Linda N. Meurer, MD, MPH

Evidence summary

Depletion of iron stores leads to IDA, which, among children, is associated with motor and cognitive deficits that may be irreversible. Little is known about whether iron deficiency, in the absence of anemia, results in physiologic sequelae. A Cochrane review of iron therapy for children with IDA aged >3 years found no short-term (5–11 days) improvement in Bayley scores of mental and motor development following iron therapy.¹ A 10-year longitudinal cohort study in Costa Rica found that adolescents treated for severe chronic IDA in infancy (n=48) scored 0.4 to 0.7 standard deviations lower on cognitive and motor testing relative to controls (n=114).² In an Indonesian randomized controlled trial (RCT), baseline Bayley scores were 10% to 15% lower (P<.01) for infants (12–18 months) with IDA compared with both nonanemic iron-deficient and iron-sufficient infants.³ Following treatment with ferrous sulfate (3 mg/kg/d of elemental iron) for 4 months, the IDA infants’ Bayley scores improved compared with those of nonanemic children.

Consensus recommendations suggest that iron deficiency should be the presumptive diagnosis in a child with anemia, and that a trial of ferrous sulfate at a dose of 3 mg/kg/d of elemental iron be instituted because of low cost, tolerability, and relative simplicity.^4,5 In a prospective study of 75 1-year-olds with anemia (hemoglobin <11.0 g/dL), 45% achieved an increase in hemoglobin ≥1 g/dL after 3 months of iron therapy (3 mg/kg/d).⁶ An RCT of 278 nonanemic 1-year-olds found no difference in adverse effects from this dose compared with placebo.⁷ However, an analysis of data from NHANES III showed that a Hgb <11.0 had a positive predictive value of just 29% and sensitivity of 30% for diagnosing iron-deficiency in children aged <3 years.⁸

The recommended dose of 3 mg/kg/d was derived from models of bioavailability and iron needs⁹; no studies compare alternative doses. An RCT of 557 anemic children under 24 months of age in Ghana demonstrated that ferrous sulfate (5 mg/kg/d) given once daily was equivalent to 3-times-daily dosing in terms of effectiveness (61% vs 56%) and tolerance.¹⁰ Less frequent dosing has been studied in developing countries with mixed results.

Because anemia may lead to developmental impairment, primary prevention is critical. In a cohort study, infants given iron-fortified formula (n=98) were less likely to become iron-deficient by their 12-month visit than infants fed whole cow milk (n=69) (11.2% vs 24.6%, number needed to treat [NNT]=8).¹¹ In a RCT of innercity children who had been switched to cows’ milk by 6 months, half (n=50) were randomized to receive iron-fortified formula for another year, resulting in a decreased risk of anemia at 24 months (0% vs 26%, NNT=4), and smaller declines in developmental functioning compared with those on cows’ milk.¹²

Recommendations from others

The CDC and the Institute of Medicine recommend parental dietary counseling, treatment with oral ferrous sulfate at 3 mg/kg/d for 3 months to restore iron stores, and monitoring of hemoglobin or hematocrit to assess response.^4,5 To prevent IDA, the American Academy of Pediatrics (AAP) recommends that all infants who are not breastfed or are partially breastfed should receive an iron-fortified formula (containing between 4.0–12 mg/L of iron) from birth to 12 months. The AAP also recommends that parents should refrain from feeding cow’s milk to infants until after age 12 months and introduce iron-enriched foods between ages 4 and 6 months.¹³

Evidence summary

Depletion of iron stores leads to IDA, which, among children, is associated with motor and cognitive deficits that may be irreversible. Little is known about whether iron deficiency, in the absence of anemia, results in physiologic sequelae. A Cochrane review of iron therapy for children with IDA aged >3 years found no short-term (5–11 days) improvement in Bayley scores of mental and motor development following iron therapy.¹ A 10-year longitudinal cohort study in Costa Rica found that adolescents treated for severe chronic IDA in infancy (n=48) scored 0.4 to 0.7 standard deviations lower on cognitive and motor testing relative to controls (n=114).² In an Indonesian randomized controlled trial (RCT), baseline Bayley scores were 10% to 15% lower (P<.01) for infants (12–18 months) with IDA compared with both nonanemic iron-deficient and iron-sufficient infants.³ Following treatment with ferrous sulfate (3 mg/kg/d of elemental iron) for 4 months, the IDA infants’ Bayley scores improved compared with those of nonanemic children.

Consensus recommendations suggest that iron deficiency should be the presumptive diagnosis in a child with anemia, and that a trial of ferrous sulfate at a dose of 3 mg/kg/d of elemental iron be instituted because of low cost, tolerability, and relative simplicity.^4,5 In a prospective study of 75 1-year-olds with anemia (hemoglobin <11.0 g/dL), 45% achieved an increase in hemoglobin ≥1 g/dL after 3 months of iron therapy (3 mg/kg/d).⁶ An RCT of 278 nonanemic 1-year-olds found no difference in adverse effects from this dose compared with placebo.⁷ However, an analysis of data from NHANES III showed that a Hgb <11.0 had a positive predictive value of just 29% and sensitivity of 30% for diagnosing iron-deficiency in children aged <3 years.⁸

The recommended dose of 3 mg/kg/d was derived from models of bioavailability and iron needs⁹; no studies compare alternative doses. An RCT of 557 anemic children under 24 months of age in Ghana demonstrated that ferrous sulfate (5 mg/kg/d) given once daily was equivalent to 3-times-daily dosing in terms of effectiveness (61% vs 56%) and tolerance.¹⁰ Less frequent dosing has been studied in developing countries with mixed results.

Because anemia may lead to developmental impairment, primary prevention is critical. In a cohort study, infants given iron-fortified formula (n=98) were less likely to become iron-deficient by their 12-month visit than infants fed whole cow milk (n=69) (11.2% vs 24.6%, number needed to treat [NNT]=8).¹¹ In a RCT of innercity children who had been switched to cows’ milk by 6 months, half (n=50) were randomized to receive iron-fortified formula for another year, resulting in a decreased risk of anemia at 24 months (0% vs 26%, NNT=4), and smaller declines in developmental functioning compared with those on cows’ milk.¹²

Recommendations from others

The CDC and the Institute of Medicine recommend parental dietary counseling, treatment with oral ferrous sulfate at 3 mg/kg/d for 3 months to restore iron stores, and monitoring of hemoglobin or hematocrit to assess response.^4,5 To prevent IDA, the American Academy of Pediatrics (AAP) recommends that all infants who are not breastfed or are partially breastfed should receive an iron-fortified formula (containing between 4.0–12 mg/L of iron) from birth to 12 months. The AAP also recommends that parents should refrain from feeding cow’s milk to infants until after age 12 months and introduce iron-enriched foods between ages 4 and 6 months.¹³

Evidence summary

Depletion of iron stores leads to IDA, which, among children, is associated with motor and cognitive deficits that may be irreversible. Little is known about whether iron deficiency, in the absence of anemia, results in physiologic sequelae. A Cochrane review of iron therapy for children with IDA aged >3 years found no short-term (5–11 days) improvement in Bayley scores of mental and motor development following iron therapy.¹ A 10-year longitudinal cohort study in Costa Rica found that adolescents treated for severe chronic IDA in infancy (n=48) scored 0.4 to 0.7 standard deviations lower on cognitive and motor testing relative to controls (n=114).² In an Indonesian randomized controlled trial (RCT), baseline Bayley scores were 10% to 15% lower (P<.01) for infants (12–18 months) with IDA compared with both nonanemic iron-deficient and iron-sufficient infants.³ Following treatment with ferrous sulfate (3 mg/kg/d of elemental iron) for 4 months, the IDA infants’ Bayley scores improved compared with those of nonanemic children.

Consensus recommendations suggest that iron deficiency should be the presumptive diagnosis in a child with anemia, and that a trial of ferrous sulfate at a dose of 3 mg/kg/d of elemental iron be instituted because of low cost, tolerability, and relative simplicity.^4,5 In a prospective study of 75 1-year-olds with anemia (hemoglobin <11.0 g/dL), 45% achieved an increase in hemoglobin ≥1 g/dL after 3 months of iron therapy (3 mg/kg/d).⁶ An RCT of 278 nonanemic 1-year-olds found no difference in adverse effects from this dose compared with placebo.⁷ However, an analysis of data from NHANES III showed that a Hgb <11.0 had a positive predictive value of just 29% and sensitivity of 30% for diagnosing iron-deficiency in children aged <3 years.⁸

The recommended dose of 3 mg/kg/d was derived from models of bioavailability and iron needs⁹; no studies compare alternative doses. An RCT of 557 anemic children under 24 months of age in Ghana demonstrated that ferrous sulfate (5 mg/kg/d) given once daily was equivalent to 3-times-daily dosing in terms of effectiveness (61% vs 56%) and tolerance.¹⁰ Less frequent dosing has been studied in developing countries with mixed results.

Because anemia may lead to developmental impairment, primary prevention is critical. In a cohort study, infants given iron-fortified formula (n=98) were less likely to become iron-deficient by their 12-month visit than infants fed whole cow milk (n=69) (11.2% vs 24.6%, number needed to treat [NNT]=8).¹¹ In a RCT of innercity children who had been switched to cows’ milk by 6 months, half (n=50) were randomized to receive iron-fortified formula for another year, resulting in a decreased risk of anemia at 24 months (0% vs 26%, NNT=4), and smaller declines in developmental functioning compared with those on cows’ milk.¹²

Recommendations from others

The CDC and the Institute of Medicine recommend parental dietary counseling, treatment with oral ferrous sulfate at 3 mg/kg/d for 3 months to restore iron stores, and monitoring of hemoglobin or hematocrit to assess response.^4,5 To prevent IDA, the American Academy of Pediatrics (AAP) recommends that all infants who are not breastfed or are partially breastfed should receive an iron-fortified formula (containing between 4.0–12 mg/L of iron) from birth to 12 months. The AAP also recommends that parents should refrain from feeding cow’s milk to infants until after age 12 months and introduce iron-enriched foods between ages 4 and 6 months.¹³

Evidence summary

Solar ultraviolet (UV) rays are grouped into 2 wavelengths: UVB (290–320 nm) causes acute inflammation, pain and erythema of sunburn; UVA (320–400 nm) is implicated in long-term damage to the skin, including photoaging and skin cancer, following carcinogenic induction by UVB.¹ Sun protection factor (SPF) refers to the dose of UVB required to produce erythema in protected skin vs unprotected skin.¹ UVA protection is offered in broad-spectrum sunscreens, but is not reflected by the SPF.

