin dependent; age >60 years; jaundice) and procedure-specific risks (aortic, cardiovascular, or liver transplant surgery) help predict which surgical candidates face the highest risk.^16,18,19 Thakar et al have developed a scoring system to identify those at greatest risk for AKI.²⁰ (See “Cardiovascular surgery and acute kidney injury: Scoring the risk” at www.jfponline.com by clicking on “Before surgery: Have you done enough to mitigate risk?” and scrolling to the end.)

Minimize renal complications. Helping patients achieve good intravascular volume and osmolar status preoperatively will reduce their risk of renal complications. Other prophylactic measures: Minimize exposure to nephrotoxins (eg, nonsteroidal anti-inflammatory drugs or contrast media) to the extent possible. Consider evaluating the serum electrolyte and creatinine levels of patients with multiple risk factors to determine whether they can safely undergo surgery; some experts suggest preoperative urinalysis, as well.¹⁸

Patients with end-stage renal disease have very high perioperative morbidity.²¹ They are at increased risk for hyperkalemia, infection, hyper- and hypotension, bleeding, arrhythmias, and clotted fistulas, in descending order of incidence.¹⁸ Preoperative planning, including the need for dialysis before surgery, is necessary to manage these risks.

Risk of postop infection: Focusing on the foreseeable
Postoperative infections, both at the surgical site and remote from the incision, are a significant cause of morbidity and mortality. Pneumonia is among the most prominent remote infections associated with surgery,²² and early ambulation, deep breathing exercises, and tight glycemic control can greatly decrease the risk.

Surgical site infection (SSI) remains an important concern, occurring in 37% of cases.²³ Risk factors include hyperglycemia, malnutrition, perioperative steroid use, preexisting infections, tobacco smoking, peripheral vascular disease, advanced age, radiation therapy, blood transfusions, prolonged preoperative stay, preoperative shaving, hypothermia, hypoxia, length of operation, and postoperative incontinence.²⁴ While many of these risk factors are dependent on interventions in the operating room and recovery room or during subsequent hospitalization, it is important to address foreseeable risks as part of the preoperative evaluation.

Glycemic control is crucial. Perhaps the most well-documented risk for SSI is hyperglycemia—a common problem among hospitalized patients.¹⁶ Hyperglycemia impairs leukocyte and complement function,^25,26 thereby increasing risk of infectious complications. Tight glycemic control in the surgical patient, especially on the surgical intensive care unit, has been associated with improved outcomes.²⁷

Identify the presence of diabetes in the preoperative consult note, and adjust the patient’s medication regimen as needed, to help him or her achieve optimal glycemic control. In some cases, it may be necessary to delay nonurgent surgery until the patient achieves adequate control.

Malnutrition is another risk factor for SSI. For patients who are undernourished or morbidly obese, checking serum albumin levels may be beneficial. Supplementation for 1 to 2 weeks prior to surgery may decrease the risk of infection for patients who are undernourished;²⁸ for obese patients, weight loss is beneficial. Although significant preoperative weight loss may not be possible, it is important to list an elevated body mass index as a risk factor in the consultation note.

Corticosteroids, used to treat conditions such as COPD, inflammatory bowel disease, allergies, and autoimmune disorders, are another risk factor for perioperative infection. In addition to their effect on glycemic control, corticosteroids directly suppress the immune system. Whenever possible, they should be discontinued preoperatively. If this is not possible, call attention to the patient’s use of corticosteroids in the consultation note.

Preexisting infection presents the possibility of the spread of organisms to the surgical site and, whenever possible, surgery should be postponed until the infection resolves. If the patient has a history of prior infection or colonization with methicillin-resistant Staphylococcus aureus, be sure to include that in the consultation note, as well.

Leukocyte-containing blood product transfusions are associated with a 2-fold increase in some postop infectious complications.^29-31 This is in addition to the well-known risk of bloodborne pathogens associated with transfusions, and is yet another reason to avoid perioperative transfusions whenever possible.

Smoking impairs tissue oxygenation, which delays healing and increases risk of infection. Smoking cessation should be strongly encouraged at every preoperative consultation. Recommend nicotine replacement therapy even for patients who aren’t willing to quit altogether; point out that giving up cigarettes for just 30 days (or more) before surgery can decrease the likelihood of complications.²⁸

In addition to these identified risk factors, anything that compromises the immune status increases the risk of infection. Alcohol or drug abusers, chronic pain patients, transplant recipients, cancer patients taking immunosuppressants, postsplenectomy patients, and patients with HIV are all at increased risk. Identify any such conditions during your preoperative evaluation, and be sure to include them in your communication with the surgical team.

A common request in preop consults relates to bacterial endocarditis prophylaxis. Only an extremely small number of cases of infective endocarditis occur with dental procedures, however, so the benefits of antibiotic prophylaxis would be minimal, even if the prophylactic therapy were 100% effective.³² As a result, the ACC/AHA guidelines recommend prophylaxis for dental procedures only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. Administration of antibiotics solely to prevent endocarditis is not recommended for patients undergoing genitourinary or gastrointestinal tract procedures.³²

Hematologic evaluation: Address risks of bleeding, clotting
Historically, a variety of tests have been employed in an effort to identify patients at risk for bleeding complications prior to surgery—including prothrombin time, partial thromboplastin time, platelet count, and bleeding time, or platelet function. While highly reproducible, automated, and inexpensive when considered individually, the cumulative cost of routine use of these tests is high.³³

A recent review of the literature indicates that, for surgical patients without synthetic liver dysfunction or a history of oral anticoagulant use, routine testing is of little value in the assessment of bleeding risk.³⁴ Patients with a negative bleeding history do not require routine coagulation screening prior to surgery.³⁵

Instead, use the medical history to identify risk factors for bleeding. These include excessive bruising, nosebleeds, prolonged bleeding after cuts, bleeding >3 minutes after brushing teeth, and heavy or prolonged menses (TABLE 1). Patients with a past medical history of liver disease; renal failure; hypersplenism; hematologic disease; collagen vascular disease; hemophilia or other inherited hemorrhagic disorder; gastrointestinal or urogenital blood loss; and severe bleeding after dental extraction, other surgery, or childbirth are also at heightened risk, as are those who take medications that affect hemostasis. Physical findings suggestive of risk include purpura, hematoma, jaundice, and signs of cirrhosis.³⁴

While laboratory testing is only appropriate to confirm those at risk in the subpopulation selected by the history and physical, here, as with other adjunctive testing, it is important to consider local standards and the preferences of the surgeon who requested the preop consult.

Treat anemia. Preoperative anemia is linked to adverse outcomes in surgical patients,³⁶ although it is not clear whether the anemia itself or the perioperative transfusions associated with the condition are at the root of the problem.³⁷ Macrocytic anemia may require treatment with vitamin B₁₂ and folate; iron deficiency anemia is treated with iron. Some physicians also recommend the use of erythropoietin starting 3 weeks prior to surgery for patients with normocytic anemia with hemoglobin <13 g/dL.^38,39

Thromboembolism risk. Excessive clotting is responsible for more perioperative complications than excessive bleeding. There is a high prevalence of venous thromboembolism (VTE) among surgical patients, with both patient- and procedure-specific risk factors. Although a variety of coagulopathies increase the baseline risk for VTE, routine laboratory screening of the general surgical population for thrombophilia is not recommended.^34,35

When risk factors are present based on both the patient’s medical history and the type of procedure, prophylactic measures may be needed (TABLE 3). Options include mechanical prophylaxis (graduated compression stockings and intermittent pneumatic devices) and chemoprophylaxis. Recommended for high-risk cases, such as patients undergoing orthopedic surgery that precludes early mobilization, chemoprophylaxis options include low-molecular-weight heparin, low-dose unfractionated heparin, fondaparinux (a synthetic factor Xa inhibitor), and vitamin K antagonists such as warfarin.⁴⁰ Aspirin alone is not recommended, as it has not been found to be an effective prophylaxis for VTE.

CASE After following this system-by-system review of your patient, Charlie H, you identify and explicitly communicate the following risk factors in your consultation note:

• Cardiovascular: type 2 diabetes, low functional capacity
• Pulmonary: advanced age
• Renal: advanced age
• Infectious: type 2 diabetes, advanced age, BMI=39
• Hematologic: advanced age, obesity

Based on these findings, you develop the following plan for Charlie H, detailed in the consultation note you submit to the surgical team:

• Continue home diabetes medications perioperatively, supplemented with a basal-bolus insulin regimen.
• Initiate incentive spirometry postoperatively; use an NG tube if postoperative nausea and vomiting occur.
• Maintain MAP >65 mm Hg.
• Institute aggressive early ambulation and use of graduated compression stockings for DVT prophylaxis.
  Submitted by ___________ on ________.

TABLE 3
Perioperative thromboembolism: Risk and prophylaxis

CORRESPONDENCE Mark K. Huntington, MD, PhD, FAAFP, Center for Family Medicine, 1115 East Twentieth Street, Sioux Falls, SD 57105; [email protected]

CASE Charlie H, an elderly man who has been your patient for more than 10 years, is scheduled for inguinal hernia repair, and has come in for a preoperative evaluation. Based on his medical history and a physical examination, you identify several risk factors for surgical complications: a low functional capacity (<4 METS), obesity (BMI=39), advanced age (70 years), and type 2 diabetes (well controlled). What should you write in your consultation note about Charlie’s perioperative risks, and what interventions should you institute—or recommend—to mitigate his risk?

A preoperative consult, a service that family physicians are well positioned to provide, requires a thorough and systematic approach. But because of time pressures—as well as a dearth of perioperative templates, guidelines, and checklists—a cursory history and physical exam often takes the place of a comprehensive evaluation.

A thorough medical history is the most valuable tool of a physician doing a preop consult, but a comprehensive evaluation also involves the assessment of perioperative risk factors, ancillary tests to consider, and interventions to recommend to mitigate risks. Although various published guidelines address specific systems, there are few places where family physicians can find a complete toolkit. The text and tables that follow, which form the core of a comprehensive resource initially compiled to help our residents conduct clear and effective preoperative consults, will help you safeguard your patients.

A system-by-system review starts with the heart

The vast majority of perioperative problems fall into a handful of categories: cardiac, pulmonary, renal, infectious, and hematologic complications (TABLE 1). When a surgeon requests a preoperative evaluation, however, the patient’s cardiac status is generally the primary concern. This is also the portion of the preop consult with the most formally structured guidelines; those issued by the American College of Cardiology and American Heart Association (ACC/AHA) are the most widely used.¹ Initially based primarily on expert opinion, the ACC/AHA guidelines are increasingly evidence-based (http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.109.192690).^1,2 These guidelines address the evaluation of patients for noncardiac surgery. Both cardiac surgery and emergent operations are beyond the scope of the guidelines, and are not addressed here.

Patients with unstable coronary syndromes—eg, unstable angina or myocardial infarction (MI) within the past 30 days, decompensated heart failure (HF), significant arrhythmias, or severe valvular disease—face an increased risk of perioperative morbidity and mortality. To reduce the risk, such patients require optimization of the underlying condition before undergoing elective surgery.¹

Is additional cardiac testing necessary? Whether you’re assessing for cardiac status or other risks, for that matter, evidence supports the use of ancillary testing in only a small minority of surgical patients. A general rule of thumb—regardless of the system you’re assessing—is to consider adjunctive testing only if the outcome has the potential to alter patient management. Thus, exercise stress testing or resting electrocardiography (EKG), among other tests, may be considered on an individual basis (TABLE 2), but studies have failed to demonstrate improved outcomes with added testing of cardiac status on a routine basis.^5,6

Evidence is insufficient to make a firm recommendation regarding additional cardiac testing, even for patients with more than 3 clinical risk factors. Nonetheless, the ACC/AHA guidelines favor the use of adjunctive testing in such cases, especially for patients who are candidates for high-risk procedures, such as vascular surgery.¹

What’s the local standard of care? Studies to determine when further testing is beneficial and which tests would benefit which patients are ongoing. In the absence of definitive findings, it behooves primary care physicians to familiarize themselves with the practices and preferences of the cardiologists and anesthesiologists at the facility where the surgery will be performed and to follow the local standard of care.

TABLE 1
Identifying—and minimizing—perioperative risk

TABLE 2
When should you order these ancillary tests?*

Identify pulmonary risks with help from ACP
Postoperative pulmonary complications are as prevalent as cardiac complications, and contribute equally to morbidity, mortality, and length of stay. But pulmonary complications are better predictors of long-term mortality after surgery.⁷

There are several well-validated risk factors for increased perioperative pulmonary morbidity and mortality—HF, chronic obstructive pulmonary disease (COPD), advanced age, and the need for assistance with activities of daily living among them. In addition to identifying patient-specific risk factors, knowledge of the type of surgery planned will provide insight into procedure-specific risk factors (TABLE 1). The approach to the surgical pulmonary patient is addressed in an American College of Physicians (ACP) guideline published in 2006 and available at http://www.annals.org/content/144/8/575.full.pdf+html.⁷

What tests to consider? The ACP guideline is notable not only for its recommendations, but for the things that are not recommended but may nevertheless be considered the standard of care in some locales. Chest radiography and spirometry are 2 such examples. Although these tests may be appropriate on an individual basis for patients with a previous diagnosis of COPD or asthma, their routine use is of little value—and the ACP does not recommend them as part of a standard preop evaluation.⁷ Some laboratory tests may aid in risk stratification, however.

A serum albumin level <35 g/L is strongly associated with postop pulmonary complications.⁸ Checking levels in all patients suspected of hypoalbuminemia, including any patient with 1 or more pulmonary risk factors, is reasonable for a physician performing a preoperative evaluation. Consider checking blood urea nitrogen (BUN) levels, as well. Uremia (BUN >21 mg/dL) is also associated with increased pulmonary complications, although not as strongly as hypoalbuminemia.

Postpone or proceed? Acute conditions are another key consideration. An upper respiratory infection (URI) increases the risk of postoperative pulmonary complications, especially in children.^9,10 A simple algorithm offers guidance in deciding when to postpone surgery in pediatric patients with a URI:⁹

Recommend that it be delayed if the procedure involves general anesthesia and 1 or more of the following risk factors is present: asthma, a history of prematurity, copious secretions, a parent who smokes, planned use of an endotracheal tube, or a procedure involving the airway.

Surgery can proceed if symptoms of the infection are mild, general anesthesia is not required, or a risk/benefit analysis supports it. Considerations include the urgency of the procedure, whether the surgery has previously been postponed, the comfort level of the clinicians involved, and the distance the family must travel for the procedure.¹¹

If you recommend that surgery proceed as planned, suggest perioperative interventions to mitigate risk. Recommend that a laryngeal mask airway be used, if needed, in place of an endotracheal tube; that pulse oximetry monitoring occur; that good hydration and humidification of air be provided; and that the patient receive anticholinergic agents for secretions.

Other measures that have been shown to be effective in reducing perioperative pulmonary complications include deep breathing exercises (incentive spirometry) and the use of a nasogastric tube for those with postoperative emesis, intolerance of oral intake, or symptomatic abdominal distension.⁷ If your patient has risk factors for pulmonary complications, include a recommendation for a postop nasogastric tube in your preop consultation note. However, newer data indicating that patients had fewer pulmonary complications, a more rapid return of normal bowel function, no increased discomfort, and no increase in anastomotic leaks without a nasogastric tube^12,13 may lead to guideline revision.

A scoring system helps evaluate renal risk
Patients with CRF face increased risk of perioperative morbidity and mortality. But as long as the glomerular filtration rate (GFR) is >25 mL/min—which is only 25% of normal—surgery is generally well tolerated. As GFR drops to 10 to 15 mL/min, the rate of surgical complications rises rapidly, reaching 55% to 60%. For such patients, preoperative dialysis is worth considering.¹⁴

Postoperative acute kidney injury (AKI), as acute renal failure is now known,¹⁵ is associated with a 58% mortality rate.¹⁶ Fortunately, this complication develops in only about 1% of surgical patients.¹⁷ Both patient-specific risk factors (CRF, with creatinine >2.1 mg/dL; HF; diabetes, particularly being insulin dependent; age >60 years; jaundice) and procedure-specific risks (aortic, cardiovascular, or liver transplant surgery) help predict which surgical candidates face the highest risk.^16,18,19 Thakar et al have developed a scoring system to identify those at greatest risk for AKI.²⁰ (See “Cardiovascular surgery and acute kidney injury: Scoring the risk” at www.jfponline.com by clicking on “Before surgery: Have you done enough to mitigate risk?” and scrolling to the end.)

Minimize renal complications. Helping patients achieve good intravascular volume and osmolar status preoperatively will reduce their risk of renal complications. Other prophylactic measures: Minimize exposure to nephrotoxins (eg, nonsteroidal anti-inflammatory drugs or contrast media) to the extent possible. Consider evaluating the serum electrolyte and creatinine levels of patients with multiple risk factors to determine whether they can safely undergo surgery; some experts suggest preoperative urinalysis, as well.¹⁸

Patients with end-stage renal disease have very high perioperative morbidity.²¹ They are at increased risk for hyperkalemia, infection, hyper- and hypotension, bleeding, arrhythmias, and clotted fistulas, in descending order of incidence.¹⁸ Preoperative planning, including the need for dialysis before surgery, is necessary to manage these risks.

Risk of postop infection: Focusing on the foreseeable
Postoperative infections, both at the surgical site and remote from the incision, are a significant cause of morbidity and mortality. Pneumonia is among the most prominent remote infections associated with surgery,²² and early ambulation, deep breathing exercises, and tight glycemic control can greatly decrease the risk.

Surgical site infection (SSI) remains an important concern, occurring in 37% of cases.²³ Risk factors include hyperglycemia, malnutrition, perioperative steroid use, preexisting infections, tobacco smoking, peripheral vascular disease, advanced age, radiation therapy, blood transfusions, prolonged preoperative stay, preoperative shaving, hypothermia, hypoxia, length of operation, and postoperative incontinence.²⁴ While many of these risk factors are dependent on interventions in the operating room and recovery room or during subsequent hospitalization, it is important to address foreseeable risks as part of the preoperative evaluation.

Glycemic control is crucial. Perhaps the most well-documented risk for SSI is hyperglycemia—a common problem among hospitalized patients.¹⁶ Hyperglycemia impairs leukocyte and complement function,^25,26 thereby increasing risk of infectious complications. Tight glycemic control in the surgical patient, especially on the surgical intensive care unit, has been associated with improved outcomes.²⁷

Identify the presence of diabetes in the preoperative consult note, and adjust the patient’s medication regimen as needed, to help him or her achieve optimal glycemic control. In some cases, it may be necessary to delay nonurgent surgery until the patient achieves adequate control.

Malnutrition is another risk factor for SSI. For patients who are undernourished or morbidly obese, checking serum albumin levels may be beneficial. Supplementation for 1 to 2 weeks prior to surgery may decrease the risk of infection for patients who are undernourished;²⁸ for obese patients, weight loss is beneficial. Although significant preoperative weight loss may not be possible, it is important to list an elevated body mass index as a risk factor in the consultation note.

Corticosteroids, used to treat conditions such as COPD, inflammatory bowel disease, allergies, and autoimmune disorders, are another risk factor for perioperative infection. In addition to their effect on glycemic control, corticosteroids directly suppress the immune system. Whenever possible, they should be discontinued preoperatively. If this is not possible, call attention to the patient’s use of corticosteroids in the consultation note.

Preexisting infection presents the possibility of the spread of organisms to the surgical site and, whenever possible, surgery should be postponed until the infection resolves. If the patient has a history of prior infection or colonization with methicillin-resistant Staphylococcus aureus, be sure to include that in the consultation note, as well.

Leukocyte-containing blood product transfusions are associated with a 2-fold increase in some postop infectious complications.^29-31 This is in addition to the well-known risk of bloodborne pathogens associated with transfusions, and is yet another reason to avoid perioperative transfusions whenever possible.

Smoking impairs tissue oxygenation, which delays healing and increases risk of infection. Smoking cessation should be strongly encouraged at every preoperative consultation. Recommend nicotine replacement therapy even for patients who aren’t willing to quit altogether; point out that giving up cigarettes for just 30 days (or more) before surgery can decrease the likelihood of complications.²⁸

In addition to these identified risk factors, anything that compromises the immune status increases the risk of infection. Alcohol or drug abusers, chronic pain patients, transplant recipients, cancer patients taking immunosuppressants, postsplenectomy patients, and patients with HIV are all at increased risk. Identify any such conditions during your preoperative evaluation, and be sure to include them in your communication with the surgical team.

A common request in preop consults relates to bacterial endocarditis prophylaxis. Only an extremely small number of cases of infective endocarditis occur with dental procedures, however, so the benefits of antibiotic prophylaxis would be minimal, even if the prophylactic therapy were 100% effective.³² As a result, the ACC/AHA guidelines recommend prophylaxis for dental procedures only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. Administration of antibiotics solely to prevent endocarditis is not recommended for patients undergoing genitourinary or gastrointestinal tract procedures.³²

Hematologic evaluation: Address risks of bleeding, clotting
Historically, a variety of tests have been employed in an effort to identify patients at risk for bleeding complications prior to surgery—including prothrombin time, partial thromboplastin time, platelet count, and bleeding time, or platelet function. While highly reproducible, automated, and inexpensive when considered individually, the cumulative cost of routine use of these tests is high.³³

A recent review of the literature indicates that, for surgical patients without synthetic liver dysfunction or a history of oral anticoagulant use, routine testing is of little value in the assessment of bleeding risk.³⁴ Patients with a negative bleeding history do not require routine coagulation screening prior to surgery.³⁵

Instead, use the medical history to identify risk factors for bleeding. These include excessive bruising, nosebleeds, prolonged bleeding after cuts, bleeding >3 minutes after brushing teeth, and heavy or prolonged menses (TABLE 1). Patients with a past medical history of liver disease; renal failure; hypersplenism; hematologic disease; collagen vascular disease; hemophilia or other inherited hemorrhagic disorder; gastrointestinal or urogenital blood loss; and severe bleeding after dental extraction, other surgery, or childbirth are also at heightened risk, as are those who take medications that affect hemostasis. Physical findings suggestive of risk include purpura, hematoma, jaundice, and signs of cirrhosis.³⁴

While laboratory testing is only appropriate to confirm those at risk in the subpopulation selected by the history and physical, here, as with other adjunctive testing, it is important to consider local standards and the preferences of the surgeon who requested the preop consult.

Treat anemia. Preoperative anemia is linked to adverse outcomes in surgical patients,³⁶ although it is not clear whether the anemia itself or the perioperative transfusions associated with the condition are at the root of the problem.³⁷ Macrocytic anemia may require treatment with vitamin B₁₂ and folate; iron deficiency anemia is treated with iron. Some physicians also recommend the use of erythropoietin starting 3 weeks prior to surgery for patients with normocytic anemia with hemoglobin <13 g/dL.^38,39

Thromboembolism risk. Excessive clotting is responsible for more perioperative complications than excessive bleeding. There is a high prevalence of venous thromboembolism (VTE) among surgical patients, with both patient- and procedure-specific risk factors. Although a variety of coagulopathies increase the baseline risk for VTE, routine laboratory screening of the general surgical population for thrombophilia is not recommended.^34,35

When risk factors are present based on both the patient’s medical history and the type of procedure, prophylactic measures may be needed (TABLE 3). Options include mechanical prophylaxis (graduated compression stockings and intermittent pneumatic devices) and chemoprophylaxis. Recommended for high-risk cases, such as patients undergoing orthopedic surgery that precludes early mobilization, chemoprophylaxis options include low-molecular-weight heparin, low-dose unfractionated heparin, fondaparinux (a synthetic factor Xa inhibitor), and vitamin K antagonists such as warfarin.⁴⁰ Aspirin alone is not recommended, as it has not been found to be an effective prophylaxis for VTE.

CASE After following this system-by-system review of your patient, Charlie H, you identify and explicitly communicate the following risk factors in your consultation note:

• Cardiovascular: type 2 diabetes, low functional capacity
• Pulmonary: advanced age
• Renal: advanced age
• Infectious: type 2 diabetes, advanced age, BMI=39
• Hematologic: advanced age, obesity

Based on these findings, you develop the following plan for Charlie H, detailed in the consultation note you submit to the surgical team:

• Continue home diabetes medications perioperatively, supplemented with a basal-bolus insulin regimen.
• Initiate incentive spirometry postoperatively; use an NG tube if postoperative nausea and vomiting occur.
• Maintain MAP >65 mm Hg.
• Institute aggressive early ambulation and use of graduated compression stockings for DVT prophylaxis.
  Submitted by ___________ on ________.

TABLE 3
Perioperative thromboembolism: Risk and prophylaxis

CORRESPONDENCE Mark K. Huntington, MD, PhD, FAAFP, Center for Family Medicine, 1115 East Twentieth Street, Sioux Falls, SD 57105; [email protected]

A long-standing 25-year-old patient of yours reports that a home-pregnancy test proved positive. You confirm the pregnancy. This will be her first child. On routine prenatal testing, her human immunodeficiency virus (HIV) test result is also positive (enzyme-linked immunosorbent assay [ELISA], with confirmatory Western blot). She is concerned that the infection may be transmitted to her child and asks what can be done to prevent it.

With the use of appropriate interventions, the likelihood of her child becoming infected is less than 2%. In the United States today, most infants born to HIV-positive women will remain uninfected. Interventions recommended by the Public Health Service Task Force (US guidelines) include giving antiretroviral medications to the woman during pregnancy; managing the delivery, with the option of vaginal delivery vs cesarean section (to be determined closer to the time of delivery, based on her response to antiretroviral agents); giving a 6-week course of zidovudine (ZDV) to her infant; and avoiding breastfeeding.^1,2

What heightens the risk?
Perinatal transmission of HIV from mother to child can occur during pregnancy, labor and delivery, or breastfeeding.³ Risk of transmission is heightened if a mother has a high viral load and low CD4+ cell count or has advanced HIV illness or AIDS; rupture of membranes is prolonged, exceeding 4 hours; or invasive obstetrical procedures are required.³

Without intervention, the risk of transmission is 15% to 30%.⁴ Approximately 70% of transmission is believed to occur before delivery (20% before 36 weeks’ gestation, 50% from 36 weeks through labor), with roughly 30% of transmission occurring during delivery and the infant’s passage through the birth canal.⁵ Breastfeeding adds 5% to 20% to baseline risk, raising the total modifiable risk to as high as 50%.⁵

A comprehensive approach from WHO

The World Health Organization (WHO) has described a comprehensive approach to preventing perinatal transmission of HIV,⁴ which takes into consideration several factors across the spectrum of women’s and children’s health and assumes the involvement of a range of health care providers, including family physicians. The WHO approach focuses on 4 main areas and their respective interventions:

• Preventing HIV infection among women of childbearing age
• Preventing unintended pregnancies among women with HIV
• Preventing HIV transmission from a mother to her infant
• Providing appropriate care, treatment, and support to mothers with HIV and their children and families.

Preventing HIV infection among women of childbearing age
In 2007, HIV/AIDS was diagnosed in nearly 11,000 American women.⁶ African American women are 22 times more likely than white women to become infected, and Hispanic women are 5 times more likely.⁶

More than 80% of women become infected with HIV through high-risk heterosexual contact, including unprotected sex with multiple partners (eg, sex in exchange for money or narcotics), sex with men who have sex with men, and sex with injection drug users.⁷

Injection drug use is associated with 1 in 6 new HIV/AIDS diagnoses in women.^6,7 Young women of childbearing age have a higher risk of becoming HIV infected than older women,^6,7 and pregnancy itself increases a woman’s vulnerability to infection.^6,7 In addition, women may not appreciate their male partner’s risk factors for HIV infection.⁷

The presence of other sexually transmitted infections (STIs) greatly increases the risk of acquiring and transmitting HIV infection.⁸ Poverty, too, is a risk factor for acquiring HIV infection. A study of African American women in North Carolina found that unemployment, receipt of public assistance, and the exchange of sex for money or housing were significantly more likely among HIV-infected women than among uninfected women.⁹

Awareness of these risk factors is important for those who care for minority and disadvantaged populations. In treating at-risk women, consider early referral to social services and reinforce HIV prevention strategies, such as condom use with each sexual contact, to help reduce new HIV infections.^7,10 Screening of young women for gonorrhea and chlamydia and prompt treatment of these and other STIs may also have an impact on HIV transmission.^8,11

Preventing unintended pregnancies among women with HIV

Many HIV-infected women do not receive regular health care,^12,13 including family planning services. And many do not know they are infected.¹²

The Centers for Disease Control and Prevention (CDC) recommends routine voluntary screening for HIV as a standard part of basic medical care.¹⁴ This is particularly important among higher-risk populations. Family physicians could offer a full range of family planning options for women who choose to undergo screening or otherwise test positive for HIV.

Preventing HIV transmission from mother to infant
As many as 40% of HIV-infected infants in the United States are born to mothers unaware of their HIV status at delivery.¹⁵ The CDC emphasizes that it is never too late for pregnant women to be tested, and recommends an “opt out” approach, thereby establishing HIV testing as a routine part of prenatal care.¹⁴ Recommendations also include repeating the HIV screen in the third trimester for women who meet certain criteria (TABLE 1);¹⁴ antiretrovirals given to a mother during labor and to the infant after birth can still significantly reduce the risk of perinatal transmission.¹⁶ Accordingly, the use of rapid HIV tests in delivery rooms is recommended for women with unclear HIV status.¹⁵ US guidelines also cover scenarios in which maternal HIV infection is first realized during labor or after a child has been born.¹

Women known to be living with HIV who wish to become pregnant can be assured that, if current US guidelines are followed, the risk of HIV transmission to their infant is less than 2%.¹ These guidelines include detailed recommendations for antiretroviral drug use by pregnant HIV-infected women that vary by clinical scenario. The guidelines are updated frequently and are available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf.¹ The full package of interventions also includes obstetric measures and a course of ZDV administered to the infant after birth.

Antiretrovirals during pregnancy. Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) was the first major study of antiretroviral use for perinatal transmission prevention.¹⁷ This randomized, placebo-controlled study evaluated antiretroviral prophylaxis with ZDV monotherapy. ZDV was given to mothers orally, beginning at 14 to 34 weeks of pregnancy, and intravenously during labor and delivery, and to newborns orally for the first 6 weeks of life. Infants were formula fed. At 18 months, HIV transmission occurred with 25.5% of women receiving placebo and 8.3% of women receiving ZDV—a 67.5% relative risk reduction.¹⁷

Subsequently, it was realized that antiretroviral regimens that use 3 medications are superior to those that use only 1 or 2.¹⁸ Current standard of care in the United States is use of a 3-drug combination during pregnancy (known as highly active antiretroviral therapy, or HAART).¹ HAART generally comprises 2 nucleoside reverse transcriptase inhibitors (ZDV, lamivudine) and either a non-nucleoside reverse transcriptase inhibitor (nevirapine) or a protease inhibitor (lopinavir/ritonavir).

Some women meet criteria for HAART based on their clinical or immunologic status (history of an AIDS-defining condition or severe HIV-associated symptoms, or a CD4+ count <350 cells/mm³, respectively). However, all pregnant women should be offered HAART, regardless of their immunologic or virologic status, as perinatal transmission may occur even at very low or undetectable viral loads.¹ HIV antiretroviral resistance should be assessed before initiating HAART.¹

A woman’s primary care and obstetric providers are important to the success of antepartum antiretroviral therapy, even though they may not directly manage the regimen. The goal of therapy is an undetectable maternal viral load at delivery,¹ an achievement that depends in large part on adherence to antiretroviral therapy,¹⁹ which may be influenced by the degree to which coordinated care is delivered.²⁰

Obstetric interventions. Compared with vaginal delivery, cesarean delivery reduces perinatal HIV transmission.^21,22 To be most effective, a cesarean section must be performed electively, before membranes rupture.¹² For most HIV-infected women, cesarean section is as safe as it is for HIV-negative women. For women with advanced disease or AIDS, cesarean section may carry a higher risk of maternal complications.²³

For women with unknown HIV RNA levels (viral load) or a viral load >1000 copies/mL near the time of delivery, US guidelines recommend that scheduled cesarean delivery be performed at 38 weeks’ gestation, whether or not they are receiving antepartum antiretroviral drugs.¹² For women taking antiretrovirals who have a viral load of <1000 copies/mL, guidelines advise that data are insufficient to evaluate the potential benefit of cesarean delivery in preventing perinatal transmission.¹² When viral load is <1000 copies/mL, administration of intravenous ZDV followed by vaginal delivery (as in PACTG 076–2 mg/kg intravenous load over 1 hour, then 1 mg/kg per hour until delivery) is an option, and is commonly used in the United States.^1,23

Antiretroviral administration to infants. All HIV-exposed newborns receive ZDV as a standard part of perinatal transmission prevention,¹ initiated as close to delivery as possible. Infants whose gestation was 35 weeks at birth receive an oral dose of 2 mg/kg (or 1.5 mg/kg intravenously if unable to take oral medications) within the first 6 to 12 hours after birth, then every 6 hours until 6 weeks of age. Infants less than 35 weeks’ gestation at birth receive 2 mg/kg orally every 12 hours (or 1.5 mg/kg intravenously), advancing to every 8 hours at 2 weeks of age if they were 30 weeks’ gestation at birth, or at 4 weeks of age if less than 30 weeks’ gestation at birth.

In unusual circumstances, such as when a mother is known to have a high viral load at delivery or an antiretroviral-resistant virus, other antiretroviral agents may be added to ZDV for infant prophylaxis.¹ The decision to use additional antiretrovirals necessitates consultation with a pediatric HIV specialist, preferably before delivery.

With the exception of efavirenz—thought to have potential teratogenicity when administered in the first trimester of pregnancy¹—antiretrovirals are generally considered safe in pregnancy and for newborns;⁷ rarely, significant organ system pathology due to mitochondrial toxicity has been observed in infants exposed to antiretrovirals.²⁴ Prophylactic ZDV use may be associated with anemia in infants, but this is generally mild and resolves by 12 weeks of age without treatment.²⁵ Follow-up of the data from PACTG 076 has shown no long-term adverse effects associated with ZDV.²⁶

TABLE 1
Repeated HIV screening is recommended for pregnant women in their third trimester who meet these criteria¹⁴

Providing care, Tx, support to mothers with HIV and their newborns
Prevention of perinatal HIV transmission does not end when an infant completes 6 weeks of ZDV therapy. The mother must have postpartum care and ongoing management of HIV infection; the infant must undergo assessment of HIV status and monitoring while receiving ZDV, and receive general infant care. The longitudinal, family-centered approach with family medicine offers an opportunity to optimize the overall wellness of a woman with HIV, including mental health, contraceptive counseling, cervical screening, and a decision on whether to continue antiretroviral therapy, based on clinical status (HIV disease stage) and immunologic (CD4) factors. ¹

In the United States and other developed countries where safe and feasible formula feeding is possible, breastfeeding is not recommended for HIV-infected mothers, due to the risk of virus transmission via breast milk.¹

Given that maternal antibodies to HIV cross the placenta and are detectable in HIV-exposed infants up to 18 months of age, antibody tests such as HIV ELISA and rapid HIV tests are not suitable for the diagnosis of HIV in infants.¹² Rather, a virologic polymerase chain reaction (PCR) test must be used.¹ While HIV DNA PCR is the gold standard for infant diagnosis, HIV RNA PCR is also sensitive and specific.¹ HIV-exposed infants should receive routine childhood immunizations according to the usual schedule.^1,27 HIV-infected infants should be referred to a pediatric HIV specialist.

Untreated HIV infection in infants may have a variable course, including rapid progression to AIDS and death.²⁸ Often the first manifestation of rapid progression is Pneumocystis jiroveci pneumonia (formerly Pneumocystis carinii pneumonia), which may be seen even before HIV diagnosis is realized in an infant who becomes HIV-infected despite prophylaxis.^1,29 Unless there is adequate proof to presumptively exclude HIV infection (negative results on 2 virologic tests conducted ≥2 weeks postpartum, 1 of which must be at least 4 weeks postpartum),^1,29 all HIV-exposed infants should be started at age 6 weeks (after completion of ZDV prophylaxis) on trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra) prophylaxis against Pneumocystis pneumonia. TMP-SMX prophylaxis should be continued until 2 virologic tests for HIV yield negative results.¹ If TMP-SMX toxicity develops, dapsone and atovaquone are alternatives.²⁹ TABLE 2 outlines the follow-up of HIV-exposed infants, including testing for HIV.

TABLE 2
Follow-up measures for infants exposed to maternal HIV^1,27

CORRESPONDENCE
Michael A. Tolle, MD, Baylor College of Medicine, 6701 Fannin Street, CC1210, Houston, TX 77030; [email protected]

Acknowledgements
The author thanks Heidi Schwarzwald, MD, Gordon Schutze, MD, and Mark Kline, MD, for their comments on this manuscript.

A long-standing 25-year-old patient of yours reports that a home-pregnancy test proved positive. You confirm the pregnancy. This will be her first child. On routine prenatal testing, her human immunodeficiency virus (HIV) test result is also positive (enzyme-linked immunosorbent assay [ELISA], with confirmatory Western blot). She is concerned that the infection may be transmitted to her child and asks what can be done to prevent it.

With the use of appropriate interventions, the likelihood of her child becoming infected is less than 2%. In the United States today, most infants born to HIV-positive women will remain uninfected. Interventions recommended by the Public Health Service Task Force (US guidelines) include giving antiretroviral medications to the woman during pregnancy; managing the delivery, with the option of vaginal delivery vs cesarean section (to be determined closer to the time of delivery, based on her response to antiretroviral agents); giving a 6-week course of zidovudine (ZDV) to her infant; and avoiding breastfeeding.^1,2

What heightens the risk?
Perinatal transmission of HIV from mother to child can occur during pregnancy, labor and delivery, or breastfeeding.³ Risk of transmission is heightened if a mother has a high viral load and low CD4+ cell count or has advanced HIV illness or AIDS; rupture of membranes is prolonged, exceeding 4 hours; or invasive obstetrical procedures are required.³

Without intervention, the risk of transmission is 15% to 30%.⁴ Approximately 70% of transmission is believed to occur before delivery (20% before 36 weeks’ gestation, 50% from 36 weeks through labor), with roughly 30% of transmission occurring during delivery and the infant’s passage through the birth canal.⁵ Breastfeeding adds 5% to 20% to baseline risk, raising the total modifiable risk to as high as 50%.⁵

A comprehensive approach from WHO

The World Health Organization (WHO) has described a comprehensive approach to preventing perinatal transmission of HIV,⁴ which takes into consideration several factors across the spectrum of women’s and children’s health and assumes the involvement of a range of health care providers, including family physicians. The WHO approach focuses on 4 main areas and their respective interventions:

• Preventing HIV infection among women of childbearing age
• Preventing unintended pregnancies among women with HIV
• Preventing HIV transmission from a mother to her infant
• Providing appropriate care, treatment, and support to mothers with HIV and their children and families.

Preventing HIV infection among women of childbearing age
In 2007, HIV/AIDS was diagnosed in nearly 11,000 American women.⁶ African American women are 22 times more likely than white women to become infected, and Hispanic women are 5 times more likely.⁶

More than 80% of women become infected with HIV through high-risk heterosexual contact, including unprotected sex with multiple partners (eg, sex in exchange for money or narcotics), sex with men who have sex with men, and sex with injection drug users.⁷

Injection drug use is associated with 1 in 6 new HIV/AIDS diagnoses in women.^6,7 Young women of childbearing age have a higher risk of becoming HIV infected than older women,^6,7 and pregnancy itself increases a woman’s vulnerability to infection.^6,7 In addition, women may not appreciate their male partner’s risk factors for HIV infection.⁷

The presence of other sexually transmitted infections (STIs) greatly increases the risk of acquiring and transmitting HIV infection.⁸ Poverty, too, is a risk factor for acquiring HIV infection. A study of African American women in North Carolina found that unemployment, receipt of public assistance, and the exchange of sex for money or housing were significantly more likely among HIV-infected women than among uninfected women.⁹

Awareness of these risk factors is important for those who care for minority and disadvantaged populations. In treating at-risk women, consider early referral to social services and reinforce HIV prevention strategies, such as condom use with each sexual contact, to help reduce new HIV infections.^7,10 Screening of young women for gonorrhea and chlamydia and prompt treatment of these and other STIs may also have an impact on HIV transmission.^8,11

Preventing unintended pregnancies among women with HIV

Many HIV-infected women do not receive regular health care,^12,13 including family planning services. And many do not know they are infected.¹²

The Centers for Disease Control and Prevention (CDC) recommends routine voluntary screening for HIV as a standard part of basic medical care.¹⁴ This is particularly important among higher-risk populations. Family physicians could offer a full range of family planning options for women who choose to undergo screening or otherwise test positive for HIV.