SPF-15 is considered by experts to be adequate to prevent sunburn, assuming use of a 2 mg/cm² layer of sunscreen (typically, 30 cc for an average adult). However, observations suggest people apply less than half that.² Most experts recommend reapplication every 2 to 3 hours, though the quantity of sunscreen applied may be more important. A paired, split-body study of children receiving supervised single vs multiple applications of SPF-25 sunscreen to randomly assigned lateral halves of their bodies found protection to be equal for 6 hours of direct sunlight exposure. When the study was repeated with 8 hours of exposure, half the children developed mild erythema on the side with 1 application.³

Because of the causal link between exposure to solar UV radiation and skin cancers, experts believe that sunscreens protect the wearer against the development of skin cancer. Case-control studies demonstrate that sunburn in childhood raises the risk of melanotic and nonmelanotic skin cancers, particularly among those with fair skin.⁴ However, studies of sunscreen’s ability to prevent skin cancer are limited due to variability in use, sun exposure, and susceptibility factors. A randomized controlled trial in adults supports that daily sunscreen use reduces the risk of squamous cell carcinoma but not basal cell carcinoma (number needed to treat=884 for 4.5 years).⁵

Sunscreen permits longer sun exposure and may increase the development of nevi, known to be associated with malignant melanoma risk.^6,7 A retrospective study of 6- to 7-year-old children found that sunscreen use correlated with an increasing number of nevi, though wearing clothing to cover skin while in the sun was protective.⁶ However, a randomized controlled trial (RCT) demonstrated that regular use of broad-spectrum sunscreen in young school-aged children resulted in fewer melanotic nevi compared with controls.⁷ A meta-analysis of 18 observational studies did not show an association between sunscreen use and melanoma incidence.⁸

Sunscreens can cause skin irritation or allergic reaction to either the active ingredient or vehicle.^9,10 A RCT of 603 adults found no allergic reactions to active sunscreen ingredients, though 19% of subjects had an irritant reaction or allergy to the base compounds.⁹ Because infants’ skin may have different absorptive characteristics from that of older children, the US Food and Drug Administration recommends avoiding sunscreen before 6 months of age. As research is lacking for this age group, and the risk of harm due to sunburn is real, it would be reasonably prudent to use sunscreen when physical protection from the sun is impossible, and to avoid ingredients that caused a previous reaction.

Recommendations from others

The Centers for Disease Control and Prevention¹⁰ and the American Academy of Pediatrics¹¹ recommend protection from sun exposure for all children and adolescents, including regular and adequate use of broad-spectrum sunscreen for children over 6 months, protective clothing, and sunglasses. The US Preventive Services Task Force¹² reports that evidence is insufficient to recommend for or against counseling by primary care clinicians to prevent skin cancer.

Evidence summary

Solar ultraviolet (UV) rays are grouped into 2 wavelengths: UVB (290–320 nm) causes acute inflammation, pain and erythema of sunburn; UVA (320–400 nm) is implicated in long-term damage to the skin, including photoaging and skin cancer, following carcinogenic induction by UVB.¹ Sun protection factor (SPF) refers to the dose of UVB required to produce erythema in protected skin vs unprotected skin.¹ UVA protection is offered in broad-spectrum sunscreens, but is not reflected by the SPF.

SPF-15 is considered by experts to be adequate to prevent sunburn, assuming use of a 2 mg/cm² layer of sunscreen (typically, 30 cc for an average adult). However, observations suggest people apply less than half that.² Most experts recommend reapplication every 2 to 3 hours, though the quantity of sunscreen applied may be more important. A paired, split-body study of children receiving supervised single vs multiple applications of SPF-25 sunscreen to randomly assigned lateral halves of their bodies found protection to be equal for 6 hours of direct sunlight exposure. When the study was repeated with 8 hours of exposure, half the children developed mild erythema on the side with 1 application.³

Because of the causal link between exposure to solar UV radiation and skin cancers, experts believe that sunscreens protect the wearer against the development of skin cancer. Case-control studies demonstrate that sunburn in childhood raises the risk of melanotic and nonmelanotic skin cancers, particularly among those with fair skin.⁴ However, studies of sunscreen’s ability to prevent skin cancer are limited due to variability in use, sun exposure, and susceptibility factors. A randomized controlled trial in adults supports that daily sunscreen use reduces the risk of squamous cell carcinoma but not basal cell carcinoma (number needed to treat=884 for 4.5 years).⁵

Sunscreen permits longer sun exposure and may increase the development of nevi, known to be associated with malignant melanoma risk.^6,7 A retrospective study of 6- to 7-year-old children found that sunscreen use correlated with an increasing number of nevi, though wearing clothing to cover skin while in the sun was protective.⁶ However, a randomized controlled trial (RCT) demonstrated that regular use of broad-spectrum sunscreen in young school-aged children resulted in fewer melanotic nevi compared with controls.⁷ A meta-analysis of 18 observational studies did not show an association between sunscreen use and melanoma incidence.⁸

Sunscreens can cause skin irritation or allergic reaction to either the active ingredient or vehicle.^9,10 A RCT of 603 adults found no allergic reactions to active sunscreen ingredients, though 19% of subjects had an irritant reaction or allergy to the base compounds.⁹ Because infants’ skin may have different absorptive characteristics from that of older children, the US Food and Drug Administration recommends avoiding sunscreen before 6 months of age. As research is lacking for this age group, and the risk of harm due to sunburn is real, it would be reasonably prudent to use sunscreen when physical protection from the sun is impossible, and to avoid ingredients that caused a previous reaction.

Recommendations from others

The Centers for Disease Control and Prevention¹⁰ and the American Academy of Pediatrics¹¹ recommend protection from sun exposure for all children and adolescents, including regular and adequate use of broad-spectrum sunscreen for children over 6 months, protective clothing, and sunglasses. The US Preventive Services Task Force¹² reports that evidence is insufficient to recommend for or against counseling by primary care clinicians to prevent skin cancer.

Evidence summary

Solar ultraviolet (UV) rays are grouped into 2 wavelengths: UVB (290–320 nm) causes acute inflammation, pain and erythema of sunburn; UVA (320–400 nm) is implicated in long-term damage to the skin, including photoaging and skin cancer, following carcinogenic induction by UVB.¹ Sun protection factor (SPF) refers to the dose of UVB required to produce erythema in protected skin vs unprotected skin.¹ UVA protection is offered in broad-spectrum sunscreens, but is not reflected by the SPF.

SPF-15 is considered by experts to be adequate to prevent sunburn, assuming use of a 2 mg/cm² layer of sunscreen (typically, 30 cc for an average adult). However, observations suggest people apply less than half that.² Most experts recommend reapplication every 2 to 3 hours, though the quantity of sunscreen applied may be more important. A paired, split-body study of children receiving supervised single vs multiple applications of SPF-25 sunscreen to randomly assigned lateral halves of their bodies found protection to be equal for 6 hours of direct sunlight exposure. When the study was repeated with 8 hours of exposure, half the children developed mild erythema on the side with 1 application.³

Because of the causal link between exposure to solar UV radiation and skin cancers, experts believe that sunscreens protect the wearer against the development of skin cancer. Case-control studies demonstrate that sunburn in childhood raises the risk of melanotic and nonmelanotic skin cancers, particularly among those with fair skin.⁴ However, studies of sunscreen’s ability to prevent skin cancer are limited due to variability in use, sun exposure, and susceptibility factors. A randomized controlled trial in adults supports that daily sunscreen use reduces the risk of squamous cell carcinoma but not basal cell carcinoma (number needed to treat=884 for 4.5 years).⁵

Sunscreen permits longer sun exposure and may increase the development of nevi, known to be associated with malignant melanoma risk.^6,7 A retrospective study of 6- to 7-year-old children found that sunscreen use correlated with an increasing number of nevi, though wearing clothing to cover skin while in the sun was protective.⁶ However, a randomized controlled trial (RCT) demonstrated that regular use of broad-spectrum sunscreen in young school-aged children resulted in fewer melanotic nevi compared with controls.⁷ A meta-analysis of 18 observational studies did not show an association between sunscreen use and melanoma incidence.⁸

Sunscreens can cause skin irritation or allergic reaction to either the active ingredient or vehicle.^9,10 A RCT of 603 adults found no allergic reactions to active sunscreen ingredients, though 19% of subjects had an irritant reaction or allergy to the base compounds.⁹ Because infants’ skin may have different absorptive characteristics from that of older children, the US Food and Drug Administration recommends avoiding sunscreen before 6 months of age. As research is lacking for this age group, and the risk of harm due to sunburn is real, it would be reasonably prudent to use sunscreen when physical protection from the sun is impossible, and to avoid ingredients that caused a previous reaction.