Preventing HIV transmission from mother to infant
As many as 40% of HIV-infected infants in the United States are born to mothers unaware of their HIV status at delivery.¹⁵ The CDC emphasizes that it is never too late for pregnant women to be tested, and recommends an “opt out” approach, thereby establishing HIV testing as a routine part of prenatal care.¹⁴ Recommendations also include repeating the HIV screen in the third trimester for women who meet certain criteria (TABLE 1);¹⁴ antiretrovirals given to a mother during labor and to the infant after birth can still significantly reduce the risk of perinatal transmission.¹⁶ Accordingly, the use of rapid HIV tests in delivery rooms is recommended for women with unclear HIV status.¹⁵ US guidelines also cover scenarios in which maternal HIV infection is first realized during labor or after a child has been born.¹

Women known to be living with HIV who wish to become pregnant can be assured that, if current US guidelines are followed, the risk of HIV transmission to their infant is less than 2%.¹ These guidelines include detailed recommendations for antiretroviral drug use by pregnant HIV-infected women that vary by clinical scenario. The guidelines are updated frequently and are available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf.¹ The full package of interventions also includes obstetric measures and a course of ZDV administered to the infant after birth.

Antiretrovirals during pregnancy. Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) was the first major study of antiretroviral use for perinatal transmission prevention.¹⁷ This randomized, placebo-controlled study evaluated antiretroviral prophylaxis with ZDV monotherapy. ZDV was given to mothers orally, beginning at 14 to 34 weeks of pregnancy, and intravenously during labor and delivery, and to newborns orally for the first 6 weeks of life. Infants were formula fed. At 18 months, HIV transmission occurred with 25.5% of women receiving placebo and 8.3% of women receiving ZDV—a 67.5% relative risk reduction.¹⁷

Subsequently, it was realized that antiretroviral regimens that use 3 medications are superior to those that use only 1 or 2.¹⁸ Current standard of care in the United States is use of a 3-drug combination during pregnancy (known as highly active antiretroviral therapy, or HAART).¹ HAART generally comprises 2 nucleoside reverse transcriptase inhibitors (ZDV, lamivudine) and either a non-nucleoside reverse transcriptase inhibitor (nevirapine) or a protease inhibitor (lopinavir/ritonavir).

Some women meet criteria for HAART based on their clinical or immunologic status (history of an AIDS-defining condition or severe HIV-associated symptoms, or a CD4+ count <350 cells/mm³, respectively). However, all pregnant women should be offered HAART, regardless of their immunologic or virologic status, as perinatal transmission may occur even at very low or undetectable viral loads.¹ HIV antiretroviral resistance should be assessed before initiating HAART.¹

A woman’s primary care and obstetric providers are important to the success of antepartum antiretroviral therapy, even though they may not directly manage the regimen. The goal of therapy is an undetectable maternal viral load at delivery,¹ an achievement that depends in large part on adherence to antiretroviral therapy,¹⁹ which may be influenced by the degree to which coordinated care is delivered.²⁰

Obstetric interventions. Compared with vaginal delivery, cesarean delivery reduces perinatal HIV transmission.^21,22 To be most effective, a cesarean section must be performed electively, before membranes rupture.¹² For most HIV-infected women, cesarean section is as safe as it is for HIV-negative women. For women with advanced disease or AIDS, cesarean section may carry a higher risk of maternal complications.²³

For women with unknown HIV RNA levels (viral load) or a viral load >1000 copies/mL near the time of delivery, US guidelines recommend that scheduled cesarean delivery be performed at 38 weeks’ gestation, whether or not they are receiving antepartum antiretroviral drugs.¹² For women taking antiretrovirals who have a viral load of <1000 copies/mL, guidelines advise that data are insufficient to evaluate the potential benefit of cesarean delivery in preventing perinatal transmission.¹² When viral load is <1000 copies/mL, administration of intravenous ZDV followed by vaginal delivery (as in PACTG 076–2 mg/kg intravenous load over 1 hour, then 1 mg/kg per hour until delivery) is an option, and is commonly used in the United States.^1,23

Antiretroviral administration to infants. All HIV-exposed newborns receive ZDV as a standard part of perinatal transmission prevention,¹ initiated as close to delivery as possible. Infants whose gestation was 35 weeks at birth receive an oral dose of 2 mg/kg (or 1.5 mg/kg intravenously if unable to take oral medications) within the first 6 to 12 hours after birth, then every 6 hours until 6 weeks of age. Infants less than 35 weeks’ gestation at birth receive 2 mg/kg orally every 12 hours (or 1.5 mg/kg intravenously), advancing to every 8 hours at 2 weeks of age if they were 30 weeks’ gestation at birth, or at 4 weeks of age if less than 30 weeks’ gestation at birth.

In unusual circumstances, such as when a mother is known to have a high viral load at delivery or an antiretroviral-resistant virus, other antiretroviral agents may be added to ZDV for infant prophylaxis.¹ The decision to use additional antiretrovirals necessitates consultation with a pediatric HIV specialist, preferably before delivery.

With the exception of efavirenz—thought to have potential teratogenicity when administered in the first trimester of pregnancy¹—antiretrovirals are generally considered safe in pregnancy and for newborns;⁷ rarely, significant organ system pathology due to mitochondrial toxicity has been observed in infants exposed to antiretrovirals.²⁴ Prophylactic ZDV use may be associated with anemia in infants, but this is generally mild and resolves by 12 weeks of age without treatment.²⁵ Follow-up of the data from PACTG 076 has shown no long-term adverse effects associated with ZDV.²⁶

TABLE 1
Repeated HIV screening is recommended for pregnant women in their third trimester who meet these criteria¹⁴

Providing care, Tx, support to mothers with HIV and their newborns
Prevention of perinatal HIV transmission does not end when an infant completes 6 weeks of ZDV therapy. The mother must have postpartum care and ongoing management of HIV infection; the infant must undergo assessment of HIV status and monitoring while receiving ZDV, and receive general infant care. The longitudinal, family-centered approach with family medicine offers an opportunity to optimize the overall wellness of a woman with HIV, including mental health, contraceptive counseling, cervical screening, and a decision on whether to continue antiretroviral therapy, based on clinical status (HIV disease stage) and immunologic (CD4) factors. ¹

In the United States and other developed countries where safe and feasible formula feeding is possible, breastfeeding is not recommended for HIV-infected mothers, due to the risk of virus transmission via breast milk.¹

Given that maternal antibodies to HIV cross the placenta and are detectable in HIV-exposed infants up to 18 months of age, antibody tests such as HIV ELISA and rapid HIV tests are not suitable for the diagnosis of HIV in infants.¹² Rather, a virologic polymerase chain reaction (PCR) test must be used.¹ While HIV DNA PCR is the gold standard for infant diagnosis, HIV RNA PCR is also sensitive and specific.¹ HIV-exposed infants should receive routine childhood immunizations according to the usual schedule.^1,27 HIV-infected infants should be referred to a pediatric HIV specialist.

Untreated HIV infection in infants may have a variable course, including rapid progression to AIDS and death.²⁸ Often the first manifestation of rapid progression is Pneumocystis jiroveci pneumonia (formerly Pneumocystis carinii pneumonia), which may be seen even before HIV diagnosis is realized in an infant who becomes HIV-infected despite prophylaxis.^1,29 Unless there is adequate proof to presumptively exclude HIV infection (negative results on 2 virologic tests conducted ≥2 weeks postpartum, 1 of which must be at least 4 weeks postpartum),^1,29 all HIV-exposed infants should be started at age 6 weeks (after completion of ZDV prophylaxis) on trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra) prophylaxis against Pneumocystis pneumonia. TMP-SMX prophylaxis should be continued until 2 virologic tests for HIV yield negative results.¹ If TMP-SMX toxicity develops, dapsone and atovaquone are alternatives.²⁹ TABLE 2 outlines the follow-up of HIV-exposed infants, including testing for HIV.

TABLE 2
Follow-up measures for infants exposed to maternal HIV^1,27

CORRESPONDENCE
Michael A. Tolle, MD, Baylor College of Medicine, 6701 Fannin Street, CC1210, Houston, TX 77030; [email protected]

Acknowledgements
The author thanks Heidi Schwarzwald, MD, Gordon Schutze, MD, and Mark Kline, MD, for their comments on this manuscript.

A long-standing 25-year-old patient of yours reports that a home-pregnancy test proved positive. You confirm the pregnancy. This will be her first child. On routine prenatal testing, her human immunodeficiency virus (HIV) test result is also positive (enzyme-linked immunosorbent assay [ELISA], with confirmatory Western blot). She is concerned that the infection may be transmitted to her child and asks what can be done to prevent it.

With the use of appropriate interventions, the likelihood of her child becoming infected is less than 2%. In the United States today, most infants born to HIV-positive women will remain uninfected. Interventions recommended by the Public Health Service Task Force (US guidelines) include giving antiretroviral medications to the woman during pregnancy; managing the delivery, with the option of vaginal delivery vs cesarean section (to be determined closer to the time of delivery, based on her response to antiretroviral agents); giving a 6-week course of zidovudine (ZDV) to her infant; and avoiding breastfeeding.^1,2

What heightens the risk?
Perinatal transmission of HIV from mother to child can occur during pregnancy, labor and delivery, or breastfeeding.³ Risk of transmission is heightened if a mother has a high viral load and low CD4+ cell count or has advanced HIV illness or AIDS; rupture of membranes is prolonged, exceeding 4 hours; or invasive obstetrical procedures are required.³

Without intervention, the risk of transmission is 15% to 30%.⁴ Approximately 70% of transmission is believed to occur before delivery (20% before 36 weeks’ gestation, 50% from 36 weeks through labor), with roughly 30% of transmission occurring during delivery and the infant’s passage through the birth canal.⁵ Breastfeeding adds 5% to 20% to baseline risk, raising the total modifiable risk to as high as 50%.⁵

A comprehensive approach from WHO

The World Health Organization (WHO) has described a comprehensive approach to preventing perinatal transmission of HIV,⁴ which takes into consideration several factors across the spectrum of women’s and children’s health and assumes the involvement of a range of health care providers, including family physicians. The WHO approach focuses on 4 main areas and their respective interventions:

• Preventing HIV infection among women of childbearing age
• Preventing unintended pregnancies among women with HIV
• Preventing HIV transmission from a mother to her infant
• Providing appropriate care, treatment, and support to mothers with HIV and their children and families.

Preventing HIV infection among women of childbearing age
In 2007, HIV/AIDS was diagnosed in nearly 11,000 American women.⁶ African American women are 22 times more likely than white women to become infected, and Hispanic women are 5 times more likely.⁶

More than 80% of women become infected with HIV through high-risk heterosexual contact, including unprotected sex with multiple partners (eg, sex in exchange for money or narcotics), sex with men who have sex with men, and sex with injection drug users.⁷

Injection drug use is associated with 1 in 6 new HIV/AIDS diagnoses in women.^6,7 Young women of childbearing age have a higher risk of becoming HIV infected than older women,^6,7 and pregnancy itself increases a woman’s vulnerability to infection.^6,7 In addition, women may not appreciate their male partner’s risk factors for HIV infection.⁷

The presence of other sexually transmitted infections (STIs) greatly increases the risk of acquiring and transmitting HIV infection.⁸ Poverty, too, is a risk factor for acquiring HIV infection. A study of African American women in North Carolina found that unemployment, receipt of public assistance, and the exchange of sex for money or housing were significantly more likely among HIV-infected women than among uninfected women.⁹

Awareness of these risk factors is important for those who care for minority and disadvantaged populations. In treating at-risk women, consider early referral to social services and reinforce HIV prevention strategies, such as condom use with each sexual contact, to help reduce new HIV infections.^7,10 Screening of young women for gonorrhea and chlamydia and prompt treatment of these and other STIs may also have an impact on HIV transmission.^8,11

Preventing unintended pregnancies among women with HIV

Many HIV-infected women do not receive regular health care,^12,13 including family planning services. And many do not know they are infected.¹²

The Centers for Disease Control and Prevention (CDC) recommends routine voluntary screening for HIV as a standard part of basic medical care.¹⁴ This is particularly important among higher-risk populations. Family physicians could offer a full range of family planning options for women who choose to undergo screening or otherwise test positive for HIV.

Preventing HIV transmission from mother to infant
As many as 40% of HIV-infected infants in the United States are born to mothers unaware of their HIV status at delivery.¹⁵ The CDC emphasizes that it is never too late for pregnant women to be tested, and recommends an “opt out” approach, thereby establishing HIV testing as a routine part of prenatal care.¹⁴ Recommendations also include repeating the HIV screen in the third trimester for women who meet certain criteria (TABLE 1);¹⁴ antiretrovirals given to a mother during labor and to the infant after birth can still significantly reduce the risk of perinatal transmission.¹⁶ Accordingly, the use of rapid HIV tests in delivery rooms is recommended for women with unclear HIV status.¹⁵ US guidelines also cover scenarios in which maternal HIV infection is first realized during labor or after a child has been born.¹

Women known to be living with HIV who wish to become pregnant can be assured that, if current US guidelines are followed, the risk of HIV transmission to their infant is less than 2%.¹ These guidelines include detailed recommendations for antiretroviral drug use by pregnant HIV-infected women that vary by clinical scenario. The guidelines are updated frequently and are available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf.¹ The full package of interventions also includes obstetric measures and a course of ZDV administered to the infant after birth.

Antiretrovirals during pregnancy. Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) was the first major study of antiretroviral use for perinatal transmission prevention.¹⁷ This randomized, placebo-controlled study evaluated antiretroviral prophylaxis with ZDV monotherapy. ZDV was given to mothers orally, beginning at 14 to 34 weeks of pregnancy, and intravenously during labor and delivery, and to newborns orally for the first 6 weeks of life. Infants were formula fed. At 18 months, HIV transmission occurred with 25.5% of women receiving placebo and 8.3% of women receiving ZDV—a 67.5% relative risk reduction.¹⁷

Subsequently, it was realized that antiretroviral regimens that use 3 medications are superior to those that use only 1 or 2.¹⁸ Current standard of care in the United States is use of a 3-drug combination during pregnancy (known as highly active antiretroviral therapy, or HAART).¹ HAART generally comprises 2 nucleoside reverse transcriptase inhibitors (ZDV, lamivudine) and either a non-nucleoside reverse transcriptase inhibitor (nevirapine) or a protease inhibitor (lopinavir/ritonavir).

Some women meet criteria for HAART based on their clinical or immunologic status (history of an AIDS-defining condition or severe HIV-associated symptoms, or a CD4+ count <350 cells/mm³, respectively). However, all pregnant women should be offered HAART, regardless of their immunologic or virologic status, as perinatal transmission may occur even at very low or undetectable viral loads.¹ HIV antiretroviral resistance should be assessed before initiating HAART.¹

A woman’s primary care and obstetric providers are important to the success of antepartum antiretroviral therapy, even though they may not directly manage the regimen. The goal of therapy is an undetectable maternal viral load at delivery,¹ an achievement that depends in large part on adherence to antiretroviral therapy,¹⁹ which may be influenced by the degree to which coordinated care is delivered.²⁰

Obstetric interventions. Compared with vaginal delivery, cesarean delivery reduces perinatal HIV transmission.^21,22 To be most effective, a cesarean section must be performed electively, before membranes rupture.¹² For most HIV-infected women, cesarean section is as safe as it is for HIV-negative women. For women with advanced disease or AIDS, cesarean section may carry a higher risk of maternal complications.²³

For women with unknown HIV RNA levels (viral load) or a viral load >1000 copies/mL near the time of delivery, US guidelines recommend that scheduled cesarean delivery be performed at 38 weeks’ gestation, whether or not they are receiving antepartum antiretroviral drugs.¹² For women taking antiretrovirals who have a viral load of <1000 copies/mL, guidelines advise that data are insufficient to evaluate the potential benefit of cesarean delivery in preventing perinatal transmission.¹² When viral load is <1000 copies/mL, administration of intravenous ZDV followed by vaginal delivery (as in PACTG 076–2 mg/kg intravenous load over 1 hour, then 1 mg/kg per hour until delivery) is an option, and is commonly used in the United States.^1,23

Antiretroviral administration to infants. All HIV-exposed newborns receive ZDV as a standard part of perinatal transmission prevention,¹ initiated as close to delivery as possible. Infants whose gestation was 35 weeks at birth receive an oral dose of 2 mg/kg (or 1.5 mg/kg intravenously if unable to take oral medications) within the first 6 to 12 hours after birth, then every 6 hours until 6 weeks of age. Infants less than 35 weeks’ gestation at birth receive 2 mg/kg orally every 12 hours (or 1.5 mg/kg intravenously), advancing to every 8 hours at 2 weeks of age if they were 30 weeks’ gestation at birth, or at 4 weeks of age if less than 30 weeks’ gestation at birth.

In unusual circumstances, such as when a mother is known to have a high viral load at delivery or an antiretroviral-resistant virus, other antiretroviral agents may be added to ZDV for infant prophylaxis.¹ The decision to use additional antiretrovirals necessitates consultation with a pediatric HIV specialist, preferably before delivery.

With the exception of efavirenz—thought to have potential teratogenicity when administered in the first trimester of pregnancy¹—antiretrovirals are generally considered safe in pregnancy and for newborns;⁷ rarely, significant organ system pathology due to mitochondrial toxicity has been observed in infants exposed to antiretrovirals.²⁴ Prophylactic ZDV use may be associated with anemia in infants, but this is generally mild and resolves by 12 weeks of age without treatment.²⁵ Follow-up of the data from PACTG 076 has shown no long-term adverse effects associated with ZDV.²⁶

TABLE 1
Repeated HIV screening is recommended for pregnant women in their third trimester who meet these criteria¹⁴

Providing care, Tx, support to mothers with HIV and their newborns
Prevention of perinatal HIV transmission does not end when an infant completes 6 weeks of ZDV therapy. The mother must have postpartum care and ongoing management of HIV infection; the infant must undergo assessment of HIV status and monitoring while receiving ZDV, and receive general infant care. The longitudinal, family-centered approach with family medicine offers an opportunity to optimize the overall wellness of a woman with HIV, including mental health, contraceptive counseling, cervical screening, and a decision on whether to continue antiretroviral therapy, based on clinical status (HIV disease stage) and immunologic (CD4) factors. ¹

In the United States and other developed countries where safe and feasible formula feeding is possible, breastfeeding is not recommended for HIV-infected mothers, due to the risk of virus transmission via breast milk.¹

Given that maternal antibodies to HIV cross the placenta and are detectable in HIV-exposed infants up to 18 months of age, antibody tests such as HIV ELISA and rapid HIV tests are not suitable for the diagnosis of HIV in infants.¹² Rather, a virologic polymerase chain reaction (PCR) test must be used.¹ While HIV DNA PCR is the gold standard for infant diagnosis, HIV RNA PCR is also sensitive and specific.¹ HIV-exposed infants should receive routine childhood immunizations according to the usual schedule.^1,27 HIV-infected infants should be referred to a pediatric HIV specialist.

Untreated HIV infection in infants may have a variable course, including rapid progression to AIDS and death.²⁸ Often the first manifestation of rapid progression is Pneumocystis jiroveci pneumonia (formerly Pneumocystis carinii pneumonia), which may be seen even before HIV diagnosis is realized in an infant who becomes HIV-infected despite prophylaxis.^1,29 Unless there is adequate proof to presumptively exclude HIV infection (negative results on 2 virologic tests conducted ≥2 weeks postpartum, 1 of which must be at least 4 weeks postpartum),^1,29 all HIV-exposed infants should be started at age 6 weeks (after completion of ZDV prophylaxis) on trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra) prophylaxis against Pneumocystis pneumonia. TMP-SMX prophylaxis should be continued until 2 virologic tests for HIV yield negative results.¹ If TMP-SMX toxicity develops, dapsone and atovaquone are alternatives.²⁹ TABLE 2 outlines the follow-up of HIV-exposed infants, including testing for HIV.

TABLE 2
Follow-up measures for infants exposed to maternal HIV^1,27

CORRESPONDENCE
Michael A. Tolle, MD, Baylor College of Medicine, 6701 Fannin Street, CC1210, Houston, TX 77030; [email protected]

Acknowledgements
The author thanks Heidi Schwarzwald, MD, Gordon Schutze, MD, and Mark Kline, MD, for their comments on this manuscript.

CASE 1 Brad S, a 39-year-old lawyer, is in your office for a follow-up visit. A month ago, you diagnosed him with generalized anxiety disorder and prescribed paroxetine. Brad reports that the medication worked “like a miracle,” rapidly resolving his constant worry and rumination. Unfortunately, though, he is experiencing a bothersome side effect—sexual dysfunction. He’s having difficulty achieving ejaculation during intercourse and wants to know if you can give him “something else that works just as well.” What would you recommend?

In any given year, about 6.8 million Americans—roughly 3.1% of people ages 18 and older—suffer from generalized anxiety disorder (GAD), according to the most recent national survey of psychiatric illness.^1,2 GAD is associated with overuse of medical services. In addition, patients with GAD frequently present with somatic illness, typically in primary care settings.^3-5 Women are twice as likely as men to be affected,⁶ and the onset of GAD more commonly occurs at or around midlife, rather than at earlier ages.⁴

Identifying and treating GAD promptly is a high priority, as it exacts a high burden of suffering. Physical and mental comorbidities are extremely common (TABLE). In fact, 66% of those with GAD have at least 1 additional psychiatric condition—most frequently, major depression.⁷

Further evidence of the toll GAD takes comes from the National Comorbidity Survey, a congressionally mandated study of more than 8000 US residents conducted in 1994. Among the respondents, 82% of those who had ever been diagnosed with GAD said they had sought professional help for the disorder, taken medication for it, or found that it interfered with their life or activities “a lot.” ⁷

Patients with GAD, like Brad, often start their search for help in primary care. And GAD can usually be treated successfully in such a setting.⁵ Thus, it is crucial for family physicians to not only be on the lookout for signs and symptoms of GAD (See “Is it GAD?”), but to familiarize themselves with the most effective pharmacological treatments.

While paroxetine, like other selective serotonin reuptake inhibitors (SSRIs), is well established as a safe and effective treatment for GAD,^8,9 1 or more of the most common side effects are often bothersome to patients. These include nausea, reported by 22% of patients; headache, reported by 12% of patients, and abnormal ejaculation/sexual dysfunction, reported by 11% of patients in a study of longterm use of paroxetine for GAD.¹⁰ This review describes the other options you may want to consider—and the ones you’ll want to avoid.

TABLE
GAD: Common comorbidities^7,44

Options are numerous, but which is best for your patient?

Many other drug classes and medications are used to treat GAD: tricyclic antidepressants, atypical antipsychotics, serotoninnorepinephrine reuptake inhibitors (SNRIs), anticonvulsants, benzodiazepines, and bupropion, among them. But a number of these options present problems of their own.

Tricyclics, for example, have demonstrated efficacy in treating GAD,¹¹ but are associated with sedation and anticholinergic side effects and are typically not as well tolerated as some other choices. Atypical antipsychotics also have troublesome side effects—primarily, somnolence and weight gain. In addition, atypical antipsychotics require monitoring for rare but life-threatening adverse reactions, such as agranulocytosis, which limits their practicality in a primary care setting.

Benzodiazepines, while rapidly alleviating feelings of anxiety, have significant withdrawal effects after long-term use. However, they are often used successfully as a short-term treatment for GAD. For that reason, we will include benzodiazepines—along with SNRIs, anticonvulsants, and bupropion—in our discussion of SSRI alternatives for GAD.

SNRIs have high efficacy
Of the 3 SNRIs on the market—desvenlafaxine, duloxetine, and venlafaxine—the latter 2 are approved for the treatment of GAD. Venlafaxine, in particular, has shown great efficacy as both a short- and long-term treatment.^12-14

A meta-analysis by Meoni et al demonstrated that venlafaxine ER (extended release) provided significantly higher response rates than placebo for the relief of both the psychological and somatic symptoms of GAD.¹³ By week 24 of treatment, the rates of improvement in the treatment group were 66% for psychological symptoms and 67% for somatic symptoms, vs 35% and 47%, respectively, for those in the placebo group. A randomized controlled trial (RCT) by Montgomery et al also found venlafaxine to be well tolerated, with no significant difference in rates of discontinuation due to adverse effects between the SNRI and placebo.¹² (In another study, duloxetine was found to be an effective treatment for GAD, but had a significantly higher dropout rate than placebo.¹⁵)

Venlafaxine has some of the same adverse effects as the SSRIs, however; commonly reported side effects include nausea, dizziness, and somnolence,^12,16 as well as a significant incidence of sexual side effects.^14,17 For this reason, venlafaxine would not be the best choice for Brad. It might, however, be an option for a patient who is bothered by sedation or weight gain caused by SSRIs.

Anticonvulsants: A newer option for anxiety
Anticonvulsants have been used only recently to treat anxiety disorders—an indication for which this class of drugs has not received approval. The mechanism of action appears to involve suppression of neuronally activated “fear circuits” in the amygdala and hippocampus. These circuits are part of the autonomic output that occurs when someone initially experiences fear, and when he or she reexperiences the fear in a nonthreatening setting. Periodic or chronic overactivation of these circuits may lead to panic attacks, GAD, and other anxiety disorders.¹⁸

Anticonvulsants suppress neuronal activation through a variety of mechanisms, including gamma-aminobutyric acid stimulation (valproate), sodium channel blockade (carbamazepine, phenytoin), and calcium channel blockade (pregabalin). Although a variety of anticonvulsants have been tested as a treatment for GAD, pregabalin is the only 1 that multiple RCTs have found to be effective.^19-22 In an RCT comparing pregabalin, lorazepam, and placebo, both pregabalin and lorazepam decreased anxiety scores significantly more than placebo. Pregabalin was better tolerated than lorazepam and had the added benefit of not being associated with withdrawal effects upon discontinuation of the drug. In addition, pregabalin showed efficacy compared with placebo in as little as 1 week.²²

In another RCT comparing pregabalin, venlafaxine, and placebo, Montgomery et al showed that both pregabalin and venlafaxine were superior to placebo.²³ Pregabalin had a faster onset of action than venlafaxine (1 vs 2 weeks) and was better tolerated.

Doses of pregabalin used in clinical trials ranged from 150 mg to 600 mg daily, given in divided doses.²⁴ In clinical practice, physicians are advised to start at the lower dose and titrate upward until either an effective dosage is reached or side effects become bothersome.

Common side effects of pregabalin include dizziness (8%-45%), somnolence (4%-28%), weight gain (up to 16%), and edema (up to 16%.) Thrombocytopenia occurs in 3% of patients; other blood dyscrasias are rare.²⁵ Laboratory monitoring is not routinely indicated, and neither sexual side effects nor gastrointestinal disturbances are commonly reported.²⁵

With evidence indicating that GAD is a chronic, recurrent disease,²⁶ long-term efficacy is important. One RCT found that longterm use of pregabalin (24 weeks) maintained remission of symptoms more effectively than placebo.²⁷

The combination of fast onset of action, high efficacy, and lack of sexual side effects makes pregabalin an attractive drug for the treatment of GAD, especially for patients who cannot tolerate SSRIs. However, cost may be a consideration. Unlike SSRIs, pregabalin is not available as a generic. At a discount retailer such as Costco, the per-pill cost of pregabalin 150 mg (typically taken twice a day) is $2.45; in contrast, paroxetine 20 mg (generally taken only once daily) is 40 cents per pill. In addition, pregabalin is a class V controlled substance, and little is known about its long-term effects.

CASE 1 Pregabalin makes sense for Brad. After discussing SSRI alternatives with Brad, he decides to switch to pregabalin, despite the higher cost. He makes an appointment for the following month. At that visit, you’re pleased to see that Brad is feeling better and happy with the treatment choice he has made. Your next GAD patient, however, is a more difficult case.

CASE 2 Janet W, a 60-year-old patient whom you “inherited” from a former partner, has been taking alprazolam 1 mg tid for many years for “excessive nervousness.” She frequently complains about lack of energy and weight gain, but resists any suggestion that she discontinue alprazolam. “I can’t function without something to calm my nerves,” Janet says.

Benzodiazepines as a “bridge”
Benzodiazepines have long been established as effective in treating anxiety symptoms. Because of their fast onset of action, drugs in this class are often used as a “bridging strategy,” to give rapid relief from symptoms while another medication, typically an SSRI, is started and titrated.

A 2005 meta-analysis comparing benzodiazepines with placebo for short-term treatment of GAD showed the drugs to be superior to placebo in reducing anxiety symptoms. Patient satisfaction with benzodiazepines was high, as evidenced by a significantly lower dropout rate among those in the benzodiazepine group (20.5%), compared with the placebo group (30.2%).²⁸ Typical side effects are somnolence and weight gain.

There is ample evidence that long-term benzodiazepine use produces tolerance and severe withdrawal effects. Discontinuing benzodiazepines after long-term use (>3 months) can be challenging, with patients reporting irritability, insomnia, and anxiety. Several strategies to ease the withdrawal process have been explored.

A 2000 RCT compared the overlapping use of imipramine or buspirone vs placebo when tapering patients off their long-term benzodiazepine regimen.²⁹ The study found that patients who took imipramine before and during their benzodiazepine taper were significantly more likely to discontinue their benzodiazepines compared with those using placebo. Successful discontinuation for those using buspirone—a 5-HT1A receptor agonist—approached statistical significance.²⁹ (Buspirone has also been studied as a primary treatment for GAD, and found to have a relatively small effect and a side effect profile that includes dizziness, nausea, and asthenia.³⁰ And there is preliminary evidence that bupropion XL may be as efficacious as escitalopram in treating GAD, with both drugs being well tolerated.³¹)

Another study focusing on the discontinuation of benzodiazepines found that adding cognitive behavioral therapy (CBT) to a gradual taper regimen significantly improved patients’ chances of complete cessation. Seventy-five percent of patients receiving CBT stopped taking benzodiazepines, compared with 37% of patients in the placebo-plus-taper group.³²

CASE 2 After educating Janet about the risks of continued long-term use of benzodiazepines, you propose a plan to enable her to decrease her dose of alprazolam over many weeks. It involves a referral to CBT to give Janet the opportunity to find nonpharmacologic ways of managing her anxiety, and a prescription for imipramine 75 mg daily, which she would take while she tapers her benzodiazepine use at a rate of 25% per week. Reluctantly, Janet agrees.

At her 1-month follow-up, Janet reports that she has followed the tapering schedule, but that she frequently feels nervous and is having trouble sleeping. She states that she does not want to be dependent on drugs, and asks if there is a natural treatment to calm her nerves.

What to tell patients about “natural” alternatives

Patients may express a preference for “natural” treatments for GAD, and ask about valerian, kava extract, or St. John’s wort (hypericum). All 3 are available in the United States and marketed for the treatment of anxiety and insomnia (valerian), depression (hypericum), and as a euphoric (kava).

Valerian. A Cochrane review found insufficient evidence to draw any conclusion about the efficacy of valerian for the treatment of GAD because of the paucity of RCTs available for review.³³ The single RCT found to be acceptable for review had a small sample size (N=36) and showed no significant difference in symptom reduction among the valerian, diazepam, and placebo groups.³⁴

Kava extract. Cochrane published a systematic review of kava extract in 2002, including a meta-analysis of 5 RCTs.³⁵ The meta-analysis showed a significant reduction in the Hamilton Anxiety Scale (HAMA) score for kava users vs placebo, although the effect size was small. The authors of this meta-analysis chose to exclude a 2002 RCT by Connor et al³⁶ because that study used a different kava preparation than the others. However, Connor found that kava extract was not superior to placebo in reducing anxiety symptoms as measured by the HAMA, and inclusion of this study would have reduced the meta-analysis conclusion to borderline significance.

In addition, there are serious concerns about the association of kava with hepatotoxicity, including liver failure.³⁷ According to the National Center for Complementary and Alternative Medicine (NCCAM), there is some evidence that kava may be beneficial in treating anxiety.³⁸ However, NCCAM-funded studies of kava were suspended after the US Food and Drug Administration issued a warning in 2002 about a link between kava supplements and the risk of severe liver damage.^38,39

St. John’s wort. There are case reports of the efficacy of St. John’s wort—commonly used as an alternative treatment for depression—in the treatment of GAD.^40,41 NCCAM is conducting studies of this supplement for a broader spectrum of mood disorders.⁴² Because of the lack of robust evidence of its effectiveness in treating GAD, however, the authors of a review article urged physicians not to recommend St. John’s wort as a treatment for anxiety.⁴³

CASE 2 You discuss “natural” alternatives with Janet, explaining that they are lacking in evidence of efficacy, and slow her tapering schedule, which minimizes her rebound symptoms. Eventually, Janet is able to reduce her benzodiazepine use to occasional prn dosing, and to discontinue her use of imipramine. At a follow-up visit 6 months later, she reports that she feels more energetic and mentally alert since she discontinued regular use of the benzodiazepine.

CASE 1 Brad stays on pregabalin with minimal sedation, no sexual dysfunction, and marked improvement in his GAD. “I hate the idea of taking medication every day, but this really works,” he says. At a follow-up visit about a year later, you ask Brad whether he would like to continue treatment. He reports that the drug is working well, and he is reluctant to stop taking it. “This has made a big improvement in my life,” Brad says.

CORRESPONDENCE
Kimberly Zoberi, MD, 2325 Dougherty Ferry Road, Suite 100, St. Louis, MO 63122; [email protected]

CASE 1 Brad S, a 39-year-old lawyer, is in your office for a follow-up visit. A month ago, you diagnosed him with generalized anxiety disorder and prescribed paroxetine. Brad reports that the medication worked “like a miracle,” rapidly resolving his constant worry and rumination. Unfortunately, though, he is experiencing a bothersome side effect—sexual dysfunction. He’s having difficulty achieving ejaculation during intercourse and wants to know if you can give him “something else that works just as well.” What would you recommend?

In any given year, about 6.8 million Americans—roughly 3.1% of people ages 18 and older—suffer from generalized anxiety disorder (GAD), according to the most recent national survey of psychiatric illness.^1,2 GAD is associated with overuse of medical services. In addition, patients with GAD frequently present with somatic illness, typically in primary care settings.^3-5 Women are twice as likely as men to be affected,⁶ and the onset of GAD more commonly occurs at or around midlife, rather than at earlier ages.⁴

Identifying and treating GAD promptly is a high priority, as it exacts a high burden of suffering. Physical and mental comorbidities are extremely common (TABLE). In fact, 66% of those with GAD have at least 1 additional psychiatric condition—most frequently, major depression.⁷

Further evidence of the toll GAD takes comes from the National Comorbidity Survey, a congressionally mandated study of more than 8000 US residents conducted in 1994. Among the respondents, 82% of those who had ever been diagnosed with GAD said they had sought professional help for the disorder, taken medication for it, or found that it interfered with their life or activities “a lot.” ⁷

Patients with GAD, like Brad, often start their search for help in primary care. And GAD can usually be treated successfully in such a setting.⁵ Thus, it is crucial for family physicians to not only be on the lookout for signs and symptoms of GAD (See “Is it GAD?”), but to familiarize themselves with the most effective pharmacological treatments.

While paroxetine, like other selective serotonin reuptake inhibitors (SSRIs), is well established as a safe and effective treatment for GAD,^8,9 1 or more of the most common side effects are often bothersome to patients. These include nausea, reported by 22% of patients; headache, reported by 12% of patients, and abnormal ejaculation/sexual dysfunction, reported by 11% of patients in a study of longterm use of paroxetine for GAD.¹⁰ This review describes the other options you may want to consider—and the ones you’ll want to avoid.

TABLE
GAD: Common comorbidities^7,44

Options are numerous, but which is best for your patient?

Many other drug classes and medications are used to treat GAD: tricyclic antidepressants, atypical antipsychotics, serotoninnorepinephrine reuptake inhibitors (SNRIs), anticonvulsants, benzodiazepines, and bupropion, among them. But a number of these options present problems of their own.

Tricyclics, for example, have demonstrated efficacy in treating GAD,¹¹ but are associated with sedation and anticholinergic side effects and are typically not as well tolerated as some other choices. Atypical antipsychotics also have troublesome side effects—primarily, somnolence and weight gain. In addition, atypical antipsychotics require monitoring for rare but life-threatening adverse reactions, such as agranulocytosis, which limits their practicality in a primary care setting.

Benzodiazepines, while rapidly alleviating feelings of anxiety, have significant withdrawal effects after long-term use. However, they are often used successfully as a short-term treatment for GAD. For that reason, we will include benzodiazepines—along with SNRIs, anticonvulsants, and bupropion—in our discussion of SSRI alternatives for GAD.

SNRIs have high efficacy
Of the 3 SNRIs on the market—desvenlafaxine, duloxetine, and venlafaxine—the latter 2 are approved for the treatment of GAD. Venlafaxine, in particular, has shown great efficacy as both a short- and long-term treatment.^12-14

A meta-analysis by Meoni et al demonstrated that venlafaxine ER (extended release) provided significantly higher response rates than placebo for the relief of both the psychological and somatic symptoms of GAD.¹³ By week 24 of treatment, the rates of improvement in the treatment group were 66% for psychological symptoms and 67% for somatic symptoms, vs 35% and 47%, respectively, for those in the placebo group. A randomized controlled trial (RCT) by Montgomery et al also found venlafaxine to be well tolerated, with no significant difference in rates of discontinuation due to adverse effects between the SNRI and placebo.¹² (In another study, duloxetine was found to be an effective treatment for GAD, but had a significantly higher dropout rate than placebo.¹⁵)

Venlafaxine has some of the same adverse effects as the SSRIs, however; commonly reported side effects include nausea, dizziness, and somnolence,^12,16 as well as a significant incidence of sexual side effects.^14,17 For this reason, venlafaxine would not be the best choice for Brad. It might, however, be an option for a patient who is bothered by sedation or weight gain caused by SSRIs.

Anticonvulsants: A newer option for anxiety
Anticonvulsants have been used only recently to treat anxiety disorders—an indication for which this class of drugs has not received approval. The mechanism of action appears to involve suppression of neuronally activated “fear circuits” in the amygdala and hippocampus. These circuits are part of the autonomic output that occurs when someone initially experiences fear, and when he or she reexperiences the fear in a nonthreatening setting. Periodic or chronic overactivation of these circuits may lead to panic attacks, GAD, and other anxiety disorders.¹⁸

Anticonvulsants suppress neuronal activation through a variety of mechanisms, including gamma-aminobutyric acid stimulation (valproate), sodium channel blockade (carbamazepine, phenytoin), and calcium channel blockade (pregabalin). Although a variety of anticonvulsants have been tested as a treatment for GAD, pregabalin is the only 1 that multiple RCTs have found to be effective.^19-22 In an RCT comparing pregabalin, lorazepam, and placebo, both pregabalin and lorazepam decreased anxiety scores significantly more than placebo. Pregabalin was better tolerated than lorazepam and had the added benefit of not being associated with withdrawal effects upon discontinuation of the drug. In addition, pregabalin showed efficacy compared with placebo in as little as 1 week.²²

In another RCT comparing pregabalin, venlafaxine, and placebo, Montgomery et al showed that both pregabalin and venlafaxine were superior to placebo.²³ Pregabalin had a faster onset of action than venlafaxine (1 vs 2 weeks) and was better tolerated.

Doses of pregabalin used in clinical trials ranged from 150 mg to 600 mg daily, given in divided doses.²⁴ In clinical practice, physicians are advised to start at the lower dose and titrate upward until either an effective dosage is reached or side effects become bothersome.

Common side effects of pregabalin include dizziness (8%-45%), somnolence (4%-28%), weight gain (up to 16%), and edema (up to 16%.) Thrombocytopenia occurs in 3% of patients; other blood dyscrasias are rare.²⁵ Laboratory monitoring is not routinely indicated, and neither sexual side effects nor gastrointestinal disturbances are commonly reported.²⁵

With evidence indicating that GAD is a chronic, recurrent disease,²⁶ long-term efficacy is important. One RCT found that longterm use of pregabalin (24 weeks) maintained remission of symptoms more effectively than placebo.²⁷

The combination of fast onset of action, high efficacy, and lack of sexual side effects makes pregabalin an attractive drug for the treatment of GAD, especially for patients who cannot tolerate SSRIs. However, cost may be a consideration. Unlike SSRIs, pregabalin is not available as a generic. At a discount retailer such as Costco, the per-pill cost of pregabalin 150 mg (typically taken twice a day) is $2.45; in contrast, paroxetine 20 mg (generally taken only once daily) is 40 cents per pill. In addition, pregabalin is a class V controlled substance, and little is known about its long-term effects.

CASE 1 Pregabalin makes sense for Brad. After discussing SSRI alternatives with Brad, he decides to switch to pregabalin, despite the higher cost. He makes an appointment for the following month. At that visit, you’re pleased to see that Brad is feeling better and happy with the treatment choice he has made. Your next GAD patient, however, is a more difficult case.

CASE 2 Janet W, a 60-year-old patient whom you “inherited” from a former partner, has been taking alprazolam 1 mg tid for many years for “excessive nervousness.” She frequently complains about lack of energy and weight gain, but resists any suggestion that she discontinue alprazolam. “I can’t function without something to calm my nerves,” Janet says.

Benzodiazepines as a “bridge”
Benzodiazepines have long been established as effective in treating anxiety symptoms. Because of their fast onset of action, drugs in this class are often used as a “bridging strategy,” to give rapid relief from symptoms while another medication, typically an SSRI, is started and titrated.

A 2005 meta-analysis comparing benzodiazepines with placebo for short-term treatment of GAD showed the drugs to be superior to placebo in reducing anxiety symptoms. Patient satisfaction with benzodiazepines was high, as evidenced by a significantly lower dropout rate among those in the benzodiazepine group (20.5%), compared with the placebo group (30.2%).²⁸ Typical side effects are somnolence and weight gain.