Recommendations from others

The Centers for Disease Control and Prevention¹⁰ and the American Academy of Pediatrics¹¹ recommend protection from sun exposure for all children and adolescents, including regular and adequate use of broad-spectrum sunscreen for children over 6 months, protective clothing, and sunglasses. The US Preventive Services Task Force¹² reports that evidence is insufficient to recommend for or against counseling by primary care clinicians to prevent skin cancer.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

TABLE
Approach to monitoring of INR for long-term anticoagulation

Evidence summary

Under- or over-treatment with warfarin can result in life-threatening complications. Limited research exists to guide the selection of an interval for monitoring anticoagulation in stabilized patients. One RCT compared INR monitoring in an anticoagulation clinic at 6 weeks and 4 weeks among 124 patients with a prosthetic heart valve on stable oral anticoagulant treatment and found no difference in thromboembolic or hemorrhagic events.¹ A study in the United Kingdom used a 14-week interval for selected patients, but it used no comparison group.² Kent et al developed a computer-based model to compute the optimum interval for monitoring anticoagulation that considers the variability of the patient’s previous levels and costs associated with testing and potential complications. This model achieved a maximum interval of 11 weeks for very stable patients.³

More frequent testing results in higher time in therapeutic range, particularly when patients selfmonitor. A German study of 200 patients with prosthetic heart valves found that they tested within a therapeutic range 48% of the time when monitored by their physician “as usual” (average interval 24 days), and 64% of the time when the interval was increased to 2 weeks.⁴ When the same patients then went to self-monitoring every 8, 4, and 2 days, they achieved therapeutic levels 76%, 89%, and 90% of the time, respectively. Bleeding and thromboembolic complications were not reported, but have been demonstrated elsewhere to be lower among patients who self-test frequently (eg, twice weekly) when compared with usual care (average interval 19 days) (4.49% and 0.9% vs 10.9% and 3.6%; number needed to treat [NNT]=15.6 for bleeding, NNT=37 for thromboembolism).⁵

Recommendations from others

The American College of Chest Physicians (ACCP) recommends individualizing management as the optimal frequency of INR monitoring varies according to patient compliance, dosing decisions, duration of therapy and changes in health, diet, or medications.⁶ The ACCP, the American Heart Association,⁷ Micromedex DrugPoints System,⁸ Goodman and Gilman’s Pharmacological Basis of Therapeutics.,⁹ and Cecil’s Textbook of Medicine.¹⁰ all recommend monthly monitoring once stable. The Institute for Clinical Systems Improvement’s Anticoagulation Therapy Supplement Management.¹¹ and Managing Oral Anticoagulation Therapy Clinical and Operation al Guidelines.¹² also recommend monthly monitoring for stable patients, but suggest that the interval can be increased to 6 weeks for selected stable patients.

TABLE
Approach to monitoring of INR for long-term anticoagulation

Evidence summary

Under- or over-treatment with warfarin can result in life-threatening complications. Limited research exists to guide the selection of an interval for monitoring anticoagulation in stabilized patients. One RCT compared INR monitoring in an anticoagulation clinic at 6 weeks and 4 weeks among 124 patients with a prosthetic heart valve on stable oral anticoagulant treatment and found no difference in thromboembolic or hemorrhagic events.¹ A study in the United Kingdom used a 14-week interval for selected patients, but it used no comparison group.² Kent et al developed a computer-based model to compute the optimum interval for monitoring anticoagulation that considers the variability of the patient’s previous levels and costs associated with testing and potential complications. This model achieved a maximum interval of 11 weeks for very stable patients.³

More frequent testing results in higher time in therapeutic range, particularly when patients selfmonitor. A German study of 200 patients with prosthetic heart valves found that they tested within a therapeutic range 48% of the time when monitored by their physician “as usual” (average interval 24 days), and 64% of the time when the interval was increased to 2 weeks.⁴ When the same patients then went to self-monitoring every 8, 4, and 2 days, they achieved therapeutic levels 76%, 89%, and 90% of the time, respectively. Bleeding and thromboembolic complications were not reported, but have been demonstrated elsewhere to be lower among patients who self-test frequently (eg, twice weekly) when compared with usual care (average interval 19 days) (4.49% and 0.9% vs 10.9% and 3.6%; number needed to treat [NNT]=15.6 for bleeding, NNT=37 for thromboembolism).⁵

Recommendations from others

The American College of Chest Physicians (ACCP) recommends individualizing management as the optimal frequency of INR monitoring varies according to patient compliance, dosing decisions, duration of therapy and changes in health, diet, or medications.⁶ The ACCP, the American Heart Association,⁷ Micromedex DrugPoints System,⁸ Goodman and Gilman’s Pharmacological Basis of Therapeutics.,⁹ and Cecil’s Textbook of Medicine.¹⁰ all recommend monthly monitoring once stable. The Institute for Clinical Systems Improvement’s Anticoagulation Therapy Supplement Management.¹¹ and Managing Oral Anticoagulation Therapy Clinical and Operation al Guidelines.¹² also recommend monthly monitoring for stable patients, but suggest that the interval can be increased to 6 weeks for selected stable patients.

TABLE
Approach to monitoring of INR for long-term anticoagulation

Evidence summary

Under- or over-treatment with warfarin can result in life-threatening complications. Limited research exists to guide the selection of an interval for monitoring anticoagulation in stabilized patients. One RCT compared INR monitoring in an anticoagulation clinic at 6 weeks and 4 weeks among 124 patients with a prosthetic heart valve on stable oral anticoagulant treatment and found no difference in thromboembolic or hemorrhagic events.¹ A study in the United Kingdom used a 14-week interval for selected patients, but it used no comparison group.² Kent et al developed a computer-based model to compute the optimum interval for monitoring anticoagulation that considers the variability of the patient’s previous levels and costs associated with testing and potential complications. This model achieved a maximum interval of 11 weeks for very stable patients.³

More frequent testing results in higher time in therapeutic range, particularly when patients selfmonitor. A German study of 200 patients with prosthetic heart valves found that they tested within a therapeutic range 48% of the time when monitored by their physician “as usual” (average interval 24 days), and 64% of the time when the interval was increased to 2 weeks.⁴ When the same patients then went to self-monitoring every 8, 4, and 2 days, they achieved therapeutic levels 76%, 89%, and 90% of the time, respectively. Bleeding and thromboembolic complications were not reported, but have been demonstrated elsewhere to be lower among patients who self-test frequently (eg, twice weekly) when compared with usual care (average interval 19 days) (4.49% and 0.9% vs 10.9% and 3.6%; number needed to treat [NNT]=15.6 for bleeding, NNT=37 for thromboembolism).⁵

Recommendations from others

The American College of Chest Physicians (ACCP) recommends individualizing management as the optimal frequency of INR monitoring varies according to patient compliance, dosing decisions, duration of therapy and changes in health, diet, or medications.⁶ The ACCP, the American Heart Association,⁷ Micromedex DrugPoints System,⁸ Goodman and Gilman’s Pharmacological Basis of Therapeutics.,⁹ and Cecil’s Textbook of Medicine.¹⁰ all recommend monthly monitoring once stable. The Institute for Clinical Systems Improvement’s Anticoagulation Therapy Supplement Management.¹¹ and Managing Oral Anticoagulation Therapy Clinical and Operation al Guidelines.¹² also recommend monthly monitoring for stable patients, but suggest that the interval can be increased to 6 weeks for selected stable patients.

Estrogen-containing hormone replacement therapy (ERT) after menopause has been implicated as a causal factor in the development of primary breast cancer.^1,2 Fearing cancer recurrence, most physicians do not offer ERT to postmenopausal women with a history of breast cancer. However, estrogen deficiency, which is especially common in women after chemotherapy, can be associated with severe symptoms, reduced quality of life, and increased risk of osteoporosis and possibly coronary artery disease. Although there are theoretical justifications to discourage the use of ERT by women at high risk for breast cancer, there is little objective evidence that hormone replacement increases the likelihood of breast cancer recurrence or of mortality among survivors of primary breast cancer. It is difficult for clinicians and patients to make rational decisions regarding ERT in these patients, given the paucity of studies and the difficulty of interpreting the few studies available.

Several observational studies have been published on the use of estrogen and/or combined estrogen–progesterone hormone replacement therapy in women who have had breast cancer. Many of these studies have reported single-institution series of outcomes among survivors who opted to take ERT for their menopausal symptoms. These studies tend to demonstrate rather unimpressive incidences of recurrence and mortality events. However, it is possible that such studies underestimate the risks because patients who are given ERT may represent a subgroup with a better prognosis than other patients (bias by indication). A smaller number of studies has used comparison groups and attempted to control for disease severity and other factors associated with recurrence.

We conducted a meta-analysis of studies comparing women who used ERT after the diagnosis of breast cancer with a control group of non-ERT users to determine whether ERT is associated with an increased risk of cancer recurrence or all-cause mortality among breast cancer survivors.

Methods

Search strategy

We identified relevant studies through independent literature searches of Medline (from 1966 to August 2001) and Cancerlit (from 1986 to August 2001) with the use of OVID software and the following search terms: estrogen replacement therapy, hormone replacement therapy, breast neoplasms, neoplasm recurrence, survivors. No language restriction was imposed. A careful review of titles and abstracts was done to identify relevant articles, and for these, the full articles were retrieved for review. Bibliographies of identified studies and review articles were examined for additional citations. Medline and Cancerlit databases were also searched by the names of authors of relevant studies to identify any missed articles. The authors of large studies and experts from our institution were asked to review the reference list for completeness and to suggest sources of unpublished data.

Inclusion criteria

Studies were considered for inclusion into the meta-analysis if they met the following criteria: (1) the population studied was women with a previous diagnosis of breast cancer, (2) the risk factor considered was the use of systemic estrogen or any combination hormone replacement therapy that included estrogen, (3) the outcome measured included the recurrence of breast cancer (whether a new or recurring primary cancer) and/or mortality, and (4) the study design was a randomized controlled trial or cohort study comparing women who used ERT after their breast cancer diagnosis with a concurrent, historical, or population-based control group of women who did not. Single-arm cohort studies were retrieved and summarized qualitatively but not included in the statistical analysis. If more than 1 publication was identified which reported the same data, the study with the most recent or complete data was selected for the analysis. We independently reviewed all studies for inclusion, and any differences were resolved through consensus.