There is ample evidence that long-term benzodiazepine use produces tolerance and severe withdrawal effects. Discontinuing benzodiazepines after long-term use (>3 months) can be challenging, with patients reporting irritability, insomnia, and anxiety. Several strategies to ease the withdrawal process have been explored.

A 2000 RCT compared the overlapping use of imipramine or buspirone vs placebo when tapering patients off their long-term benzodiazepine regimen.²⁹ The study found that patients who took imipramine before and during their benzodiazepine taper were significantly more likely to discontinue their benzodiazepines compared with those using placebo. Successful discontinuation for those using buspirone—a 5-HT1A receptor agonist—approached statistical significance.²⁹ (Buspirone has also been studied as a primary treatment for GAD, and found to have a relatively small effect and a side effect profile that includes dizziness, nausea, and asthenia.³⁰ And there is preliminary evidence that bupropion XL may be as efficacious as escitalopram in treating GAD, with both drugs being well tolerated.³¹)

Another study focusing on the discontinuation of benzodiazepines found that adding cognitive behavioral therapy (CBT) to a gradual taper regimen significantly improved patients’ chances of complete cessation. Seventy-five percent of patients receiving CBT stopped taking benzodiazepines, compared with 37% of patients in the placebo-plus-taper group.³²

CASE 2 After educating Janet about the risks of continued long-term use of benzodiazepines, you propose a plan to enable her to decrease her dose of alprazolam over many weeks. It involves a referral to CBT to give Janet the opportunity to find nonpharmacologic ways of managing her anxiety, and a prescription for imipramine 75 mg daily, which she would take while she tapers her benzodiazepine use at a rate of 25% per week. Reluctantly, Janet agrees.

At her 1-month follow-up, Janet reports that she has followed the tapering schedule, but that she frequently feels nervous and is having trouble sleeping. She states that she does not want to be dependent on drugs, and asks if there is a natural treatment to calm her nerves.

What to tell patients about “natural” alternatives

Patients may express a preference for “natural” treatments for GAD, and ask about valerian, kava extract, or St. John’s wort (hypericum). All 3 are available in the United States and marketed for the treatment of anxiety and insomnia (valerian), depression (hypericum), and as a euphoric (kava).

Valerian. A Cochrane review found insufficient evidence to draw any conclusion about the efficacy of valerian for the treatment of GAD because of the paucity of RCTs available for review.³³ The single RCT found to be acceptable for review had a small sample size (N=36) and showed no significant difference in symptom reduction among the valerian, diazepam, and placebo groups.³⁴

Kava extract. Cochrane published a systematic review of kava extract in 2002, including a meta-analysis of 5 RCTs.³⁵ The meta-analysis showed a significant reduction in the Hamilton Anxiety Scale (HAMA) score for kava users vs placebo, although the effect size was small. The authors of this meta-analysis chose to exclude a 2002 RCT by Connor et al³⁶ because that study used a different kava preparation than the others. However, Connor found that kava extract was not superior to placebo in reducing anxiety symptoms as measured by the HAMA, and inclusion of this study would have reduced the meta-analysis conclusion to borderline significance.

In addition, there are serious concerns about the association of kava with hepatotoxicity, including liver failure.³⁷ According to the National Center for Complementary and Alternative Medicine (NCCAM), there is some evidence that kava may be beneficial in treating anxiety.³⁸ However, NCCAM-funded studies of kava were suspended after the US Food and Drug Administration issued a warning in 2002 about a link between kava supplements and the risk of severe liver damage.^38,39

St. John’s wort. There are case reports of the efficacy of St. John’s wort—commonly used as an alternative treatment for depression—in the treatment of GAD.^40,41 NCCAM is conducting studies of this supplement for a broader spectrum of mood disorders.⁴² Because of the lack of robust evidence of its effectiveness in treating GAD, however, the authors of a review article urged physicians not to recommend St. John’s wort as a treatment for anxiety.⁴³

CASE 2 You discuss “natural” alternatives with Janet, explaining that they are lacking in evidence of efficacy, and slow her tapering schedule, which minimizes her rebound symptoms. Eventually, Janet is able to reduce her benzodiazepine use to occasional prn dosing, and to discontinue her use of imipramine. At a follow-up visit 6 months later, she reports that she feels more energetic and mentally alert since she discontinued regular use of the benzodiazepine.

CASE 1 Brad stays on pregabalin with minimal sedation, no sexual dysfunction, and marked improvement in his GAD. “I hate the idea of taking medication every day, but this really works,” he says. At a follow-up visit about a year later, you ask Brad whether he would like to continue treatment. He reports that the drug is working well, and he is reluctant to stop taking it. “This has made a big improvement in my life,” Brad says.

CORRESPONDENCE
Kimberly Zoberi, MD, 2325 Dougherty Ferry Road, Suite 100, St. Louis, MO 63122; [email protected]

CASE 1 Brad S, a 39-year-old lawyer, is in your office for a follow-up visit. A month ago, you diagnosed him with generalized anxiety disorder and prescribed paroxetine. Brad reports that the medication worked “like a miracle,” rapidly resolving his constant worry and rumination. Unfortunately, though, he is experiencing a bothersome side effect—sexual dysfunction. He’s having difficulty achieving ejaculation during intercourse and wants to know if you can give him “something else that works just as well.” What would you recommend?

In any given year, about 6.8 million Americans—roughly 3.1% of people ages 18 and older—suffer from generalized anxiety disorder (GAD), according to the most recent national survey of psychiatric illness.^1,2 GAD is associated with overuse of medical services. In addition, patients with GAD frequently present with somatic illness, typically in primary care settings.^3-5 Women are twice as likely as men to be affected,⁶ and the onset of GAD more commonly occurs at or around midlife, rather than at earlier ages.⁴

Identifying and treating GAD promptly is a high priority, as it exacts a high burden of suffering. Physical and mental comorbidities are extremely common (TABLE). In fact, 66% of those with GAD have at least 1 additional psychiatric condition—most frequently, major depression.⁷

Further evidence of the toll GAD takes comes from the National Comorbidity Survey, a congressionally mandated study of more than 8000 US residents conducted in 1994. Among the respondents, 82% of those who had ever been diagnosed with GAD said they had sought professional help for the disorder, taken medication for it, or found that it interfered with their life or activities “a lot.” ⁷

Patients with GAD, like Brad, often start their search for help in primary care. And GAD can usually be treated successfully in such a setting.⁵ Thus, it is crucial for family physicians to not only be on the lookout for signs and symptoms of GAD (See “Is it GAD?”), but to familiarize themselves with the most effective pharmacological treatments.

While paroxetine, like other selective serotonin reuptake inhibitors (SSRIs), is well established as a safe and effective treatment for GAD,^8,9 1 or more of the most common side effects are often bothersome to patients. These include nausea, reported by 22% of patients; headache, reported by 12% of patients, and abnormal ejaculation/sexual dysfunction, reported by 11% of patients in a study of longterm use of paroxetine for GAD.¹⁰ This review describes the other options you may want to consider—and the ones you’ll want to avoid.

TABLE
GAD: Common comorbidities^7,44

Options are numerous, but which is best for your patient?

Many other drug classes and medications are used to treat GAD: tricyclic antidepressants, atypical antipsychotics, serotoninnorepinephrine reuptake inhibitors (SNRIs), anticonvulsants, benzodiazepines, and bupropion, among them. But a number of these options present problems of their own.

Tricyclics, for example, have demonstrated efficacy in treating GAD,¹¹ but are associated with sedation and anticholinergic side effects and are typically not as well tolerated as some other choices. Atypical antipsychotics also have troublesome side effects—primarily, somnolence and weight gain. In addition, atypical antipsychotics require monitoring for rare but life-threatening adverse reactions, such as agranulocytosis, which limits their practicality in a primary care setting.

Benzodiazepines, while rapidly alleviating feelings of anxiety, have significant withdrawal effects after long-term use. However, they are often used successfully as a short-term treatment for GAD. For that reason, we will include benzodiazepines—along with SNRIs, anticonvulsants, and bupropion—in our discussion of SSRI alternatives for GAD.

SNRIs have high efficacy
Of the 3 SNRIs on the market—desvenlafaxine, duloxetine, and venlafaxine—the latter 2 are approved for the treatment of GAD. Venlafaxine, in particular, has shown great efficacy as both a short- and long-term treatment.^12-14

A meta-analysis by Meoni et al demonstrated that venlafaxine ER (extended release) provided significantly higher response rates than placebo for the relief of both the psychological and somatic symptoms of GAD.¹³ By week 24 of treatment, the rates of improvement in the treatment group were 66% for psychological symptoms and 67% for somatic symptoms, vs 35% and 47%, respectively, for those in the placebo group. A randomized controlled trial (RCT) by Montgomery et al also found venlafaxine to be well tolerated, with no significant difference in rates of discontinuation due to adverse effects between the SNRI and placebo.¹² (In another study, duloxetine was found to be an effective treatment for GAD, but had a significantly higher dropout rate than placebo.¹⁵)

Venlafaxine has some of the same adverse effects as the SSRIs, however; commonly reported side effects include nausea, dizziness, and somnolence,^12,16 as well as a significant incidence of sexual side effects.^14,17 For this reason, venlafaxine would not be the best choice for Brad. It might, however, be an option for a patient who is bothered by sedation or weight gain caused by SSRIs.

Anticonvulsants: A newer option for anxiety
Anticonvulsants have been used only recently to treat anxiety disorders—an indication for which this class of drugs has not received approval. The mechanism of action appears to involve suppression of neuronally activated “fear circuits” in the amygdala and hippocampus. These circuits are part of the autonomic output that occurs when someone initially experiences fear, and when he or she reexperiences the fear in a nonthreatening setting. Periodic or chronic overactivation of these circuits may lead to panic attacks, GAD, and other anxiety disorders.¹⁸

Anticonvulsants suppress neuronal activation through a variety of mechanisms, including gamma-aminobutyric acid stimulation (valproate), sodium channel blockade (carbamazepine, phenytoin), and calcium channel blockade (pregabalin). Although a variety of anticonvulsants have been tested as a treatment for GAD, pregabalin is the only 1 that multiple RCTs have found to be effective.^19-22 In an RCT comparing pregabalin, lorazepam, and placebo, both pregabalin and lorazepam decreased anxiety scores significantly more than placebo. Pregabalin was better tolerated than lorazepam and had the added benefit of not being associated with withdrawal effects upon discontinuation of the drug. In addition, pregabalin showed efficacy compared with placebo in as little as 1 week.²²

In another RCT comparing pregabalin, venlafaxine, and placebo, Montgomery et al showed that both pregabalin and venlafaxine were superior to placebo.²³ Pregabalin had a faster onset of action than venlafaxine (1 vs 2 weeks) and was better tolerated.

Doses of pregabalin used in clinical trials ranged from 150 mg to 600 mg daily, given in divided doses.²⁴ In clinical practice, physicians are advised to start at the lower dose and titrate upward until either an effective dosage is reached or side effects become bothersome.

Common side effects of pregabalin include dizziness (8%-45%), somnolence (4%-28%), weight gain (up to 16%), and edema (up to 16%.) Thrombocytopenia occurs in 3% of patients; other blood dyscrasias are rare.²⁵ Laboratory monitoring is not routinely indicated, and neither sexual side effects nor gastrointestinal disturbances are commonly reported.²⁵

With evidence indicating that GAD is a chronic, recurrent disease,²⁶ long-term efficacy is important. One RCT found that longterm use of pregabalin (24 weeks) maintained remission of symptoms more effectively than placebo.²⁷

The combination of fast onset of action, high efficacy, and lack of sexual side effects makes pregabalin an attractive drug for the treatment of GAD, especially for patients who cannot tolerate SSRIs. However, cost may be a consideration. Unlike SSRIs, pregabalin is not available as a generic. At a discount retailer such as Costco, the per-pill cost of pregabalin 150 mg (typically taken twice a day) is $2.45; in contrast, paroxetine 20 mg (generally taken only once daily) is 40 cents per pill. In addition, pregabalin is a class V controlled substance, and little is known about its long-term effects.

CASE 1 Pregabalin makes sense for Brad. After discussing SSRI alternatives with Brad, he decides to switch to pregabalin, despite the higher cost. He makes an appointment for the following month. At that visit, you’re pleased to see that Brad is feeling better and happy with the treatment choice he has made. Your next GAD patient, however, is a more difficult case.

CASE 2 Janet W, a 60-year-old patient whom you “inherited” from a former partner, has been taking alprazolam 1 mg tid for many years for “excessive nervousness.” She frequently complains about lack of energy and weight gain, but resists any suggestion that she discontinue alprazolam. “I can’t function without something to calm my nerves,” Janet says.

Benzodiazepines as a “bridge”
Benzodiazepines have long been established as effective in treating anxiety symptoms. Because of their fast onset of action, drugs in this class are often used as a “bridging strategy,” to give rapid relief from symptoms while another medication, typically an SSRI, is started and titrated.

A 2005 meta-analysis comparing benzodiazepines with placebo for short-term treatment of GAD showed the drugs to be superior to placebo in reducing anxiety symptoms. Patient satisfaction with benzodiazepines was high, as evidenced by a significantly lower dropout rate among those in the benzodiazepine group (20.5%), compared with the placebo group (30.2%).²⁸ Typical side effects are somnolence and weight gain.

There is ample evidence that long-term benzodiazepine use produces tolerance and severe withdrawal effects. Discontinuing benzodiazepines after long-term use (>3 months) can be challenging, with patients reporting irritability, insomnia, and anxiety. Several strategies to ease the withdrawal process have been explored.

A 2000 RCT compared the overlapping use of imipramine or buspirone vs placebo when tapering patients off their long-term benzodiazepine regimen.²⁹ The study found that patients who took imipramine before and during their benzodiazepine taper were significantly more likely to discontinue their benzodiazepines compared with those using placebo. Successful discontinuation for those using buspirone—a 5-HT1A receptor agonist—approached statistical significance.²⁹ (Buspirone has also been studied as a primary treatment for GAD, and found to have a relatively small effect and a side effect profile that includes dizziness, nausea, and asthenia.³⁰ And there is preliminary evidence that bupropion XL may be as efficacious as escitalopram in treating GAD, with both drugs being well tolerated.³¹)

Another study focusing on the discontinuation of benzodiazepines found that adding cognitive behavioral therapy (CBT) to a gradual taper regimen significantly improved patients’ chances of complete cessation. Seventy-five percent of patients receiving CBT stopped taking benzodiazepines, compared with 37% of patients in the placebo-plus-taper group.³²

CASE 2 After educating Janet about the risks of continued long-term use of benzodiazepines, you propose a plan to enable her to decrease her dose of alprazolam over many weeks. It involves a referral to CBT to give Janet the opportunity to find nonpharmacologic ways of managing her anxiety, and a prescription for imipramine 75 mg daily, which she would take while she tapers her benzodiazepine use at a rate of 25% per week. Reluctantly, Janet agrees.

At her 1-month follow-up, Janet reports that she has followed the tapering schedule, but that she frequently feels nervous and is having trouble sleeping. She states that she does not want to be dependent on drugs, and asks if there is a natural treatment to calm her nerves.

What to tell patients about “natural” alternatives

Patients may express a preference for “natural” treatments for GAD, and ask about valerian, kava extract, or St. John’s wort (hypericum). All 3 are available in the United States and marketed for the treatment of anxiety and insomnia (valerian), depression (hypericum), and as a euphoric (kava).

Valerian. A Cochrane review found insufficient evidence to draw any conclusion about the efficacy of valerian for the treatment of GAD because of the paucity of RCTs available for review.³³ The single RCT found to be acceptable for review had a small sample size (N=36) and showed no significant difference in symptom reduction among the valerian, diazepam, and placebo groups.³⁴

Kava extract. Cochrane published a systematic review of kava extract in 2002, including a meta-analysis of 5 RCTs.³⁵ The meta-analysis showed a significant reduction in the Hamilton Anxiety Scale (HAMA) score for kava users vs placebo, although the effect size was small. The authors of this meta-analysis chose to exclude a 2002 RCT by Connor et al³⁶ because that study used a different kava preparation than the others. However, Connor found that kava extract was not superior to placebo in reducing anxiety symptoms as measured by the HAMA, and inclusion of this study would have reduced the meta-analysis conclusion to borderline significance.

In addition, there are serious concerns about the association of kava with hepatotoxicity, including liver failure.³⁷ According to the National Center for Complementary and Alternative Medicine (NCCAM), there is some evidence that kava may be beneficial in treating anxiety.³⁸ However, NCCAM-funded studies of kava were suspended after the US Food and Drug Administration issued a warning in 2002 about a link between kava supplements and the risk of severe liver damage.^38,39

St. John’s wort. There are case reports of the efficacy of St. John’s wort—commonly used as an alternative treatment for depression—in the treatment of GAD.^40,41 NCCAM is conducting studies of this supplement for a broader spectrum of mood disorders.⁴² Because of the lack of robust evidence of its effectiveness in treating GAD, however, the authors of a review article urged physicians not to recommend St. John’s wort as a treatment for anxiety.⁴³

CASE 2 You discuss “natural” alternatives with Janet, explaining that they are lacking in evidence of efficacy, and slow her tapering schedule, which minimizes her rebound symptoms. Eventually, Janet is able to reduce her benzodiazepine use to occasional prn dosing, and to discontinue her use of imipramine. At a follow-up visit 6 months later, she reports that she feels more energetic and mentally alert since she discontinued regular use of the benzodiazepine.

CASE 1 Brad stays on pregabalin with minimal sedation, no sexual dysfunction, and marked improvement in his GAD. “I hate the idea of taking medication every day, but this really works,” he says. At a follow-up visit about a year later, you ask Brad whether he would like to continue treatment. He reports that the drug is working well, and he is reluctant to stop taking it. “This has made a big improvement in my life,” Brad says.

CORRESPONDENCE
Kimberly Zoberi, MD, 2325 Dougherty Ferry Road, Suite 100, St. Louis, MO 63122; [email protected]

CASE Joe H is a 64-year-old African American man with a history of heart failure, hypertension, coronary artery disease (CAD), type 2 diabetes, chronic kidney disease, atrial fibrillation, and gout. His ejection fraction (EF), measured several years ago by echocardiography, was 20%, and he has New York Heart Association class II–III symptoms. Joe is taking an angiotensin-converting enzyme (ACE) inhibitor, a beta-blocker, an aldosterone antagonist, a loop diuretic, a nitrate, and digoxin, and he has an implantable cardioverter defibrillator (ICD). He recently spent 2 days in the hospital after being admitted for chest pain.

As an inpatient, Joe underwent stress echocardiography, which showed no inducible ischemia and an EF of 50%. Should the normalization of Joe’s EF prompt a change in his therapy?

Heart failure (HF), which affects an estimated 5 million Americans, is the leading cause of hospitalization in people older than 65 years.¹ The condition—characterized by signs and symptoms of congestion and objective evidence of structural or functional heart disease—has historically been divided into 2 categories: Patients with HF and a reduced ejection fraction (EF) were said to have systolic dysfunction, while the term “diastolic dysfunction” was applied to those with HF and a preserved EF.

The distinction between systolic and diastolic dysfunction is not so simple, though, and the definition of diastolic dysfunction, in particular, is not so clearcut.

Diastolic dysfunction is sometimes described on the basis of echocardiographic criteria, such as the ratio of early-to-late diastolic filling, short deceleration times, and isovolumic relaxation times.^2,3 But demographic and physiologic variables make interpretation of these parameters difficult, and the parameters themselves are not uniformly applied. What’s more, echocardiographic evidence of diastolic dysfunction is not specific to HF with a preserved EF.⁴ Some patients may be shown to have diastolic dysfunction and reduced EF.

As understanding of these variations grows, momentum about the need to change the clinical terminology has begun to develop. The suggested revision is simply to distinguish between HF with reduced EF and HF with preserved EF.⁵

To provide the best possible care for HF patients—including those who, like Joe, have gone from a reduced to a normal EF after receiving aggressive treatment—you need to be familiar with these changing parameters, recent research findings, and implications for treatment.

Managing both types of HF: What the evidence shows

Evidence-based management of HF with reduced EF is distinctly different from that of HF with preserved EF (TABLE).^6-8 In fact, the vast majority of the evidence involves patients with reduced EF, as most randomized clinical trials (RCTs)—and the only trials demonstrating a reduction in mortality—have excluded patients with preserved EF. Thus, in diagnosing and treating HF patients, it is crucial to assess for, and to distinguish between, the 2 EF states. Documentation of this assessment is a core quality measure for HF management, according to the Joint Commission.⁹

Treating HF with reduced EF. Barring any contraindications, ACE inhibitors and beta-blockers are core treatments for patients with reduced EF.⁸ Aldosterone antagonists are also indicated for patients with reduced EF who have, or recently had, rest dyspnea. They are also indicated for patients with reduced EF who are 3 to 14 days post-MI and have diabetes or symptomatic HF.⁸ Nitrates are indicated for African American patients who have persistent symptoms despite treatment with ACE inhibitors, beta-blockers, and diuretics, as needed.⁸ Consider an ICD as well, as these devices have been found to significantly reduce the risk of death for patients who have an EF <35% with either ischemic cardiomyopathy or symptomatic HF.

Treating HF with preserved EF. Because of the dearth of trials involving patients with HF and a preserved EF, there is limited evidence-based treatment. Nonetheless, it is reasonable to control signs and symptoms of congestion with diuretics.⁶ In addition, the CHARM-Preserved trial demonstrated the efficacy of candesartan—an angiotensin receptor blocker—in decreasing rates of hospital admissions among symptomatic patients with a preserved EF.¹⁰

TABLE
Heart failure: Ejection fraction status dictates treatment^6-8

How to treat the patient with normalized EF

These 2 options, however, do not clearly address the question of what to do with patients like Joe, whose case is described in our opener. Should patients whose EF has normalized after months, or years, of aggressive treatment remain on the medication regimen they followed when they had reduced EF? Should they be treated as HF patients with preserved EF? Is there another option? How often should patients who initially had a reduced EF be reassessed? To answer these questions, let’s take a closer look at the evidence.

Measurement of EF. No large clinical trials have investigated the impact of serial measurement of EF. Two small studies showed prognostic significance with serial measurements that demonstrated improvements in EF,^11,12 but their reproducibility and clinical significance are unclear. The American College of Cardiology/American Heart Association and the European Society of Cardiology recommend repeat measurement of EF only when it is clinically indicated.^6,13

Accuracy of the results. Echocardiogram is among the most widely used cardiac imaging modalities because it is fast, portable, and noninvasive. However, physiologic limitations and the challenges of calculating a 3-dimensional parameter with 2-dimensional images (FIGURE) limit the usefulness of echocardiography for the measurement of EF. Among other things, echocardiography lacks the ability to reliably identify small changes or improvements. Newer techniques—such as contrast or radionuclide ventriculography—have shown improved reliability in early studies.¹⁴ Compared with echocardiography, however, ventriculography is more costly and more invasive.

McGowan et al¹⁵ conducted a systematic review of studies comparing echocardiography with reference standards of contrast or radionuclide ventriculography. They concluded that no method in general use to calculate EF from echocardiographic images could provide a 95% confidence interval (CI) of <±10% in the measurement of EF. The American Society of Echocardiography has published standards to improve measurement technique and minimize variability in EF measurement.¹⁶

FIGURE
Echocardiographic evidence of heart failure? Systolic image tells the story

Normalization of EF is not a cure
In treating patients with HF, it is crucial to distinguish between what is reversible and what is not. Diuretics, oxygen, and other supportive therapy may reverse symptoms of congestion. Reversible causes of HF may include alcohol toxicity, thyroid disease, tachycardia, anemia, valvular heart disease, and CAD, among others. However, reversing the symptoms or the cause does not necessarily reverse HF itself. Further, normalization of EF does not necessarily imply that HF has been cured.

In a prospective study of 42 HF patients whose EF had normalized, the aggregate initial EF was 26%. It increased to ≥40%, with an absolute increase in EF ≥10%. During 41 months of follow-up, 19% of the patients had a recurrence of reduced EF. The likelihood of recurrence was greater among those who had discontinued their HF medications, the researchers found.¹⁷

In another prospective study, researchers followed 110 patients with reduced EF who were managed medically according to guideline-prescribed therapy.¹⁸ During a 17-month follow-up period, 18% had a normal EF at some point—but in more than half the cases (55%), the improvement was transient. Factors that were predictive of normalization included the presence of arterial hypertension (odds ratio [OR]=8.5; P=.01), nonischemic etiology (OR=4.9; P=.02), the absence of diabetes (OR=9.5; P=.01), beta-blocker therapy with carvedilol (OR=3.9, P=.02), and a higher beta-blocker dosage (OR=1.1; P=.04). Normalization occurred, on average, at 13 months (±6 months). The only difference between those who had a sustained improvement and those for whom the normalization was transient was the rate of chronic obstructive pulmonary disease (COPD). None of the patients who had a sustained improvement had COPD; 36% of those with transient improvement did (P=.04).

Finally, researchers used an Italian registry to follow prospectively 581 patients with dilated cardiomyopathy who were enrolled over a 25-year period.¹⁹ The team found that “healing” (reverse remodeling) occurred in 16% of the patients in response to treatment with ACE inhibitors and beta-blockers. Thus, in the vast majority of patients, the underlying disorder that caused the cardiomyopathy was maintained.

Keep patients on the same meds
There are no prospective RCTs investigating the continuation of ACE inhibitors, beta-blockers, or other therapy among HF patients whose EF normalized in response to treatment. Given the dramatic benefit of these medications for patients with a reduced EF, no such trial is likely to be performed. The trials noted above are instructive, however, and show that maintenance of HF medications¹⁷ (and the absence of COPD¹⁸) are predictors of sustained improvement.

Other factors to consider: Diastolic dysfunction is an ill-defined condition, and normalization of EF does not necessarily restore a patient to the same status as that of someone who never had a reduced EF. In addition, many patients with a reduced EF have concomitant CAD. In such cases, beta-blockers and ACE inhibitors are indicated as part of secondary prevention—another reason for continuation of the medication regimen, despite EF normalization.

CASE That was true for Joe, who suffered from a host of comorbidities, including CAD, as well as HF, and had been hospitalized for chest pain. His negative stress echocardiogram and improved EF suggested—although neither was definitive evidence—that his chest pain may have had a noncardiac cause. At his postdischarge follow-up visit, he was not experiencing any additional pain.

Despite Joe’s improved EF, however, his medical regimen remains unchanged. He comes in every 1 to 2 months for surveillance.

CORRESPONDENCE
William E. Chavey, MD, MS, University of Michigan, 1500 East Medical Center Drive, L2003 Women’s Hospital, Ann Arbor, Mich 48109-5239; [email protected]

CASE Joe H is a 64-year-old African American man with a history of heart failure, hypertension, coronary artery disease (CAD), type 2 diabetes, chronic kidney disease, atrial fibrillation, and gout. His ejection fraction (EF), measured several years ago by echocardiography, was 20%, and he has New York Heart Association class II–III symptoms. Joe is taking an angiotensin-converting enzyme (ACE) inhibitor, a beta-blocker, an aldosterone antagonist, a loop diuretic, a nitrate, and digoxin, and he has an implantable cardioverter defibrillator (ICD). He recently spent 2 days in the hospital after being admitted for chest pain.

As an inpatient, Joe underwent stress echocardiography, which showed no inducible ischemia and an EF of 50%. Should the normalization of Joe’s EF prompt a change in his therapy?

Heart failure (HF), which affects an estimated 5 million Americans, is the leading cause of hospitalization in people older than 65 years.¹ The condition—characterized by signs and symptoms of congestion and objective evidence of structural or functional heart disease—has historically been divided into 2 categories: Patients with HF and a reduced ejection fraction (EF) were said to have systolic dysfunction, while the term “diastolic dysfunction” was applied to those with HF and a preserved EF.

The distinction between systolic and diastolic dysfunction is not so simple, though, and the definition of diastolic dysfunction, in particular, is not so clearcut.

Diastolic dysfunction is sometimes described on the basis of echocardiographic criteria, such as the ratio of early-to-late diastolic filling, short deceleration times, and isovolumic relaxation times.^2,3 But demographic and physiologic variables make interpretation of these parameters difficult, and the parameters themselves are not uniformly applied. What’s more, echocardiographic evidence of diastolic dysfunction is not specific to HF with a preserved EF.⁴ Some patients may be shown to have diastolic dysfunction and reduced EF.

As understanding of these variations grows, momentum about the need to change the clinical terminology has begun to develop. The suggested revision is simply to distinguish between HF with reduced EF and HF with preserved EF.⁵

To provide the best possible care for HF patients—including those who, like Joe, have gone from a reduced to a normal EF after receiving aggressive treatment—you need to be familiar with these changing parameters, recent research findings, and implications for treatment.

Managing both types of HF: What the evidence shows

Evidence-based management of HF with reduced EF is distinctly different from that of HF with preserved EF (TABLE).^6-8 In fact, the vast majority of the evidence involves patients with reduced EF, as most randomized clinical trials (RCTs)—and the only trials demonstrating a reduction in mortality—have excluded patients with preserved EF. Thus, in diagnosing and treating HF patients, it is crucial to assess for, and to distinguish between, the 2 EF states. Documentation of this assessment is a core quality measure for HF management, according to the Joint Commission.⁹

Treating HF with reduced EF. Barring any contraindications, ACE inhibitors and beta-blockers are core treatments for patients with reduced EF.⁸ Aldosterone antagonists are also indicated for patients with reduced EF who have, or recently had, rest dyspnea. They are also indicated for patients with reduced EF who are 3 to 14 days post-MI and have diabetes or symptomatic HF.⁸ Nitrates are indicated for African American patients who have persistent symptoms despite treatment with ACE inhibitors, beta-blockers, and diuretics, as needed.⁸ Consider an ICD as well, as these devices have been found to significantly reduce the risk of death for patients who have an EF <35% with either ischemic cardiomyopathy or symptomatic HF.

Treating HF with preserved EF. Because of the dearth of trials involving patients with HF and a preserved EF, there is limited evidence-based treatment. Nonetheless, it is reasonable to control signs and symptoms of congestion with diuretics.⁶ In addition, the CHARM-Preserved trial demonstrated the efficacy of candesartan—an angiotensin receptor blocker—in decreasing rates of hospital admissions among symptomatic patients with a preserved EF.¹⁰

TABLE
Heart failure: Ejection fraction status dictates treatment^6-8

How to treat the patient with normalized EF

These 2 options, however, do not clearly address the question of what to do with patients like Joe, whose case is described in our opener. Should patients whose EF has normalized after months, or years, of aggressive treatment remain on the medication regimen they followed when they had reduced EF? Should they be treated as HF patients with preserved EF? Is there another option? How often should patients who initially had a reduced EF be reassessed? To answer these questions, let’s take a closer look at the evidence.

Measurement of EF. No large clinical trials have investigated the impact of serial measurement of EF. Two small studies showed prognostic significance with serial measurements that demonstrated improvements in EF,^11,12 but their reproducibility and clinical significance are unclear. The American College of Cardiology/American Heart Association and the European Society of Cardiology recommend repeat measurement of EF only when it is clinically indicated.^6,13

Accuracy of the results. Echocardiogram is among the most widely used cardiac imaging modalities because it is fast, portable, and noninvasive. However, physiologic limitations and the challenges of calculating a 3-dimensional parameter with 2-dimensional images (FIGURE) limit the usefulness of echocardiography for the measurement of EF. Among other things, echocardiography lacks the ability to reliably identify small changes or improvements. Newer techniques—such as contrast or radionuclide ventriculography—have shown improved reliability in early studies.¹⁴ Compared with echocardiography, however, ventriculography is more costly and more invasive.

McGowan et al¹⁵ conducted a systematic review of studies comparing echocardiography with reference standards of contrast or radionuclide ventriculography. They concluded that no method in general use to calculate EF from echocardiographic images could provide a 95% confidence interval (CI) of <±10% in the measurement of EF. The American Society of Echocardiography has published standards to improve measurement technique and minimize variability in EF measurement.¹⁶

FIGURE
Echocardiographic evidence of heart failure? Systolic image tells the story

Normalization of EF is not a cure
In treating patients with HF, it is crucial to distinguish between what is reversible and what is not. Diuretics, oxygen, and other supportive therapy may reverse symptoms of congestion. Reversible causes of HF may include alcohol toxicity, thyroid disease, tachycardia, anemia, valvular heart disease, and CAD, among others. However, reversing the symptoms or the cause does not necessarily reverse HF itself. Further, normalization of EF does not necessarily imply that HF has been cured.

In a prospective study of 42 HF patients whose EF had normalized, the aggregate initial EF was 26%. It increased to ≥40%, with an absolute increase in EF ≥10%. During 41 months of follow-up, 19% of the patients had a recurrence of reduced EF. The likelihood of recurrence was greater among those who had discontinued their HF medications, the researchers found.¹⁷

In another prospective study, researchers followed 110 patients with reduced EF who were managed medically according to guideline-prescribed therapy.¹⁸ During a 17-month follow-up period, 18% had a normal EF at some point—but in more than half the cases (55%), the improvement was transient. Factors that were predictive of normalization included the presence of arterial hypertension (odds ratio [OR]=8.5; P=.01), nonischemic etiology (OR=4.9; P=.02), the absence of diabetes (OR=9.5; P=.01), beta-blocker therapy with carvedilol (OR=3.9, P=.02), and a higher beta-blocker dosage (OR=1.1; P=.04). Normalization occurred, on average, at 13 months (±6 months). The only difference between those who had a sustained improvement and those for whom the normalization was transient was the rate of chronic obstructive pulmonary disease (COPD). None of the patients who had a sustained improvement had COPD; 36% of those with transient improvement did (P=.04).

Finally, researchers used an Italian registry to follow prospectively 581 patients with dilated cardiomyopathy who were enrolled over a 25-year period.¹⁹ The team found that “healing” (reverse remodeling) occurred in 16% of the patients in response to treatment with ACE inhibitors and beta-blockers. Thus, in the vast majority of patients, the underlying disorder that caused the cardiomyopathy was maintained.

Keep patients on the same meds
There are no prospective RCTs investigating the continuation of ACE inhibitors, beta-blockers, or other therapy among HF patients whose EF normalized in response to treatment. Given the dramatic benefit of these medications for patients with a reduced EF, no such trial is likely to be performed. The trials noted above are instructive, however, and show that maintenance of HF medications¹⁷ (and the absence of COPD¹⁸) are predictors of sustained improvement.

Other factors to consider: Diastolic dysfunction is an ill-defined condition, and normalization of EF does not necessarily restore a patient to the same status as that of someone who never had a reduced EF. In addition, many patients with a reduced EF have concomitant CAD. In such cases, beta-blockers and ACE inhibitors are indicated as part of secondary prevention—another reason for continuation of the medication regimen, despite EF normalization.

CASE That was true for Joe, who suffered from a host of comorbidities, including CAD, as well as HF, and had been hospitalized for chest pain. His negative stress echocardiogram and improved EF suggested—although neither was definitive evidence—that his chest pain may have had a noncardiac cause. At his postdischarge follow-up visit, he was not experiencing any additional pain.

Despite Joe’s improved EF, however, his medical regimen remains unchanged. He comes in every 1 to 2 months for surveillance.

CORRESPONDENCE
William E. Chavey, MD, MS, University of Michigan, 1500 East Medical Center Drive, L2003 Women’s Hospital, Ann Arbor, Mich 48109-5239; [email protected]

CASE Joe H is a 64-year-old African American man with a history of heart failure, hypertension, coronary artery disease (CAD), type 2 diabetes, chronic kidney disease, atrial fibrillation, and gout. His ejection fraction (EF), measured several years ago by echocardiography, was 20%, and he has New York Heart Association class II–III symptoms. Joe is taking an angiotensin-converting enzyme (ACE) inhibitor, a beta-blocker, an aldosterone antagonist, a loop diuretic, a nitrate, and digoxin, and he has an implantable cardioverter defibrillator (ICD). He recently spent 2 days in the hospital after being admitted for chest pain.

As an inpatient, Joe underwent stress echocardiography, which showed no inducible ischemia and an EF of 50%. Should the normalization of Joe’s EF prompt a change in his therapy?

Heart failure (HF), which affects an estimated 5 million Americans, is the leading cause of hospitalization in people older than 65 years.¹ The condition—characterized by signs and symptoms of congestion and objective evidence of structural or functional heart disease—has historically been divided into 2 categories: Patients with HF and a reduced ejection fraction (EF) were said to have systolic dysfunction, while the term “diastolic dysfunction” was applied to those with HF and a preserved EF.

The distinction between systolic and diastolic dysfunction is not so simple, though, and the definition of diastolic dysfunction, in particular, is not so clearcut.

Diastolic dysfunction is sometimes described on the basis of echocardiographic criteria, such as the ratio of early-to-late diastolic filling, short deceleration times, and isovolumic relaxation times.^2,3 But demographic and physiologic variables make interpretation of these parameters difficult, and the parameters themselves are not uniformly applied. What’s more, echocardiographic evidence of diastolic dysfunction is not specific to HF with a preserved EF.⁴ Some patients may be shown to have diastolic dysfunction and reduced EF.

As understanding of these variations grows, momentum about the need to change the clinical terminology has begun to develop. The suggested revision is simply to distinguish between HF with reduced EF and HF with preserved EF.⁵

To provide the best possible care for HF patients—including those who, like Joe, have gone from a reduced to a normal EF after receiving aggressive treatment—you need to be familiar with these changing parameters, recent research findings, and implications for treatment.

Managing both types of HF: What the evidence shows

Evidence-based management of HF with reduced EF is distinctly different from that of HF with preserved EF (TABLE).^6-8 In fact, the vast majority of the evidence involves patients with reduced EF, as most randomized clinical trials (RCTs)—and the only trials demonstrating a reduction in mortality—have excluded patients with preserved EF. Thus, in diagnosing and treating HF patients, it is crucial to assess for, and to distinguish between, the 2 EF states. Documentation of this assessment is a core quality measure for HF management, according to the Joint Commission.⁹

Treating HF with reduced EF. Barring any contraindications, ACE inhibitors and beta-blockers are core treatments for patients with reduced EF.⁸ Aldosterone antagonists are also indicated for patients with reduced EF who have, or recently had, rest dyspnea. They are also indicated for patients with reduced EF who are 3 to 14 days post-MI and have diabetes or symptomatic HF.⁸ Nitrates are indicated for African American patients who have persistent symptoms despite treatment with ACE inhibitors, beta-blockers, and diuretics, as needed.⁸ Consider an ICD as well, as these devices have been found to significantly reduce the risk of death for patients who have an EF <35% with either ischemic cardiomyopathy or symptomatic HF.

Treating HF with preserved EF. Because of the dearth of trials involving patients with HF and a preserved EF, there is limited evidence-based treatment. Nonetheless, it is reasonable to control signs and symptoms of congestion with diuretics.⁶ In addition, the CHARM-Preserved trial demonstrated the efficacy of candesartan—an angiotensin receptor blocker—in decreasing rates of hospital admissions among symptomatic patients with a preserved EF.¹⁰

TABLE
Heart failure: Ejection fraction status dictates treatment^6-8

How to treat the patient with normalized EF

These 2 options, however, do not clearly address the question of what to do with patients like Joe, whose case is described in our opener. Should patients whose EF has normalized after months, or years, of aggressive treatment remain on the medication regimen they followed when they had reduced EF? Should they be treated as HF patients with preserved EF? Is there another option? How often should patients who initially had a reduced EF be reassessed? To answer these questions, let’s take a closer look at the evidence.

Measurement of EF. No large clinical trials have investigated the impact of serial measurement of EF. Two small studies showed prognostic significance with serial measurements that demonstrated improvements in EF,^11,12 but their reproducibility and clinical significance are unclear. The American College of Cardiology/American Heart Association and the European Society of Cardiology recommend repeat measurement of EF only when it is clinically indicated.^6,13

Accuracy of the results. Echocardiogram is among the most widely used cardiac imaging modalities because it is fast, portable, and noninvasive. However, physiologic limitations and the challenges of calculating a 3-dimensional parameter with 2-dimensional images (FIGURE) limit the usefulness of echocardiography for the measurement of EF. Among other things, echocardiography lacks the ability to reliably identify small changes or improvements. Newer techniques—such as contrast or radionuclide ventriculography—have shown improved reliability in early studies.¹⁴ Compared with echocardiography, however, ventriculography is more costly and more invasive.

McGowan et al¹⁵ conducted a systematic review of studies comparing echocardiography with reference standards of contrast or radionuclide ventriculography. They concluded that no method in general use to calculate EF from echocardiographic images could provide a 95% confidence interval (CI) of <±10% in the measurement of EF. The American Society of Echocardiography has published standards to improve measurement technique and minimize variability in EF measurement.¹⁶

FIGURE
Echocardiographic evidence of heart failure? Systolic image tells the story

Normalization of EF is not a cure
In treating patients with HF, it is crucial to distinguish between what is reversible and what is not. Diuretics, oxygen, and other supportive therapy may reverse symptoms of congestion. Reversible causes of HF may include alcohol toxicity, thyroid disease, tachycardia, anemia, valvular heart disease, and CAD, among others. However, reversing the symptoms or the cause does not necessarily reverse HF itself. Further, normalization of EF does not necessarily imply that HF has been cured.