Validity assessment

All included studies were assessed for validity by 2 independent reviewers, blinded to study results, for the following characteristics: (1) prospective data collection, (2) clear subject inclusion criteria, (3) reliability of exposure, (4) similarity between exposed and unexposed groups, (5) loss to follow-up, and (6) reliability of outcome assessment. When threats to study validity were identified, attempts were made to determine whether these threats were likely to significantly influence the results of the study and to estimate the direction of the influence of these threats on the resulting data. Because baseline differences between the study groups are such an important threat to the validity of these studies, the studies were graded as higher quality and lower quality based on whether significant differences in known prognostic factors existed.

Data management and analysis

A data extraction form was created to aid consistent recording of data from all studies, and both investigators extracted data independently. Any discrepancies in data interpretation or abstraction were resolved through consensus. Study characteristics and results for single-arm cohort studies were presented descriptively. For controlled studies, data were entered as dichotomous variables into Review Manager 4.1 software, as distributed by the Cochrane Collaboration. Summary relative risk (RR) estimates were calculated by using a fixed effects model (Mantel-Haenszel method) unless the results were found to be statistically heterogeneous (P < .1) through the use of a Q statistic, in which case the more conservative random effects model (DerSimonian-Laird method) was used. A subanalysis was performed based on the quality ratings, with a lower rating given to studies in which the exposed and unexposed groups differed significantly on important prognostic factors such as age, tumor stage, and time since diagnosis. Funnel plots were constructed to identify possible publication bias.

Results

Description of studies

The original search yielded 24 relevant reports, including 1 unpublished report (Bluming AZ, personal communication, 2000) with 2 separate studies. One of these and 12 published single-arm cohort studies^3-14 were excluded because they lacked a control group, but a summary of these studies can be found online (Table W1, available on the JFP Web site: www.jfponline.com). Twelve reports^15-25 met the inclusion criteria and provided data comparing the rates of recurrence or mortality among patients who used ERT after the diagnosis of breast cancer and users vs controls. Among these studies were 8 independent cohort studies from the published literature,^{15-17,20,21,23-25} one set of unpublished data from Bluming et al, and one 6-month pilot randomized controlled trial.¹⁹ One matched cohort study¹⁸ presented recurrence data for 90 patients and 180 controls who were later included in a larger, non-matched study reporting recurrence and mortality.¹⁵ Another small study²² reported only deaths from breast cancer from a data set included at least in part in another report¹⁶ and was therefore excluded. Overall, the included studies accounted for 717 subjects who used hormone replacement therapy at some time after their diagnosis of breast cancer compared with 2545 nonusers. Characteristics of included studies are summarized in the Table.

TABLE
Characteristics of included studies

Methodologic quality

The quality of the studies was variable. The only randomized controlled trial¹⁹ was a 6-month pilot study, after which the allocation code was broken and patients were free to choose whether to be on treatment. Of the cohort studies, only 1 trial²¹ began with an inception cohort that combined data from 62 patients who elected to be part of a randomized controlled trial with that from another 257 who declined to be randomized but chose on their own whether to take ERT.²¹ One study was clearly retrospective²³ ; patients with ductal carcinoma in situ were identified through a cancer registry, and their exposures and recurrences were determined through a mailed questionnaire. The remaining studies used clinic records to identify patients who had been prescribed ERT and compared those recurrence and mortality rates with those of a control group comprising the remaining clinic patients^{15,18,20,24,25} or matched subjects selected from a regional cancer surveillance database.^15,16 Although the matching process controlled for some important prognostic factors (age, stage, and time since diagnosis), post-diagnosis ERT use was not recorded in the surveillance database, so these control groups may have contained patients who took ERT at some time, thereby diluting any differences that might be observed. Conversely, none of the cohort studies reported means confirming that those for whom HRT had been prescribed actually took it regularly.

Across all studies, the studied interventions included a systemic estrogen, usually in combination with progesterone unless the subject had had a hysterectomy. The mean age at diagnosis of cancer varied among studies, from 42 to 65 years. There was also wide variability among subjects between and within the studies with regard to disease-free interval (the time between diagnosis of cancer and initiating ERT), duration of ERT use, and length of follow-up (Table). A few studies matched controls to ERT users based on these variables^16-18,24 or demonstrated that the groups were comparable.^19,21 In no study were subjects matched on type of treatment, race, estrogen receptor status, smoking, or other potentially important prognostic factors. Estrogen receptor status was unavailable for a large number of patients in these studies and could not be used for comparison.

Several studies contained methodologic flaws that resulted in important differences between comparison groups. Bluming and colleagues provided an unpublished analysis of recurrences in a sample of ERT users with previous T1N0 (stage I) cancers compared with a separate data set of similar patients who did not use ERT. In that study, tumor size was not known for 62% of the control group and 36% of the ERT group. Median follow-up was shorter in the ERT group, the tumors were smaller, the diagnoses were later, and patients were more likely to have received chemotherapy. Natrajan et al²⁰ compared 50 ERT users with 18 nonusers who left their clinic and were followed elsewhere. ERT users were younger than the nonusers and had longer follow-up. Little information was given regarding the cancer stages of the nonusers, and this was the only study primarily using hormone pellets and combining estrogen with testosterone in most patients. Habel et al²³ included only patients with ductal carcinoma in situ in a retrospective cohort study in which exposure was ascertained by mailed survey. Only 67% responded to the survey, and no baseline data comparing the ERT users with nonusers on important prognostic factors were provided. In a study by Beckman et al,²⁵ users were younger and less likely than nonusers to have grade 3 cancer (16% vs 30%), although this difference was reported to be nonsignificant. Median duration of follow-up was also longer in nonusers than in users (42 vs 37 months). In an unmatched study¹⁵ of ERT users and nonusers from the same practices in Australia, significant differences were found between groups in age, stage, and type of treatment rendered.

Because of the strong potential for bias due to baseline differences in risk of breast cancer recurrence, subanalyses included only those studies for which differences in important prognostic factors were not apparent.^16-19,21,24 In the case of the Australian study, a subset of the data, matched 2:1 on age, node status, tumor diameter, disease-free interval, and year of diagnosis, was found in an earlier report¹⁸ and used in the subanalysis.

Meta-analysis results

Overall, 8 studies reported the recurrence of breast cancer as an outcome. A meta-analysis of these studies showed that breast cancer survivors using ERT experienced no increase in the risk of recurrence compared with nonusers (8.2% vs 10.2%; RR, 0.72, 95% confidence interval [CI], 0.47–1.10). Because no statistical heterogeneity was demonstrated, a fixed effects model was used. Studies were analyzed separately depending on whether patients were matched or reportedly similar on factors such as age at diagnosis, tumor stage, and disease-free interval. Results were similar (Figure 1).

Six studies were included in a combined analysis of overall mortality (Figure 2). The ERT users in these studies experienced significantly fewer deaths (3.0%) than the nonusers (11.4%) over the combined study periods (RR, 0.18; 95% CI, 0.10–0.31; numbers needed to treat = 12). Subanalyses of those studies in which groups were comparable showed similar results (RR, 0.21; 95% CI, 0.10–0.46).

Despite the variability in study designs and subjects, all tests for heterogeneity were nonsignificant. In addition, funnel plots showed no evidence of publication bias (Figure W1, available on the JFP Web site: www.jfponline.com).

All studies, controlled or not, that reported data on control of menopausal symptoms reported significant benefit with ERT.^{2,7-9,11,19,25}

FIGURE 1
Graphic summary of studies on recurrence of breast cancer in ERT users vs nonusers

FIGURE 2
Graphic summary of studies of total mortality among users vs nonusers of estrogen replacement therapy

Discussion

This meta-analysis of observational studies in breast cancer survivors refutes the hypothesis that ERT increases the risk of breast cancer recurrence and suggests that it may in fact reduce all-cause mortality. However, conclusions drawn from observational studies can be seriously limited by potential sources of bias. For example, the studies likely had a bias by indication. That is, patients with more aggressive prognostic factors may not have been prescribed ERT, thereby making the treatment group likely to have represented a subgroup with a lower risk of recurrence than the general population used for comparison. However, several studies matched controls on important prognostic factors, and elimination of the unmatched study did not significantly affect study results. Similarly, in the absence of randomization, unmeasured confounders may have played a role. The treatment and control groups might have differed on other predictors of mortality that were not considered, such as in a healthy user effect in which subjects on ERT may have been more informed of its benefits and followed other, more healthy lifestyle behaviors than the comparison groups. They also may have been followed more closely by their physicians than the average breast cancer survivor.

In general, the subjects of the included studies over-represented patients with lower severity of disease than the general population of breast cancer survivors. Few studies included any subjects with a history of stage IV cancer (1 case with distant metastases), and several included patients with stage II or lower. Therefore, the results of this systematic review may be best generalized only to patients with lower stage disease. In addition, although subjects used ERT for as long as 32 years, the average duration of ERT use was shorter than 4 years in all but 1 study; longer follow-up is needed to truly assess the long-term effects of ERT in these high-risk patients. Available published studies also do not provide the detail needed to explore the potential contributions of estrogen receptor status or concomitant tamoxifen use.

Our finding of no significant difference in cancer recurrence associated with ERT use among patients with breast cancer is consistent with that of another recent meta-analysis.²⁶ Those researchers constructed expected control groups by using the average disease free interval before starting ERT, and known nodal status distribution from several single-arm cohort studies to calculate relative risks of recurrence for these studies. This method introduces additional bias and several assumptions that may not be warranted. For instance, risk of recurrence is much higher in the first few years after treatment for primary breast cancer. Therefore, the remarkable variability in the disease-free intervals and duration of follow-up among subjects within each of these studies make it very difficult to estimate expected recurrence rates without the detailed individual data from the original studies. Despite the “within-study” and “between-study” variabilities, the results of the individual studies are quite similar.

Observational studies, although limited, do not hold the ethical problems inherent to randomized controlled trials and are especially appropriate with a treatment as controversial as estrogen in breast cancer survivors. Available studies have produced findings contrary to conventional belief and to the theory that likens ERT to “fuel on the fire” in breast cancer. Such a theory has, until recently, made it seem unethical to justify a randomized controlled trial of ERT in these patients. However, data from some of these individual studies have provided enough support that enrollment for such trials have begun.²⁷ Previous studies of breast cancer risk with estrogen use have suggested that more than 10 years of treatment are required to see an increase in primary breast cancer,²⁸ so we may not have definitive evidence for some time. Meanwhile, there is no compelling evidence to support universal withholding of estrogen from well-informed women with symptomatic menopause, particularly among survivors of low-stage breast cancer.

Estrogen-containing hormone replacement therapy (ERT) after menopause has been implicated as a causal factor in the development of primary breast cancer.^1,2 Fearing cancer recurrence, most physicians do not offer ERT to postmenopausal women with a history of breast cancer. However, estrogen deficiency, which is especially common in women after chemotherapy, can be associated with severe symptoms, reduced quality of life, and increased risk of osteoporosis and possibly coronary artery disease. Although there are theoretical justifications to discourage the use of ERT by women at high risk for breast cancer, there is little objective evidence that hormone replacement increases the likelihood of breast cancer recurrence or of mortality among survivors of primary breast cancer. It is difficult for clinicians and patients to make rational decisions regarding ERT in these patients, given the paucity of studies and the difficulty of interpreting the few studies available.

Several observational studies have been published on the use of estrogen and/or combined estrogen–progesterone hormone replacement therapy in women who have had breast cancer. Many of these studies have reported single-institution series of outcomes among survivors who opted to take ERT for their menopausal symptoms. These studies tend to demonstrate rather unimpressive incidences of recurrence and mortality events. However, it is possible that such studies underestimate the risks because patients who are given ERT may represent a subgroup with a better prognosis than other patients (bias by indication). A smaller number of studies has used comparison groups and attempted to control for disease severity and other factors associated with recurrence.

We conducted a meta-analysis of studies comparing women who used ERT after the diagnosis of breast cancer with a control group of non-ERT users to determine whether ERT is associated with an increased risk of cancer recurrence or all-cause mortality among breast cancer survivors.

Methods

Search strategy

We identified relevant studies through independent literature searches of Medline (from 1966 to August 2001) and Cancerlit (from 1986 to August 2001) with the use of OVID software and the following search terms: estrogen replacement therapy, hormone replacement therapy, breast neoplasms, neoplasm recurrence, survivors. No language restriction was imposed. A careful review of titles and abstracts was done to identify relevant articles, and for these, the full articles were retrieved for review. Bibliographies of identified studies and review articles were examined for additional citations. Medline and Cancerlit databases were also searched by the names of authors of relevant studies to identify any missed articles. The authors of large studies and experts from our institution were asked to review the reference list for completeness and to suggest sources of unpublished data.

Inclusion criteria

Studies were considered for inclusion into the meta-analysis if they met the following criteria: (1) the population studied was women with a previous diagnosis of breast cancer, (2) the risk factor considered was the use of systemic estrogen or any combination hormone replacement therapy that included estrogen, (3) the outcome measured included the recurrence of breast cancer (whether a new or recurring primary cancer) and/or mortality, and (4) the study design was a randomized controlled trial or cohort study comparing women who used ERT after their breast cancer diagnosis with a concurrent, historical, or population-based control group of women who did not. Single-arm cohort studies were retrieved and summarized qualitatively but not included in the statistical analysis. If more than 1 publication was identified which reported the same data, the study with the most recent or complete data was selected for the analysis. We independently reviewed all studies for inclusion, and any differences were resolved through consensus.

Validity assessment

All included studies were assessed for validity by 2 independent reviewers, blinded to study results, for the following characteristics: (1) prospective data collection, (2) clear subject inclusion criteria, (3) reliability of exposure, (4) similarity between exposed and unexposed groups, (5) loss to follow-up, and (6) reliability of outcome assessment. When threats to study validity were identified, attempts were made to determine whether these threats were likely to significantly influence the results of the study and to estimate the direction of the influence of these threats on the resulting data. Because baseline differences between the study groups are such an important threat to the validity of these studies, the studies were graded as higher quality and lower quality based on whether significant differences in known prognostic factors existed.

Data management and analysis

A data extraction form was created to aid consistent recording of data from all studies, and both investigators extracted data independently. Any discrepancies in data interpretation or abstraction were resolved through consensus. Study characteristics and results for single-arm cohort studies were presented descriptively. For controlled studies, data were entered as dichotomous variables into Review Manager 4.1 software, as distributed by the Cochrane Collaboration. Summary relative risk (RR) estimates were calculated by using a fixed effects model (Mantel-Haenszel method) unless the results were found to be statistically heterogeneous (P < .1) through the use of a Q statistic, in which case the more conservative random effects model (DerSimonian-Laird method) was used. A subanalysis was performed based on the quality ratings, with a lower rating given to studies in which the exposed and unexposed groups differed significantly on important prognostic factors such as age, tumor stage, and time since diagnosis. Funnel plots were constructed to identify possible publication bias.

Results

Description of studies

The original search yielded 24 relevant reports, including 1 unpublished report (Bluming AZ, personal communication, 2000) with 2 separate studies. One of these and 12 published single-arm cohort studies^3-14 were excluded because they lacked a control group, but a summary of these studies can be found online (Table W1, available on the JFP Web site: www.jfponline.com). Twelve reports^15-25 met the inclusion criteria and provided data comparing the rates of recurrence or mortality among patients who used ERT after the diagnosis of breast cancer and users vs controls. Among these studies were 8 independent cohort studies from the published literature,^{15-17,20,21,23-25} one set of unpublished data from Bluming et al, and one 6-month pilot randomized controlled trial.¹⁹ One matched cohort study¹⁸ presented recurrence data for 90 patients and 180 controls who were later included in a larger, non-matched study reporting recurrence and mortality.¹⁵ Another small study²² reported only deaths from breast cancer from a data set included at least in part in another report¹⁶ and was therefore excluded. Overall, the included studies accounted for 717 subjects who used hormone replacement therapy at some time after their diagnosis of breast cancer compared with 2545 nonusers. Characteristics of included studies are summarized in the Table.

TABLE
Characteristics of included studies

Methodologic quality

The quality of the studies was variable. The only randomized controlled trial¹⁹ was a 6-month pilot study, after which the allocation code was broken and patients were free to choose whether to be on treatment. Of the cohort studies, only 1 trial²¹ began with an inception cohort that combined data from 62 patients who elected to be part of a randomized controlled trial with that from another 257 who declined to be randomized but chose on their own whether to take ERT.²¹ One study was clearly retrospective²³ ; patients with ductal carcinoma in situ were identified through a cancer registry, and their exposures and recurrences were determined through a mailed questionnaire. The remaining studies used clinic records to identify patients who had been prescribed ERT and compared those recurrence and mortality rates with those of a control group comprising the remaining clinic patients^{15,18,20,24,25} or matched subjects selected from a regional cancer surveillance database.^15,16 Although the matching process controlled for some important prognostic factors (age, stage, and time since diagnosis), post-diagnosis ERT use was not recorded in the surveillance database, so these control groups may have contained patients who took ERT at some time, thereby diluting any differences that might be observed. Conversely, none of the cohort studies reported means confirming that those for whom HRT had been prescribed actually took it regularly.

Across all studies, the studied interventions included a systemic estrogen, usually in combination with progesterone unless the subject had had a hysterectomy. The mean age at diagnosis of cancer varied among studies, from 42 to 65 years. There was also wide variability among subjects between and within the studies with regard to disease-free interval (the time between diagnosis of cancer and initiating ERT), duration of ERT use, and length of follow-up (Table). A few studies matched controls to ERT users based on these variables^16-18,24 or demonstrated that the groups were comparable.^19,21 In no study were subjects matched on type of treatment, race, estrogen receptor status, smoking, or other potentially important prognostic factors. Estrogen receptor status was unavailable for a large number of patients in these studies and could not be used for comparison.

Several studies contained methodologic flaws that resulted in important differences between comparison groups. Bluming and colleagues provided an unpublished analysis of recurrences in a sample of ERT users with previous T1N0 (stage I) cancers compared with a separate data set of similar patients who did not use ERT. In that study, tumor size was not known for 62% of the control group and 36% of the ERT group. Median follow-up was shorter in the ERT group, the tumors were smaller, the diagnoses were later, and patients were more likely to have received chemotherapy. Natrajan et al²⁰ compared 50 ERT users with 18 nonusers who left their clinic and were followed elsewhere. ERT users were younger than the nonusers and had longer follow-up. Little information was given regarding the cancer stages of the nonusers, and this was the only study primarily using hormone pellets and combining estrogen with testosterone in most patients. Habel et al²³ included only patients with ductal carcinoma in situ in a retrospective cohort study in which exposure was ascertained by mailed survey. Only 67% responded to the survey, and no baseline data comparing the ERT users with nonusers on important prognostic factors were provided. In a study by Beckman et al,²⁵ users were younger and less likely than nonusers to have grade 3 cancer (16% vs 30%), although this difference was reported to be nonsignificant. Median duration of follow-up was also longer in nonusers than in users (42 vs 37 months). In an unmatched study¹⁵ of ERT users and nonusers from the same practices in Australia, significant differences were found between groups in age, stage, and type of treatment rendered.

Because of the strong potential for bias due to baseline differences in risk of breast cancer recurrence, subanalyses included only those studies for which differences in important prognostic factors were not apparent.^16-19,21,24 In the case of the Australian study, a subset of the data, matched 2:1 on age, node status, tumor diameter, disease-free interval, and year of diagnosis, was found in an earlier report¹⁸ and used in the subanalysis.

Meta-analysis results

Overall, 8 studies reported the recurrence of breast cancer as an outcome. A meta-analysis of these studies showed that breast cancer survivors using ERT experienced no increase in the risk of recurrence compared with nonusers (8.2% vs 10.2%; RR, 0.72, 95% confidence interval [CI], 0.47–1.10). Because no statistical heterogeneity was demonstrated, a fixed effects model was used. Studies were analyzed separately depending on whether patients were matched or reportedly similar on factors such as age at diagnosis, tumor stage, and disease-free interval. Results were similar (Figure 1).