In a prospective study of 42 HF patients whose EF had normalized, the aggregate initial EF was 26%. It increased to ≥40%, with an absolute increase in EF ≥10%. During 41 months of follow-up, 19% of the patients had a recurrence of reduced EF. The likelihood of recurrence was greater among those who had discontinued their HF medications, the researchers found.¹⁷

In another prospective study, researchers followed 110 patients with reduced EF who were managed medically according to guideline-prescribed therapy.¹⁸ During a 17-month follow-up period, 18% had a normal EF at some point—but in more than half the cases (55%), the improvement was transient. Factors that were predictive of normalization included the presence of arterial hypertension (odds ratio [OR]=8.5; P=.01), nonischemic etiology (OR=4.9; P=.02), the absence of diabetes (OR=9.5; P=.01), beta-blocker therapy with carvedilol (OR=3.9, P=.02), and a higher beta-blocker dosage (OR=1.1; P=.04). Normalization occurred, on average, at 13 months (±6 months). The only difference between those who had a sustained improvement and those for whom the normalization was transient was the rate of chronic obstructive pulmonary disease (COPD). None of the patients who had a sustained improvement had COPD; 36% of those with transient improvement did (P=.04).

Finally, researchers used an Italian registry to follow prospectively 581 patients with dilated cardiomyopathy who were enrolled over a 25-year period.¹⁹ The team found that “healing” (reverse remodeling) occurred in 16% of the patients in response to treatment with ACE inhibitors and beta-blockers. Thus, in the vast majority of patients, the underlying disorder that caused the cardiomyopathy was maintained.

Keep patients on the same meds
There are no prospective RCTs investigating the continuation of ACE inhibitors, beta-blockers, or other therapy among HF patients whose EF normalized in response to treatment. Given the dramatic benefit of these medications for patients with a reduced EF, no such trial is likely to be performed. The trials noted above are instructive, however, and show that maintenance of HF medications¹⁷ (and the absence of COPD¹⁸) are predictors of sustained improvement.

Other factors to consider: Diastolic dysfunction is an ill-defined condition, and normalization of EF does not necessarily restore a patient to the same status as that of someone who never had a reduced EF. In addition, many patients with a reduced EF have concomitant CAD. In such cases, beta-blockers and ACE inhibitors are indicated as part of secondary prevention—another reason for continuation of the medication regimen, despite EF normalization.

CASE That was true for Joe, who suffered from a host of comorbidities, including CAD, as well as HF, and had been hospitalized for chest pain. His negative stress echocardiogram and improved EF suggested—although neither was definitive evidence—that his chest pain may have had a noncardiac cause. At his postdischarge follow-up visit, he was not experiencing any additional pain.

Despite Joe’s improved EF, however, his medical regimen remains unchanged. He comes in every 1 to 2 months for surveillance.

CORRESPONDENCE
William E. Chavey, MD, MS, University of Michigan, 1500 East Medical Center Drive, L2003 Women’s Hospital, Ann Arbor, Mich 48109-5239; [email protected]

Detection of Chlamydia trachomatis infection—the most commonly reported bacterial infection in the United States—falls primarily to patients’ personal physicians, not to sexually transmitted disease (STD) clinics or local health departments, as we’ll describe in a bit. And yet, fewer than half of personal physicians routinely screen for it.¹

Left untreated or allowed to recur, chlamydial infections are significant causes of pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and infertility. Chlamydia cases reported to the Centers for Disease Control and Prevention (CDC) exceeded 1 million for the first time in 2006, and the CDC estimates that more than 2 million Americans between the ages of 14 and 39 years are infected.² Most, if not all, of this increase is likely due to increased test sensitivity, expanded screening services and opportunities, and improved reporting, as well as the continuing high disease burden. Recent work suggests there may also be an increase in prevalence in the Pacific Northwest.³

The CDC established screening guidelines for chlamydial infection more than 10 years ago. However, despite long-standing and widely published screening guidelines, most young women who should receive this service do not. This fact has led the US Preventive Services Task Force (USPSTF) to identify chlamydia screening as one of the most important underused clinical preventive services.^4,5

USPSTF screening guidelines for chlamydia infection⁶

• Screen for chlamydial infection in all sexually active nonpregnant women ages 24 and younger, and in older nonpregnant women who are at increased risk. (Grade A recommendation)
• Screen for chlamydial infection in all pregnant women ages 24 and younger, and in older pregnant women who are at increased risk. (Grade B recommendation)
• Routinely screening for chlamydial infection in women ages 25 and older is not recommended, whether or not they are pregnant, if they are not at increased risk. (Grade C recommendation)
• Current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydial infection in men. (Grade I statement)

Most patients are screened by their personal physicians
To help improve screening rates, we must understand the status of screening site availability as well as usage patterns. Using state case and Infertility Prevention Program data, we examined screening sites in Illinois counties (defined as urban or rural) for women who tested positive for chlamydia in the period 2002 through 2006. For both urban and rural counties, more cases were identified by personal physicians than any other site or provider type (39% of all urban cases; 58% of all rural cases). Personal physicians and hospitals, combined, accounted for more than 53% of reported cases in each group. This is important because most chlamydia cases were identified at health care sites other than those that usually receive federal and state funding for chlamydia screening—local health departments and STD clinics. Reliance on these institutions to significantly reduce the chlamydia epidemic is unrealistic.

To address the issue of screening by personal physicians, the CDC’s Division of STD Prevention collaborated with the National Committee for Quality Assurance to develop the “Chlamydia Screening in Women” measure for the Health Care Effectiveness Data and Information Set (HEDIS). Chlamydia screening is now a covered benefit in many managed care plans, but actual screening rates in physician offices are still only approximately 37%.¹ What are the barriers that contribute to such a low rate?

Barriers to chlamydia screening

There are many reasons for inconsistent screening, including flaws in training and practice at the individual level and flaws in regional and national health system design and implementation. Following are several barriers that we must overcome to optimize screening:

1. Lack of awareness by physicians. The extent of chlamydial infections, locally and nationally, may not be sufficiently understood. Likewise, physicians may lack awareness of screening guidelines and not appreciate their role in detecting infection. Every medical school and training program (even postgraduate) should use the guidelines to reinforce the critical role personal physicians have in addressing this national epidemic. Without consistent and widespread compliance with screening guidelines by physicians, reductions in chlamydia rates are unlikely.
2. Uneasy patient-physician relationships. Many patients and their physicians lack relationships that foster open discussions of sexual issues. Adolescents and young adults are notoriously reticent about discussing sexual behavior, and approximately 70% of chlamydial infections in females are asymptomatic.⁷ Therefore, physicians cannot rely solely on suggestive health histories and clinical presentations to prompt a discussion of chlamydia.
3. Wide prevalence of chlamydial infection. While there are significant correlations between minority and socioeconomic status and infection rates, chlamydial infection is too widespread to base screening decisions on these criteria alone. A particularly important factor contributing to the chain of infection is local social-sexual networks. Perpetuation of these networks contributes to sustaining endemic disease levels through infection and reinfection. Interrupting these networks can directly affect the health of a wide circle of individuals.
4. Insufficient time and reimbursement. Primary care physicians report significant dissatisfaction with the short time allocated for individual visits and a relative decline in reimbursement. Such time pressure often leads to a focus on chief complaints; health maintenance and screening discussions are often omitted. Future payment mechanisms for care coordination and performance may remedy this problem.
5. Inadequate health information technology. The promises of health information technology are often unfulfilled, and office-based electronic health records (EHRs) frequently do not provide point-of-service information that would improve screening compliance. Lack of efficient interfaces for electronic records and databases makes regional health information exchange difficult. Improving electronic communication among health care professionals will likely improve primary and secondary prevention measures.
6. Generally poor integration of public health and medicine. The United States spends a smaller portion of its health care budget on public health than most other industrialized nations. Academically, a vast divide exists between most institutions of public health and medicine. And at the community level, there is a lack of integration of public health services and physician practices. The example of chlamydia screening underscores the need for reform of the US health care system to include greater emphasis on, and integration with, public health, preventive medicine, and primary care.
7. Deficient access to health care. One-sixth of the US population is without health insurance,⁸ and many who have insurance lack benefits that fully cover preventive medicine and screening. Reform of the US health care system to provide easy access to care is more likely to improve a broad range of health outcomes than the development of smaller, fragmented programs focused on specific conditions. This, again, has direct implications for chlamydia control and spread via social-sexual networks.

Our recommendations

1. Reacquaint yourself with the USPSTF screening guidelines and commit to following them rigorously in practice. This will necessitate examining your relationship with eligible patients, developing mechanisms to regularly discuss sexual health and STD issues, and consistently providing screening.
2. Make screening a routine part of care at recommended opportunities. If you use an EHR, consider working with the vendor to construct appropriate automatic prompts. Those with traditional systems may want to include a systematic chart addition and audit.
3. Consider becoming a policy advocate. There are serious health system flaws that hinder efforts to stem the chlamydia epidemic. Many of these system flaws are best addressed by state or national policy change and through new incentives for financial rewards for physicians.
4. Actively partner with local public health departments to expand screening services to those at risk. A study by Ward demonstrated that increasing screening in communities with endemic disease might have the greatest effect on the local population and its sexual networks.⁹

CORRESPONDENCE
Wiley D. Jenkins, Department of Family and Community Medicine, Southern Illinois University School of Medicine, 913 N. Rutledge Street, P.O. Box 19671, Springfield, IL 62794-9671; [email protected]

Detection of Chlamydia trachomatis infection—the most commonly reported bacterial infection in the United States—falls primarily to patients’ personal physicians, not to sexually transmitted disease (STD) clinics or local health departments, as we’ll describe in a bit. And yet, fewer than half of personal physicians routinely screen for it.¹

Left untreated or allowed to recur, chlamydial infections are significant causes of pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and infertility. Chlamydia cases reported to the Centers for Disease Control and Prevention (CDC) exceeded 1 million for the first time in 2006, and the CDC estimates that more than 2 million Americans between the ages of 14 and 39 years are infected.² Most, if not all, of this increase is likely due to increased test sensitivity, expanded screening services and opportunities, and improved reporting, as well as the continuing high disease burden. Recent work suggests there may also be an increase in prevalence in the Pacific Northwest.³

The CDC established screening guidelines for chlamydial infection more than 10 years ago. However, despite long-standing and widely published screening guidelines, most young women who should receive this service do not. This fact has led the US Preventive Services Task Force (USPSTF) to identify chlamydia screening as one of the most important underused clinical preventive services.^4,5

USPSTF screening guidelines for chlamydia infection⁶

• Screen for chlamydial infection in all sexually active nonpregnant women ages 24 and younger, and in older nonpregnant women who are at increased risk. (Grade A recommendation)
• Screen for chlamydial infection in all pregnant women ages 24 and younger, and in older pregnant women who are at increased risk. (Grade B recommendation)
• Routinely screening for chlamydial infection in women ages 25 and older is not recommended, whether or not they are pregnant, if they are not at increased risk. (Grade C recommendation)
• Current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydial infection in men. (Grade I statement)

Most patients are screened by their personal physicians
To help improve screening rates, we must understand the status of screening site availability as well as usage patterns. Using state case and Infertility Prevention Program data, we examined screening sites in Illinois counties (defined as urban or rural) for women who tested positive for chlamydia in the period 2002 through 2006. For both urban and rural counties, more cases were identified by personal physicians than any other site or provider type (39% of all urban cases; 58% of all rural cases). Personal physicians and hospitals, combined, accounted for more than 53% of reported cases in each group. This is important because most chlamydia cases were identified at health care sites other than those that usually receive federal and state funding for chlamydia screening—local health departments and STD clinics. Reliance on these institutions to significantly reduce the chlamydia epidemic is unrealistic.

To address the issue of screening by personal physicians, the CDC’s Division of STD Prevention collaborated with the National Committee for Quality Assurance to develop the “Chlamydia Screening in Women” measure for the Health Care Effectiveness Data and Information Set (HEDIS). Chlamydia screening is now a covered benefit in many managed care plans, but actual screening rates in physician offices are still only approximately 37%.¹ What are the barriers that contribute to such a low rate?

Barriers to chlamydia screening

There are many reasons for inconsistent screening, including flaws in training and practice at the individual level and flaws in regional and national health system design and implementation. Following are several barriers that we must overcome to optimize screening:

1. Lack of awareness by physicians. The extent of chlamydial infections, locally and nationally, may not be sufficiently understood. Likewise, physicians may lack awareness of screening guidelines and not appreciate their role in detecting infection. Every medical school and training program (even postgraduate) should use the guidelines to reinforce the critical role personal physicians have in addressing this national epidemic. Without consistent and widespread compliance with screening guidelines by physicians, reductions in chlamydia rates are unlikely.
2. Uneasy patient-physician relationships. Many patients and their physicians lack relationships that foster open discussions of sexual issues. Adolescents and young adults are notoriously reticent about discussing sexual behavior, and approximately 70% of chlamydial infections in females are asymptomatic.⁷ Therefore, physicians cannot rely solely on suggestive health histories and clinical presentations to prompt a discussion of chlamydia.
3. Wide prevalence of chlamydial infection. While there are significant correlations between minority and socioeconomic status and infection rates, chlamydial infection is too widespread to base screening decisions on these criteria alone. A particularly important factor contributing to the chain of infection is local social-sexual networks. Perpetuation of these networks contributes to sustaining endemic disease levels through infection and reinfection. Interrupting these networks can directly affect the health of a wide circle of individuals.
4. Insufficient time and reimbursement. Primary care physicians report significant dissatisfaction with the short time allocated for individual visits and a relative decline in reimbursement. Such time pressure often leads to a focus on chief complaints; health maintenance and screening discussions are often omitted. Future payment mechanisms for care coordination and performance may remedy this problem.
5. Inadequate health information technology. The promises of health information technology are often unfulfilled, and office-based electronic health records (EHRs) frequently do not provide point-of-service information that would improve screening compliance. Lack of efficient interfaces for electronic records and databases makes regional health information exchange difficult. Improving electronic communication among health care professionals will likely improve primary and secondary prevention measures.
6. Generally poor integration of public health and medicine. The United States spends a smaller portion of its health care budget on public health than most other industrialized nations. Academically, a vast divide exists between most institutions of public health and medicine. And at the community level, there is a lack of integration of public health services and physician practices. The example of chlamydia screening underscores the need for reform of the US health care system to include greater emphasis on, and integration with, public health, preventive medicine, and primary care.
7. Deficient access to health care. One-sixth of the US population is without health insurance,⁸ and many who have insurance lack benefits that fully cover preventive medicine and screening. Reform of the US health care system to provide easy access to care is more likely to improve a broad range of health outcomes than the development of smaller, fragmented programs focused on specific conditions. This, again, has direct implications for chlamydia control and spread via social-sexual networks.

Our recommendations

1. Reacquaint yourself with the USPSTF screening guidelines and commit to following them rigorously in practice. This will necessitate examining your relationship with eligible patients, developing mechanisms to regularly discuss sexual health and STD issues, and consistently providing screening.
2. Make screening a routine part of care at recommended opportunities. If you use an EHR, consider working with the vendor to construct appropriate automatic prompts. Those with traditional systems may want to include a systematic chart addition and audit.
3. Consider becoming a policy advocate. There are serious health system flaws that hinder efforts to stem the chlamydia epidemic. Many of these system flaws are best addressed by state or national policy change and through new incentives for financial rewards for physicians.
4. Actively partner with local public health departments to expand screening services to those at risk. A study by Ward demonstrated that increasing screening in communities with endemic disease might have the greatest effect on the local population and its sexual networks.⁹

CORRESPONDENCE
Wiley D. Jenkins, Department of Family and Community Medicine, Southern Illinois University School of Medicine, 913 N. Rutledge Street, P.O. Box 19671, Springfield, IL 62794-9671; [email protected]

Detection of Chlamydia trachomatis infection—the most commonly reported bacterial infection in the United States—falls primarily to patients’ personal physicians, not to sexually transmitted disease (STD) clinics or local health departments, as we’ll describe in a bit. And yet, fewer than half of personal physicians routinely screen for it.¹

Left untreated or allowed to recur, chlamydial infections are significant causes of pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and infertility. Chlamydia cases reported to the Centers for Disease Control and Prevention (CDC) exceeded 1 million for the first time in 2006, and the CDC estimates that more than 2 million Americans between the ages of 14 and 39 years are infected.² Most, if not all, of this increase is likely due to increased test sensitivity, expanded screening services and opportunities, and improved reporting, as well as the continuing high disease burden. Recent work suggests there may also be an increase in prevalence in the Pacific Northwest.³

The CDC established screening guidelines for chlamydial infection more than 10 years ago. However, despite long-standing and widely published screening guidelines, most young women who should receive this service do not. This fact has led the US Preventive Services Task Force (USPSTF) to identify chlamydia screening as one of the most important underused clinical preventive services.^4,5

USPSTF screening guidelines for chlamydia infection⁶

• Screen for chlamydial infection in all sexually active nonpregnant women ages 24 and younger, and in older nonpregnant women who are at increased risk. (Grade A recommendation)
• Screen for chlamydial infection in all pregnant women ages 24 and younger, and in older pregnant women who are at increased risk. (Grade B recommendation)
• Routinely screening for chlamydial infection in women ages 25 and older is not recommended, whether or not they are pregnant, if they are not at increased risk. (Grade C recommendation)
• Current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydial infection in men. (Grade I statement)

Most patients are screened by their personal physicians
To help improve screening rates, we must understand the status of screening site availability as well as usage patterns. Using state case and Infertility Prevention Program data, we examined screening sites in Illinois counties (defined as urban or rural) for women who tested positive for chlamydia in the period 2002 through 2006. For both urban and rural counties, more cases were identified by personal physicians than any other site or provider type (39% of all urban cases; 58% of all rural cases). Personal physicians and hospitals, combined, accounted for more than 53% of reported cases in each group. This is important because most chlamydia cases were identified at health care sites other than those that usually receive federal and state funding for chlamydia screening—local health departments and STD clinics. Reliance on these institutions to significantly reduce the chlamydia epidemic is unrealistic.

To address the issue of screening by personal physicians, the CDC’s Division of STD Prevention collaborated with the National Committee for Quality Assurance to develop the “Chlamydia Screening in Women” measure for the Health Care Effectiveness Data and Information Set (HEDIS). Chlamydia screening is now a covered benefit in many managed care plans, but actual screening rates in physician offices are still only approximately 37%.¹ What are the barriers that contribute to such a low rate?

Barriers to chlamydia screening

There are many reasons for inconsistent screening, including flaws in training and practice at the individual level and flaws in regional and national health system design and implementation. Following are several barriers that we must overcome to optimize screening:

1. Lack of awareness by physicians. The extent of chlamydial infections, locally and nationally, may not be sufficiently understood. Likewise, physicians may lack awareness of screening guidelines and not appreciate their role in detecting infection. Every medical school and training program (even postgraduate) should use the guidelines to reinforce the critical role personal physicians have in addressing this national epidemic. Without consistent and widespread compliance with screening guidelines by physicians, reductions in chlamydia rates are unlikely.
2. Uneasy patient-physician relationships. Many patients and their physicians lack relationships that foster open discussions of sexual issues. Adolescents and young adults are notoriously reticent about discussing sexual behavior, and approximately 70% of chlamydial infections in females are asymptomatic.⁷ Therefore, physicians cannot rely solely on suggestive health histories and clinical presentations to prompt a discussion of chlamydia.
3. Wide prevalence of chlamydial infection. While there are significant correlations between minority and socioeconomic status and infection rates, chlamydial infection is too widespread to base screening decisions on these criteria alone. A particularly important factor contributing to the chain of infection is local social-sexual networks. Perpetuation of these networks contributes to sustaining endemic disease levels through infection and reinfection. Interrupting these networks can directly affect the health of a wide circle of individuals.
4. Insufficient time and reimbursement. Primary care physicians report significant dissatisfaction with the short time allocated for individual visits and a relative decline in reimbursement. Such time pressure often leads to a focus on chief complaints; health maintenance and screening discussions are often omitted. Future payment mechanisms for care coordination and performance may remedy this problem.
5. Inadequate health information technology. The promises of health information technology are often unfulfilled, and office-based electronic health records (EHRs) frequently do not provide point-of-service information that would improve screening compliance. Lack of efficient interfaces for electronic records and databases makes regional health information exchange difficult. Improving electronic communication among health care professionals will likely improve primary and secondary prevention measures.
6. Generally poor integration of public health and medicine. The United States spends a smaller portion of its health care budget on public health than most other industrialized nations. Academically, a vast divide exists between most institutions of public health and medicine. And at the community level, there is a lack of integration of public health services and physician practices. The example of chlamydia screening underscores the need for reform of the US health care system to include greater emphasis on, and integration with, public health, preventive medicine, and primary care.
7. Deficient access to health care. One-sixth of the US population is without health insurance,⁸ and many who have insurance lack benefits that fully cover preventive medicine and screening. Reform of the US health care system to provide easy access to care is more likely to improve a broad range of health outcomes than the development of smaller, fragmented programs focused on specific conditions. This, again, has direct implications for chlamydia control and spread via social-sexual networks.