Six studies were included in a combined analysis of overall mortality (Figure 2). The ERT users in these studies experienced significantly fewer deaths (3.0%) than the nonusers (11.4%) over the combined study periods (RR, 0.18; 95% CI, 0.10–0.31; numbers needed to treat = 12). Subanalyses of those studies in which groups were comparable showed similar results (RR, 0.21; 95% CI, 0.10–0.46).

Despite the variability in study designs and subjects, all tests for heterogeneity were nonsignificant. In addition, funnel plots showed no evidence of publication bias (Figure W1, available on the JFP Web site: www.jfponline.com).

All studies, controlled or not, that reported data on control of menopausal symptoms reported significant benefit with ERT.^{2,7-9,11,19,25}

FIGURE 1
Graphic summary of studies on recurrence of breast cancer in ERT users vs nonusers

FIGURE 2
Graphic summary of studies of total mortality among users vs nonusers of estrogen replacement therapy

Discussion

This meta-analysis of observational studies in breast cancer survivors refutes the hypothesis that ERT increases the risk of breast cancer recurrence and suggests that it may in fact reduce all-cause mortality. However, conclusions drawn from observational studies can be seriously limited by potential sources of bias. For example, the studies likely had a bias by indication. That is, patients with more aggressive prognostic factors may not have been prescribed ERT, thereby making the treatment group likely to have represented a subgroup with a lower risk of recurrence than the general population used for comparison. However, several studies matched controls on important prognostic factors, and elimination of the unmatched study did not significantly affect study results. Similarly, in the absence of randomization, unmeasured confounders may have played a role. The treatment and control groups might have differed on other predictors of mortality that were not considered, such as in a healthy user effect in which subjects on ERT may have been more informed of its benefits and followed other, more healthy lifestyle behaviors than the comparison groups. They also may have been followed more closely by their physicians than the average breast cancer survivor.

In general, the subjects of the included studies over-represented patients with lower severity of disease than the general population of breast cancer survivors. Few studies included any subjects with a history of stage IV cancer (1 case with distant metastases), and several included patients with stage II or lower. Therefore, the results of this systematic review may be best generalized only to patients with lower stage disease. In addition, although subjects used ERT for as long as 32 years, the average duration of ERT use was shorter than 4 years in all but 1 study; longer follow-up is needed to truly assess the long-term effects of ERT in these high-risk patients. Available published studies also do not provide the detail needed to explore the potential contributions of estrogen receptor status or concomitant tamoxifen use.

Our finding of no significant difference in cancer recurrence associated with ERT use among patients with breast cancer is consistent with that of another recent meta-analysis.²⁶ Those researchers constructed expected control groups by using the average disease free interval before starting ERT, and known nodal status distribution from several single-arm cohort studies to calculate relative risks of recurrence for these studies. This method introduces additional bias and several assumptions that may not be warranted. For instance, risk of recurrence is much higher in the first few years after treatment for primary breast cancer. Therefore, the remarkable variability in the disease-free intervals and duration of follow-up among subjects within each of these studies make it very difficult to estimate expected recurrence rates without the detailed individual data from the original studies. Despite the “within-study” and “between-study” variabilities, the results of the individual studies are quite similar.

Observational studies, although limited, do not hold the ethical problems inherent to randomized controlled trials and are especially appropriate with a treatment as controversial as estrogen in breast cancer survivors. Available studies have produced findings contrary to conventional belief and to the theory that likens ERT to “fuel on the fire” in breast cancer. Such a theory has, until recently, made it seem unethical to justify a randomized controlled trial of ERT in these patients. However, data from some of these individual studies have provided enough support that enrollment for such trials have begun.²⁷ Previous studies of breast cancer risk with estrogen use have suggested that more than 10 years of treatment are required to see an increase in primary breast cancer,²⁸ so we may not have definitive evidence for some time. Meanwhile, there is no compelling evidence to support universal withholding of estrogen from well-informed women with symptomatic menopause, particularly among survivors of low-stage breast cancer.

Estrogen-containing hormone replacement therapy (ERT) after menopause has been implicated as a causal factor in the development of primary breast cancer.^1,2 Fearing cancer recurrence, most physicians do not offer ERT to postmenopausal women with a history of breast cancer. However, estrogen deficiency, which is especially common in women after chemotherapy, can be associated with severe symptoms, reduced quality of life, and increased risk of osteoporosis and possibly coronary artery disease. Although there are theoretical justifications to discourage the use of ERT by women at high risk for breast cancer, there is little objective evidence that hormone replacement increases the likelihood of breast cancer recurrence or of mortality among survivors of primary breast cancer. It is difficult for clinicians and patients to make rational decisions regarding ERT in these patients, given the paucity of studies and the difficulty of interpreting the few studies available.

Several observational studies have been published on the use of estrogen and/or combined estrogen–progesterone hormone replacement therapy in women who have had breast cancer. Many of these studies have reported single-institution series of outcomes among survivors who opted to take ERT for their menopausal symptoms. These studies tend to demonstrate rather unimpressive incidences of recurrence and mortality events. However, it is possible that such studies underestimate the risks because patients who are given ERT may represent a subgroup with a better prognosis than other patients (bias by indication). A smaller number of studies has used comparison groups and attempted to control for disease severity and other factors associated with recurrence.

We conducted a meta-analysis of studies comparing women who used ERT after the diagnosis of breast cancer with a control group of non-ERT users to determine whether ERT is associated with an increased risk of cancer recurrence or all-cause mortality among breast cancer survivors.

Methods

Search strategy

We identified relevant studies through independent literature searches of Medline (from 1966 to August 2001) and Cancerlit (from 1986 to August 2001) with the use of OVID software and the following search terms: estrogen replacement therapy, hormone replacement therapy, breast neoplasms, neoplasm recurrence, survivors. No language restriction was imposed. A careful review of titles and abstracts was done to identify relevant articles, and for these, the full articles were retrieved for review. Bibliographies of identified studies and review articles were examined for additional citations. Medline and Cancerlit databases were also searched by the names of authors of relevant studies to identify any missed articles. The authors of large studies and experts from our institution were asked to review the reference list for completeness and to suggest sources of unpublished data.

Inclusion criteria

Studies were considered for inclusion into the meta-analysis if they met the following criteria: (1) the population studied was women with a previous diagnosis of breast cancer, (2) the risk factor considered was the use of systemic estrogen or any combination hormone replacement therapy that included estrogen, (3) the outcome measured included the recurrence of breast cancer (whether a new or recurring primary cancer) and/or mortality, and (4) the study design was a randomized controlled trial or cohort study comparing women who used ERT after their breast cancer diagnosis with a concurrent, historical, or population-based control group of women who did not. Single-arm cohort studies were retrieved and summarized qualitatively but not included in the statistical analysis. If more than 1 publication was identified which reported the same data, the study with the most recent or complete data was selected for the analysis. We independently reviewed all studies for inclusion, and any differences were resolved through consensus.

Validity assessment

All included studies were assessed for validity by 2 independent reviewers, blinded to study results, for the following characteristics: (1) prospective data collection, (2) clear subject inclusion criteria, (3) reliability of exposure, (4) similarity between exposed and unexposed groups, (5) loss to follow-up, and (6) reliability of outcome assessment. When threats to study validity were identified, attempts were made to determine whether these threats were likely to significantly influence the results of the study and to estimate the direction of the influence of these threats on the resulting data. Because baseline differences between the study groups are such an important threat to the validity of these studies, the studies were graded as higher quality and lower quality based on whether significant differences in known prognostic factors existed.

Data management and analysis

A data extraction form was created to aid consistent recording of data from all studies, and both investigators extracted data independently. Any discrepancies in data interpretation or abstraction were resolved through consensus. Study characteristics and results for single-arm cohort studies were presented descriptively. For controlled studies, data were entered as dichotomous variables into Review Manager 4.1 software, as distributed by the Cochrane Collaboration. Summary relative risk (RR) estimates were calculated by using a fixed effects model (Mantel-Haenszel method) unless the results were found to be statistically heterogeneous (P < .1) through the use of a Q statistic, in which case the more conservative random effects model (DerSimonian-Laird method) was used. A subanalysis was performed based on the quality ratings, with a lower rating given to studies in which the exposed and unexposed groups differed significantly on important prognostic factors such as age, tumor stage, and time since diagnosis. Funnel plots were constructed to identify possible publication bias.

Results

Description of studies

The original search yielded 24 relevant reports, including 1 unpublished report (Bluming AZ, personal communication, 2000) with 2 separate studies. One of these and 12 published single-arm cohort studies^3-14 were excluded because they lacked a control group, but a summary of these studies can be found online (Table W1, available on the JFP Web site: www.jfponline.com). Twelve reports^15-25 met the inclusion criteria and provided data comparing the rates of recurrence or mortality among patients who used ERT after the diagnosis of breast cancer and users vs controls. Among these studies were 8 independent cohort studies from the published literature,^{15-17,20,21,23-25} one set of unpublished data from Bluming et al, and one 6-month pilot randomized controlled trial.¹⁹ One matched cohort study¹⁸ presented recurrence data for 90 patients and 180 controls who were later included in a larger, non-matched study reporting recurrence and mortality.¹⁵ Another small study²² reported only deaths from breast cancer from a data set included at least in part in another report¹⁶ and was therefore excluded. Overall, the included studies accounted for 717 subjects who used hormone replacement therapy at some time after their diagnosis of breast cancer compared with 2545 nonusers. Characteristics of included studies are summarized in the Table.

TABLE
Characteristics of included studies

Methodologic quality

The quality of the studies was variable. The only randomized controlled trial¹⁹ was a 6-month pilot study, after which the allocation code was broken and patients were free to choose whether to be on treatment. Of the cohort studies, only 1 trial²¹ began with an inception cohort that combined data from 62 patients who elected to be part of a randomized controlled trial with that from another 257 who declined to be randomized but chose on their own whether to take ERT.²¹ One study was clearly retrospective²³ ; patients with ductal carcinoma in situ were identified through a cancer registry, and their exposures and recurrences were determined through a mailed questionnaire. The remaining studies used clinic records to identify patients who had been prescribed ERT and compared those recurrence and mortality rates with those of a control group comprising the remaining clinic patients^{15,18,20,24,25} or matched subjects selected from a regional cancer surveillance database.^15,16 Although the matching process controlled for some important prognostic factors (age, stage, and time since diagnosis), post-diagnosis ERT use was not recorded in the surveillance database, so these control groups may have contained patients who took ERT at some time, thereby diluting any differences that might be observed. Conversely, none of the cohort studies reported means confirming that those for whom HRT had been prescribed actually took it regularly.

Across all studies, the studied interventions included a systemic estrogen, usually in combination with progesterone unless the subject had had a hysterectomy. The mean age at diagnosis of cancer varied among studies, from 42 to 65 years. There was also wide variability among subjects between and within the studies with regard to disease-free interval (the time between diagnosis of cancer and initiating ERT), duration of ERT use, and length of follow-up (Table). A few studies matched controls to ERT users based on these variables^16-18,24 or demonstrated that the groups were comparable.^19,21 In no study were subjects matched on type of treatment, race, estrogen receptor status, smoking, or other potentially important prognostic factors. Estrogen receptor status was unavailable for a large number of patients in these studies and could not be used for comparison.

Several studies contained methodologic flaws that resulted in important differences between comparison groups. Bluming and colleagues provided an unpublished analysis of recurrences in a sample of ERT users with previous T1N0 (stage I) cancers compared with a separate data set of similar patients who did not use ERT. In that study, tumor size was not known for 62% of the control group and 36% of the ERT group. Median follow-up was shorter in the ERT group, the tumors were smaller, the diagnoses were later, and patients were more likely to have received chemotherapy. Natrajan et al²⁰ compared 50 ERT users with 18 nonusers who left their clinic and were followed elsewhere. ERT users were younger than the nonusers and had longer follow-up. Little information was given regarding the cancer stages of the nonusers, and this was the only study primarily using hormone pellets and combining estrogen with testosterone in most patients. Habel et al²³ included only patients with ductal carcinoma in situ in a retrospective cohort study in which exposure was ascertained by mailed survey. Only 67% responded to the survey, and no baseline data comparing the ERT users with nonusers on important prognostic factors were provided. In a study by Beckman et al,²⁵ users were younger and less likely than nonusers to have grade 3 cancer (16% vs 30%), although this difference was reported to be nonsignificant. Median duration of follow-up was also longer in nonusers than in users (42 vs 37 months). In an unmatched study¹⁵ of ERT users and nonusers from the same practices in Australia, significant differences were found between groups in age, stage, and type of treatment rendered.

Because of the strong potential for bias due to baseline differences in risk of breast cancer recurrence, subanalyses included only those studies for which differences in important prognostic factors were not apparent.^16-19,21,24 In the case of the Australian study, a subset of the data, matched 2:1 on age, node status, tumor diameter, disease-free interval, and year of diagnosis, was found in an earlier report¹⁸ and used in the subanalysis.

Meta-analysis results

Overall, 8 studies reported the recurrence of breast cancer as an outcome. A meta-analysis of these studies showed that breast cancer survivors using ERT experienced no increase in the risk of recurrence compared with nonusers (8.2% vs 10.2%; RR, 0.72, 95% confidence interval [CI], 0.47–1.10). Because no statistical heterogeneity was demonstrated, a fixed effects model was used. Studies were analyzed separately depending on whether patients were matched or reportedly similar on factors such as age at diagnosis, tumor stage, and disease-free interval. Results were similar (Figure 1).

Six studies were included in a combined analysis of overall mortality (Figure 2). The ERT users in these studies experienced significantly fewer deaths (3.0%) than the nonusers (11.4%) over the combined study periods (RR, 0.18; 95% CI, 0.10–0.31; numbers needed to treat = 12). Subanalyses of those studies in which groups were comparable showed similar results (RR, 0.21; 95% CI, 0.10–0.46).

Despite the variability in study designs and subjects, all tests for heterogeneity were nonsignificant. In addition, funnel plots showed no evidence of publication bias (Figure W1, available on the JFP Web site: www.jfponline.com).

All studies, controlled or not, that reported data on control of menopausal symptoms reported significant benefit with ERT.^{2,7-9,11,19,25}

FIGURE 1
Graphic summary of studies on recurrence of breast cancer in ERT users vs nonusers

FIGURE 2
Graphic summary of studies of total mortality among users vs nonusers of estrogen replacement therapy

Discussion

This meta-analysis of observational studies in breast cancer survivors refutes the hypothesis that ERT increases the risk of breast cancer recurrence and suggests that it may in fact reduce all-cause mortality. However, conclusions drawn from observational studies can be seriously limited by potential sources of bias. For example, the studies likely had a bias by indication. That is, patients with more aggressive prognostic factors may not have been prescribed ERT, thereby making the treatment group likely to have represented a subgroup with a lower risk of recurrence than the general population used for comparison. However, several studies matched controls on important prognostic factors, and elimination of the unmatched study did not significantly affect study results. Similarly, in the absence of randomization, unmeasured confounders may have played a role. The treatment and control groups might have differed on other predictors of mortality that were not considered, such as in a healthy user effect in which subjects on ERT may have been more informed of its benefits and followed other, more healthy lifestyle behaviors than the comparison groups. They also may have been followed more closely by their physicians than the average breast cancer survivor.

In general, the subjects of the included studies over-represented patients with lower severity of disease than the general population of breast cancer survivors. Few studies included any subjects with a history of stage IV cancer (1 case with distant metastases), and several included patients with stage II or lower. Therefore, the results of this systematic review may be best generalized only to patients with lower stage disease. In addition, although subjects used ERT for as long as 32 years, the average duration of ERT use was shorter than 4 years in all but 1 study; longer follow-up is needed to truly assess the long-term effects of ERT in these high-risk patients. Available published studies also do not provide the detail needed to explore the potential contributions of estrogen receptor status or concomitant tamoxifen use.

Our finding of no significant difference in cancer recurrence associated with ERT use among patients with breast cancer is consistent with that of another recent meta-analysis.²⁶ Those researchers constructed expected control groups by using the average disease free interval before starting ERT, and known nodal status distribution from several single-arm cohort studies to calculate relative risks of recurrence for these studies. This method introduces additional bias and several assumptions that may not be warranted. For instance, risk of recurrence is much higher in the first few years after treatment for primary breast cancer. Therefore, the remarkable variability in the disease-free intervals and duration of follow-up among subjects within each of these studies make it very difficult to estimate expected recurrence rates without the detailed individual data from the original studies. Despite the “within-study” and “between-study” variabilities, the results of the individual studies are quite similar.

Observational studies, although limited, do not hold the ethical problems inherent to randomized controlled trials and are especially appropriate with a treatment as controversial as estrogen in breast cancer survivors. Available studies have produced findings contrary to conventional belief and to the theory that likens ERT to “fuel on the fire” in breast cancer. Such a theory has, until recently, made it seem unethical to justify a randomized controlled trial of ERT in these patients. However, data from some of these individual studies have provided enough support that enrollment for such trials have begun.²⁷ Previous studies of breast cancer risk with estrogen use have suggested that more than 10 years of treatment are required to see an increase in primary breast cancer,²⁸ so we may not have definitive evidence for some time. Meanwhile, there is no compelling evidence to support universal withholding of estrogen from well-informed women with symptomatic menopause, particularly among survivors of low-stage breast cancer.

BACKGROUND: Syncope is a very common complaint in primary care and is often very difficult to diagnose. Most previous studies have focused only on high-risk patients and on selected diagnostic tests.

POPULATION STUDIED: All patients were eligible for inclusion who were 18 years or older and who presented to the emergency department (ED) of a large primary and tertiary care teaching hospital with a chief complaint of syncope. Syncope was defined as a sudden transient loss of consciousness with an inability to maintain postural tone, with spontaneous recovery. Patients with a seizure disorder, vertigo, dizziness, coma, or shock were excluded. Of 788 eligible patients, 115 did not complete the standardized evaluation, and 23 refused to participate. The remaining 650 patients ranged in age from 18 to 93 years (mean age = 60 years) and represented both men and women equally.

STUDY DESIGN AND VALIDITY: Patients underwent a standard evaluation including a complete history and physical examination, laboratory evaluation (hematocrit, serum creatine kinase and glucose), electrocardiogram (EKG), testing for orthostatic hypotension, and bilateral carotid massage unless contraindicated. If this approach did not lead to a diagnosis, a second series of tests was conducted: 24-hour Holter monitoring, ambulatory loop monitoring or electrophysiologic studies as guided by an abnormal EKG, or a tilt-table test to identify neurocardiogenic or orthostatic syncope. A committee of 2 internists and a cardiologist reviewed the findings of each case, and explicit and reproducible criteria were used to verify the etiology of the syncope. Some of the diagnoses relied on clinical judgment, since no gold standard reference was available.

OUTCOMES MEASURED: The cause of syncope for each patient based on the sequential evaluation. Follow-up information about mortality and recurrent syncope was obtained at 3 6-month intervals from primary physicians, patients, or their families.

RESULTS: A diagnosis was made in 69% of patients following the initial round of examination. In this group, vasovagal disorders accounted for 53% of the diagnoses, along with orthostatic hypotension (35%), arrhythmia (5%), and other causes (5%). Targeted testing was performed in 67 patients, and the suspected diagnosis was confirmed in an additional 49 patients (8%). Extensive cardiovascular testing of 122 of the remaining 155 patients established a diagnosis in 30 of them through the use of Holter or ambulatory loop monitoring, tilt-table, or electrophysiologic testing. No etiology was found in 92 patients (14%). Overall mortality (9% over 18 months) and sudden death were more common among patients with cardiac causes of syncope compared with other causes of syncope.