Our recommendations

1. Reacquaint yourself with the USPSTF screening guidelines and commit to following them rigorously in practice. This will necessitate examining your relationship with eligible patients, developing mechanisms to regularly discuss sexual health and STD issues, and consistently providing screening.
2. Make screening a routine part of care at recommended opportunities. If you use an EHR, consider working with the vendor to construct appropriate automatic prompts. Those with traditional systems may want to include a systematic chart addition and audit.
3. Consider becoming a policy advocate. There are serious health system flaws that hinder efforts to stem the chlamydia epidemic. Many of these system flaws are best addressed by state or national policy change and through new incentives for financial rewards for physicians.
4. Actively partner with local public health departments to expand screening services to those at risk. A study by Ward demonstrated that increasing screening in communities with endemic disease might have the greatest effect on the local population and its sexual networks.⁹

CORRESPONDENCE
Wiley D. Jenkins, Department of Family and Community Medicine, Southern Illinois University School of Medicine, 913 N. Rutledge Street, P.O. Box 19671, Springfield, IL 62794-9671; [email protected]

Dyslipidemia is a primary contributor to coronary heart disease (CHD), the No. 1 cause of death in the United States.^1,2 Mortality rates from CHD have declined sharply over the last 3 decades as a result of improvements in acute care and in secondary prevention, notably by means of lipid-lowering statin therapy.^3,4 Studies confirm that the decline in cardiovascular events is largely due to decreases in low-density lipoprotein (LDL)-cholesterol and other atherogenic particles.^2,5 Still, despite these gains, CHD continues to be a major threat, and the search to find ways to lower CHD risk further continues. Additional avenues being explored include reducing triglycerides and raising high-density lipoprotein (HDL)-cholesterol through lifestyle intervention and other means in patients with mixed dyslipidemia whose statin therapy is already optimal.² This article reviews the LDL-cholesterol lowering “standard of care” and discusses the potential of addressing other lipoproteins to reduce the residual cardiovascular risk that frequently remains.

Lower LDL levels remain the primary target

The National Cholesterol Education Program (NCEP) has focused on reduction of serum levels of LDL-cholesterol for the primary and secondary prevention of CHD. This approach is biologically reasonable, because LDL is the major atherogenic lipoprotein and is directly implicated in the development of atherosclerosis. Further, the benefit of LDL lowering has been validated by the results of many randomized clinical trials using a combination of lifestyle changes and statins.²

Data on 90,000 patients confirm efficacy of lowering LDL
In an important meta-analysis, the Cholesterol Treatment Trialists’ (CTT) Collaborators compiled data from more than 90,000 people in 14 large-scale, randomized statin trials that included high-risk populations.⁶ The investigators found that each 39-mg/dL (1-mmol/L) reduction in LDL-cholesterol sustained over 5 years reduced the incidence of a first major coronary event by 23% and the incidence of CHD death by 19%. In the high-risk subgroup with preexisting CHD, a 39-mg/dL (1-mmol/L) reduction in LDL-cholesterol prevented 14 deaths per 1000 participants. These benefits were significant even in the first year of treatment (P<.0001) and were greater in subsequent years.⁶ The nearly linear relationship between lower LDL-cholesterol levels and fewer major vascular events held true regardless of baseline LDL-cholesterol levels, even when the baseline levels were <100 mg/dL.⁶

The greatest absolute benefit was noted in the high-risk and very-high-risk groups, especially in individuals with diabetes and those older than 75 years. Moreover, long-term follow-up comparing the original statin-treated participants with the original placebo group showed that lowering LDL-cholesterol continued to reduce cardiovascular risk for 10 years after the study ended.⁷

Optimal LDL levels may be even lower than we thought

Observational studies have suggested that the relationship between cholesterol and CHD mortality has no apparent lower threshold, and that the physiologic norm for LDL-cholesterol may be lower than that typically seen in Western countries. For example, in a study done in the 1970s in an urban Chinese population of more than 9000 middle-aged men and women, the mean baseline total cholesterol level was 162 mg/dL, and only 7% of deaths were attributed to CHD in 13 years of follow-up.⁸ Nevertheless, there was an independent and strongly positive (P<.001) relationship between total cholesterol and risk of CHD death, starting at a level as low as 147 mg/dL, which may be equivalent to an LDL-cholesterol of 100 mg/dL. Some data indicate the physiologic norm for LDL-cholesterol levels may be in the range of 50 to 70 mg/dL, which is much lower than the US average of approximately 130 mg/dL.⁹

Lower LDL-cholesterol protects against atherosclerosis
Lifetime exposure to a lower LDL-cholesterol level may be responsible for a lower burden of atherosclerotic disease later in life. Analyses of data from major statin clinical trials indicate that atherosclerosis does not progress when LDL-cholesterol levels are maintained at <67 mg/dL, while other data suggest that CHD event rates could be minimized at LDL-cholesterol levels of 57 mg/dL for primary prevention and 30 mg/dL for secondary prevention.⁹

Intensive regimens yield better outcomes

Controlled clinical trials have compared more intensive and less intensive statin and lifestyle modification regimens in high-risk subjects, most of whom already had CHD. These trials found that lower LDL-cholesterol values achieved by more intensive regimens produced incremental CHD benefits.^10-16 Major findings of these trials are summarized in TABLE 1.

TABLE 1
Intensive LDL-C lowering in high-risk patients: What the research tells us

Treating to New Targets (TNT)
After an 8-week run-in period with atorvastatin 10 mg/d, the TNT researchers randomized 10,000 patients with stable CHD and mean baseline LDL-cholesterol levels of 98 mg/dL to atorvastatin 80 mg/d or continued with atorvastatin 10 mg/d.¹⁰ Patients in the high-dose group achieved a mean LDL-cholesterol level of 77 mg/dL, which was associated with a 22% relative reduction in risk of a major cardiovascular event (P<.001) and significant reductions in stroke (25%) and cerebrovascular events (23%).^10,17

PROVE IT
The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial enrolled 4162 patients who had been hospitalized for acute coronary syndrome within the previous 10 days.¹² Patients were randomly assigned to intensive (atorvastatin 80 mg/d) or moderate (pravastatin 40 mg/d) therapy for 24 months—in addition to therapeutic lifestyle interventions. Median LDL-cholesterol levels fell from 106 mg/dL at baseline to 62 mg/dL in the intensive-therapy group and to 95 mg/dL in the standard-therapy group. At 2 years, the primary end point—a composite of cardiovascular events—was 16% lower (P=.005) in patients on intensive therapy than in patients on moderate therapy, with the greatest apparent benefit in those with baseline LDL-cholesterol levels of at least 125 mg/dL.¹² Favorable outcomes were more closely related to the on-treatment levels of LDL-cholesterol and C-reactive protein than to the specific agent used.¹⁸

Taken together, the TNT and PROVE IT trials show that in high-risk patients with CHD, achieving LDL-cholesterol levels of 60 to 80 mg/dL results in better outcomes than regimens that achieve LDL-cholesterol levels of approximately 100 mg/dL.

Moving the goal posts

The 2002 NCEP Adult Treatment Panel III (ATP III) guidelines recommend LDL-cholesterol goals depending on the patient’s level of risk, with <100 mg/dL as the goal for those in the highest risk category.² Statin-treated patients in the Heart Protection Study (HPS) achieved a mean LDL-cholesterol level of 89 mg/dL, and investigators reported a “highly significant” 18% reduction in coronary deaths (P=.0005), even in individuals who entered the study with baseline LDL-cholesterol level of <116 mg/dL.¹³ No indication of a threshold effect was found. For that reason, the HPS investigators suggested that reducing LDL-cholesterol still further with dietary and statin therapy might produce even greater reductions in cardiovascular events.¹³

In 2004, <70 was a “therapeutic option”
The 2004 update of the NCEP guidelines took into account the findings of the HPS and several other statin trials—most of them secondary prevention studies—that provided further evidence for the benefit of lowering LDL-cholesterol to levels well below 100 mg/dL.^12-16,19 The mean achieved LDL-cholesterol levels in these trials and the impact on CHD events are summarized in TABLE 1. The more intensive vs less intensive LDL-cholesterol lowering trials discussed earlier provided evidence that reducing LDL-cholesterol levels to <70 mg/dL is a “therapeutic option” for people at very high CHD risk. The “very-high-risk” category includes those with established cardiovascular disease and additional risk factors such as diabetes mellitus, continued cigarette smoking, metabolic syndrome, and acute coronary syndrome.¹⁹ TABLE 2 summarizes the 2004 NCEP goals.

TABLE 2
NCEP risk categories and LDL-cholesterol goals^2,19

In 2006, <70 became a “reasonable goal”
Guidelines for secondary prevention jointly issued by the American Heart Association and the American College of Cardiology in 2006 and endorsed by the National Heart, Lung, and Blood Institute (NHLBI) agree that a goal of <70 mg/dL is “reasonable” for all patients with CHD and other clinical forms of atherosclerotic disease, even those whose baseline LDL-cholesterol level is between 70 and 100 mg/dL.⁵

Lowering LDL may cause atherosclerosis to regress

Intensive lipid lowering has shown promise in inducing regression of atherosclerotic plaque.^20,21 The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared the effects on atheroma volume, as measured by intracoronary intravascular ultrasound, of intensive (atorvastatin 80 mg/d) vs moderate (pravastatin 40 mg/d) lipid lowering over 18 months in patients who had 1 or more vessels with a luminal narrowing of 20% or more.²⁰ In the intensive treatment group, which attained a mean LDL-cholesterol level of 79 mg/dL, the 0.4% reduction in atheroma volume indicated no disease progression from baseline and a significantly lower progression rate (P=.02). By contrast, the group on moderate treatment that achieved a mean LDL-cholesterol level of 110 mg/dL had a 2.7% increase in atheroma volume, indicating net progression of atheroma volume compared with baseline.²⁰

ASTEROID shows actual regression
A study of the effect of rosuvastatin on disease progression (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden, or ASTEROID) evaluated the effect of rosuvastatin 40 mg/d on coronary disease progression assessed by intravascular ultrasound at baseline and after 24 months, with the patients serving as their own controls.²¹ The results showed the mean change in percent atheroma volume (PAV), a measure of disease progression and regression, for the entire vessel being measured was –0.98%, compared with baseline (P<.001). A second efficacy measure, change in atheroma volume in the 10-mm subsegment with the greatest disease severity, also showed a reduction, with a mean change of –6.1 mm³ compared with baseline (P<.001).²¹ The ASTEROID investigators attributed disease regression to intensive statin treatment, leading to an LDL-cholesterol mean of 61 mg/dL together with significantly increasing HDL-cholesterol levels to 49 mg/dL, up 5% from baseline.²¹

Combination therapy fails to ENHANCE atherosclerosis regression
In a controversial study in patients with familial hypercholesterolemia utilizing B-mode ultrasound measurements of carotid intima-media thickness, lowered LDL-cholesterol levels did not result in regression of atherosclerosis. The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial evaluated simvastatin 80 mg plus ezetimibe 10 mg compared with simvastatin 80 mg alone.²² Despite a significant 16.5% greater lowering of LDL-cholesterol with combination therapy (P<.01), no difference was observed in progression of carotid intima-media thickness between the 2 treatment groups.

No LDL is too low for safety

Given the physiologic importance of cholesterol in the body, the very low cholesterol levels achieved with intensive statin therapy in some trials has raised questions about the safety of such an approach.²³ A substudy of the PROVE IT-TIMI 22 trial focused on the 11% of 1825 atorvastatin-treated patients whose LDL-cholesterol levels had dropped to 40 mg/dL or lower after 4 months of treatment. There were fewer cardiovascular events in this group compared with the patients with LDL-cholesterol levels between 80 and 100 mg/dL, and no relationship between this low level and adverse events over 24 months.²³ Similarly, the TNT study group analyzed cardiovascular events across quintiles of LDL-cholesterol and found that the lowest quintile (LDL <64 mg/dL, mean 54 mg/dL) had the lowest event rate, without a difference in adverse events over 5 years.²⁴

LDL isn’t the whole story

It is clear from the statin clinical trials that cardiovascular events occur even after LDL-cholesterol is optimally treated. Why is this so? One possibility is that levels of other lipids—too-high triglycerides or too-low HDL-cholesterol—also contribute to CHD risk. These lipid abnormalities often cluster with other risk factors, including obesity, insulin resistance, hyperglycemia, and hypertension. Such patients are considered to have mixed, or atherogenic, dyslipidemia, and frequently include those with metabolic syndrome and type 2 diabetes. In patients whose triglyceride levels remain high (>200 mg/dL) or HDL-cholesterol levels low (<40 mg/dL) even after they have achieved their LDL-cholesterol goals, the NCEP ATP III guidelines recommend non–HDL-cholesterol as a secondary target of therapy.² Non–HDL-cholesterol (calculated as total cholesterol minus HDL-cholesterol) is a measure of all the atherogenic, apolipoprotein B-containing lipoproteins (LDL, intermediate-density lipoprotein [IDL], and very-low-density lipoprotein [VLDL]).

In mixed, or atherogenic, dyslipidemia, the LDL particles are usually smaller and the calculated LDL-cholesterol content does not reflect the increased particle number. Several observational studies suggest that non–HDL-cholesterol is a better predictor of risk at any given LDL-cholesterol level.

The IDEAL predictor
To highlight the predictive value of non–HDL-cholesterol, Kastelein and colleagues analyzed pooled data from TNT and IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering). IDEAL was a large (N=8888), randomized clinical trial in which patients with established CHD were assigned to usual-dose or high-dose statin treatment.²⁵ In the investigators’ statistical models, while LDL-cholesterol levels were positively associated with cardiovascular outcome, that relationship turned out to be less significant than the relationship with non–HDL-cholesterol and apolipoprotein B. The ratio of total cholesterol to HDL (Total/HDL) and the ratio of apolipoprotein B to apolipoprotein A-I were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters.²⁵

Another post hoc analysis of TNT data has shown that HDL-cholesterol levels in patients receiving statins predicted major cardiovascular events. Among subjects with LDL-cholesterol levels <70 mg/dL, those in the highest quintile of HDL-cholesterol were at less risk for major cardiovascular events than those in the lowest quintile (P=.03).²⁶ Both of these analyses support the concept that there is residual CHD risk after optimal statin treatment, and that the easily obtained non–HDL-cholesterol and HDL-cholesterol levels are predictive of that risk.

Setting goals for non–HDL-cholesterol
The ATP III–recommended goal for non–HDL-cholesterol is 30 mg/dL above the LDL goal, since maximum acceptable cholesterol carried in the triglyceride-rich lipoproteins (VLDL/IDL) is one-fifth of the acceptable triglyceride level (150/5=30 mg/dL). Thus, a high-risk person whose LDL-cholesterol goal is <100 mg/dL would have a non–HDL-cholesterol goal of <130 mg/dL. ATP III recommends lowering non–HDL-cholesterol by intensifying statin therapy to further reduce LDL as well as considering the addition of niacin or a fibrate to further decrease VLDL and triglycerides.² Although not specifically recommended by ATP III, omega-3 fatty acids at a sufficient dose (3-4 g/d of ecosapentanoic acid + decosahexanoic acid) can reduce triglycerides as monotherapy, or when added to statins.²⁷

Total atherogenic particles
A 2008 consensus conference report from the American Diabetes Association and the American College of Cardiology states that in patients with high cardiometabolic risk, LDL-cholesterol levels alone do not adequately capture risk and that measurements of total atherogenic particles are better.²⁸ These measurements include non–HDL-cholesterol, apolipoprotein B, and the number of LDL particles identified by nuclear magnetic resonance. In individuals in the highest-risk category (known clinical cardiovascular disease or diabetes plus 1 or more CHD risk factors in addition to dyslipidemia), the report recommends a non–HDL-cholesterol goal of <100 mg/dL and an apolipoprotein B goal of <80 mg/dL.²⁸

Combining therapies: AIM-HIGH and ACCORD
Two ongoing trials are comparing combination therapy (statin with either niacin or a fibrate) with statin therapy alone in patients with atherogenic dyslipidemia to assess the incremental benefit of combination therapy. AIM-HIGH (Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides and Impact on Global Health outcomes) is a 5-year study in 3300 patients with vascular disease and low HDL-cholesterol. This study is designed to find out whether lowering LDL to <80 mg/dL with simvastatin plus niacin can delay the time to a first major cardiovascular event for longer than simvastatin therapy alone.²⁹

The 6-year ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) randomizes patients with type 2 diabetes into 2 groups, 1 receiving statin-fibrate combination therapy and the other statin monotherapy. ACCORD is designed to find out whether raising HDL-cholesterol and lowering triglycerides along with targeted reductions in LDL-cholesterol will improve CHD outcomes more than LDL lowering alone.²⁹

Raising HDL-cholesterol is promising, but complex

Improving residual CHD risk after statin treatment has emphasized raising HDL-cholesterol as a therapeutic target. The validity of raising HDL-cholesterol is supported by epidemiologic evidence showing an inverse relationship between HDL-cholesterol levels and cardiovascular risk: an increase of 1 mg/dL in HDL-cholesterol is associated with a 2% to 3% decrease in risk of cardiovascular disease.³⁰ Therapeutic lifestyle changes, such as weight loss, exercise, and smoking cessation are effective at increasing HDL-cholesterol and these interventions are always encouraged. Most statins modestly (5%-10%) increase HDL-cholesterol, with rosuvastatin generally producing the largest increases, as shown in the ASTEROID study.

Niacin raises HDL
Currently, the most efficacious HDL-raising drug is niacin. As monotherapy, niacin can increase HDL-cholesterol by 15% to 35%.² The problem is that niacin often causes flushing, a side effect patients find unpleasant enough that they don’t continue therapy.³¹ Extended-release preparations cause less flushing than immediate-release forms of niacin, and specific flush-reducing agents (laropiprant) are under investigation to improve tolerance.³²

Fibrates, alone and combined, with statins
By activating the nuclear transcription factor peroxisome proliferator-activated receptor-α, fibrates increase HDL-cholesterol by 8% to 35%.³³ The Veterans Affairs HDL Intervention Trial (VA-HIT)³⁴ studied the effects of gemfibrozil in men with CHD and HDL-cholesterol <40 mg/dL. After a median follow-up of 5 years, gemfibrozil raised HDL-cholesterol by 6% more than placebo and lowered triglycerides by 31% more (P<.001 for both), but did not affect levels of LDL-cholesterol. Compared to placebo, gemfibrozil treatment reduced the risk of CHD death and nonfatal myocardial infarction by 22% (P=.006). In post hoc analysis, each 5-mg/dL increase in HDL-cholesterol was associated with an 11% decrease in the risk of these CHD events.³⁴

The Helsinki Heart Study³⁵ reported similar results with gemfibrozil in a population without CHD. Fibrates may be combined with statins: small studies using rosuvastatin and fenofibrate³⁶ and atorvastatin and fenofibrate³⁷ have shown positive effects on dyslipidemia. Gemfibrozil may be associated with increased risks of myositis, whereas fenofibrate combined with statins has not shown this effect.³⁸

High hopes, sobering findings, for torcetrapib
The glycoprotein cholesteryl ester transfer protein (CETP) can make HDL particles smaller and more readily removed by the kidneys, with the overall effect of a reduction in HDL-cholesterol.³⁹ Inhibiting this effect, then, should raise HDL levels. Expectations were high for torcetrapib, the first CETP inhibitor, which had been shown to increase HDL-cholesterol by >50% in early clinical trials.⁴⁰ However, a clinical outcomes trial comparing torcetrapib and atorvastatin with atorvastatin alone was stopped early because the combination therapy was associated with a higher incidence of adverse cardiovascular events, including total mortality.⁴¹ Significant increases in average systolic blood pressure with torcetrapib were reported, but it is not clear if this was the cause of the unfavorable outcome. Further, substantial HDL-cholesterol increases of 54% and 61% achieved with torcetrapib in 2 surrogate outcomes trials did not have a beneficial effect on atherosclerosis.^42,43

Other CETP inhibitors are currently in development that, investigators hope, will not have the adverse effects associated with torcetrapib.^44,45 Additional investigative approaches for increasing HDL-cholesterol levels or increasing reverse cholesterol transport include both intravenous and oral therapies such as apolipoprotein A1-Milano, apolipoprotein A1-mimetic peptides, and phospholipid-directed therapies.^46-49

CORRESPONDENCE Peter Jones, MD, 6565 Fannin Street, MSA-601, Suite B157, Houston, TX 77030; [email protected]