BACKGROUND: Syncope is a very common complaint in primary care and is often very difficult to diagnose. Most previous studies have focused only on high-risk patients and on selected diagnostic tests.

POPULATION STUDIED: All patients were eligible for inclusion who were 18 years or older and who presented to the emergency department (ED) of a large primary and tertiary care teaching hospital with a chief complaint of syncope. Syncope was defined as a sudden transient loss of consciousness with an inability to maintain postural tone, with spontaneous recovery. Patients with a seizure disorder, vertigo, dizziness, coma, or shock were excluded. Of 788 eligible patients, 115 did not complete the standardized evaluation, and 23 refused to participate. The remaining 650 patients ranged in age from 18 to 93 years (mean age = 60 years) and represented both men and women equally.

STUDY DESIGN AND VALIDITY: Patients underwent a standard evaluation including a complete history and physical examination, laboratory evaluation (hematocrit, serum creatine kinase and glucose), electrocardiogram (EKG), testing for orthostatic hypotension, and bilateral carotid massage unless contraindicated. If this approach did not lead to a diagnosis, a second series of tests was conducted: 24-hour Holter monitoring, ambulatory loop monitoring or electrophysiologic studies as guided by an abnormal EKG, or a tilt-table test to identify neurocardiogenic or orthostatic syncope. A committee of 2 internists and a cardiologist reviewed the findings of each case, and explicit and reproducible criteria were used to verify the etiology of the syncope. Some of the diagnoses relied on clinical judgment, since no gold standard reference was available.

OUTCOMES MEASURED: The cause of syncope for each patient based on the sequential evaluation. Follow-up information about mortality and recurrent syncope was obtained at 3 6-month intervals from primary physicians, patients, or their families.

RESULTS: A diagnosis was made in 69% of patients following the initial round of examination. In this group, vasovagal disorders accounted for 53% of the diagnoses, along with orthostatic hypotension (35%), arrhythmia (5%), and other causes (5%). Targeted testing was performed in 67 patients, and the suspected diagnosis was confirmed in an additional 49 patients (8%). Extensive cardiovascular testing of 122 of the remaining 155 patients established a diagnosis in 30 of them through the use of Holter or ambulatory loop monitoring, tilt-table, or electrophysiologic testing. No etiology was found in 92 patients (14%). Overall mortality (9% over 18 months) and sudden death were more common among patients with cardiac causes of syncope compared with other causes of syncope.

BACKGROUND: Syncope is a very common complaint in primary care and is often very difficult to diagnose. Most previous studies have focused only on high-risk patients and on selected diagnostic tests.

POPULATION STUDIED: All patients were eligible for inclusion who were 18 years or older and who presented to the emergency department (ED) of a large primary and tertiary care teaching hospital with a chief complaint of syncope. Syncope was defined as a sudden transient loss of consciousness with an inability to maintain postural tone, with spontaneous recovery. Patients with a seizure disorder, vertigo, dizziness, coma, or shock were excluded. Of 788 eligible patients, 115 did not complete the standardized evaluation, and 23 refused to participate. The remaining 650 patients ranged in age from 18 to 93 years (mean age = 60 years) and represented both men and women equally.

STUDY DESIGN AND VALIDITY: Patients underwent a standard evaluation including a complete history and physical examination, laboratory evaluation (hematocrit, serum creatine kinase and glucose), electrocardiogram (EKG), testing for orthostatic hypotension, and bilateral carotid massage unless contraindicated. If this approach did not lead to a diagnosis, a second series of tests was conducted: 24-hour Holter monitoring, ambulatory loop monitoring or electrophysiologic studies as guided by an abnormal EKG, or a tilt-table test to identify neurocardiogenic or orthostatic syncope. A committee of 2 internists and a cardiologist reviewed the findings of each case, and explicit and reproducible criteria were used to verify the etiology of the syncope. Some of the diagnoses relied on clinical judgment, since no gold standard reference was available.

OUTCOMES MEASURED: The cause of syncope for each patient based on the sequential evaluation. Follow-up information about mortality and recurrent syncope was obtained at 3 6-month intervals from primary physicians, patients, or their families.

RESULTS: A diagnosis was made in 69% of patients following the initial round of examination. In this group, vasovagal disorders accounted for 53% of the diagnoses, along with orthostatic hypotension (35%), arrhythmia (5%), and other causes (5%). Targeted testing was performed in 67 patients, and the suspected diagnosis was confirmed in an additional 49 patients (8%). Extensive cardiovascular testing of 122 of the remaining 155 patients established a diagnosis in 30 of them through the use of Holter or ambulatory loop monitoring, tilt-table, or electrophysiologic testing. No etiology was found in 92 patients (14%). Overall mortality (9% over 18 months) and sudden death were more common among patients with cardiac causes of syncope compared with other causes of syncope.

BACKGROUND: Acute conjunctivitis (pinkeye) accounts for 1% to 4% of primary care office visits. Although often viral, common bacterial pathogens include Streptococcus pneumoniae, Haemophilus influenza, and Staphylococcus aureus. Antibiotics are commonly prescribed in the belief that they hasten recovery and reduce complications, although little data are available to support this assertion.

POPULATION STUDIED: The authors of this meta-analysis performed a comprehensive search of MEDLINE, The Cochrane Library, the Cochrane Eyes and Vision Group Register, Science Citation Index, the bibliographies of retrieved reports, and inquiry to authors and pharmaceutical companies producing relevant ophthalmic preparations. They identified 5 randomized controlled trials comparing topical antibiotics with placebo for the treatment of bacterial conjunctivitis. Two trials were excluded because of incomplete blinding or deficient reporting of data. The remaining 3 trials involved 527 patients of various ages (1 studied children only, 1 did not specify, and 1 studied adults) treated with: (1) polymyxin and bacitracin, (2) ciprofloxacin or tobramycin, or (3) norfloxacin.

STUDY DESIGN AND VALIDITY: Two authors determined whether studies met inclusion criteria and graded eligible studies for quality. Relative benefit (relative risk of clinical or microbial remission) was calculated using Review Manager software (Cochrane Collaboration).The 3 included studies were not homogeneous in their populations studied (children vs adults), the method of diagnosis (culture vs clinical assessment), and the outcomes measured (clinical vs microbiologic resolution, time to resolution measured). However, the results of the 3 studies were statistically homogenous, supporting the combination of the results by meta-analysis. The criteria used to make clinical assessments for inclusion or for evaluating outcomes are not discussed, making it difficult to assess their validity. In 1 study, data were combined from of 2 trials, 1 comparing the use of ciprofloxacin with placebo, and the other comparing ciprofloxacin with tobramycin. Details about the nature of the allocation process for this study are lacking, but exclusion of this study does not significantly change the results. The greatest limitation of this study is its applicability to the primary care setting. The majority of the patients come from hospital-based clinics, and 2 of the 3 studies used subjects with culture-confirmed bacterial conjunctivitis, while most patients in primary care are treated empirically without culture confirmation.

OUTCOMES MEASURED: Outcomes included clinical cure (not otherwise described) or microbiologic cure (by culture) at 2 time frames: early (2-5 days) and late (6-10 days). One of the 3 studies measured microbiologic remission only at day 3. results By clinical cure, conjunctivitis was resolved by day 2 to 5 in 64% of patients using placebo and in 83% of those using topical antibiotics (relative risk [RR]=1.31; 95% confidence interval [CI], 1.11-1.55; number needed to treat [NNT]=5.3). This relative benefit was not statistically significant after 5 days (RR=1.27; 95% CI, 1.00-1.61) in the 1 study providing evaluation at this time. The relative benefit was also smaller in the study that used clinical assessment to diagnose bacterial infection (RR=1.31; 95% CI, 1.11-1.55; NNT=6.25). Microbiologic remission was also more often attained in the patients receiving antibiotics than in those on placebo, with a relative benefit of 1.71 (95% CI, 1.32-2.21), which remained stable at 6 to 10 days as well. No serious adverse reactions were reported in either the treatment groups or the placebo groups.

BACKGROUND: Acute conjunctivitis (pinkeye) accounts for 1% to 4% of primary care office visits. Although often viral, common bacterial pathogens include Streptococcus pneumoniae, Haemophilus influenza, and Staphylococcus aureus. Antibiotics are commonly prescribed in the belief that they hasten recovery and reduce complications, although little data are available to support this assertion.

POPULATION STUDIED: The authors of this meta-analysis performed a comprehensive search of MEDLINE, The Cochrane Library, the Cochrane Eyes and Vision Group Register, Science Citation Index, the bibliographies of retrieved reports, and inquiry to authors and pharmaceutical companies producing relevant ophthalmic preparations. They identified 5 randomized controlled trials comparing topical antibiotics with placebo for the treatment of bacterial conjunctivitis. Two trials were excluded because of incomplete blinding or deficient reporting of data. The remaining 3 trials involved 527 patients of various ages (1 studied children only, 1 did not specify, and 1 studied adults) treated with: (1) polymyxin and bacitracin, (2) ciprofloxacin or tobramycin, or (3) norfloxacin.

STUDY DESIGN AND VALIDITY: Two authors determined whether studies met inclusion criteria and graded eligible studies for quality. Relative benefit (relative risk of clinical or microbial remission) was calculated using Review Manager software (Cochrane Collaboration).The 3 included studies were not homogeneous in their populations studied (children vs adults), the method of diagnosis (culture vs clinical assessment), and the outcomes measured (clinical vs microbiologic resolution, time to resolution measured). However, the results of the 3 studies were statistically homogenous, supporting the combination of the results by meta-analysis. The criteria used to make clinical assessments for inclusion or for evaluating outcomes are not discussed, making it difficult to assess their validity. In 1 study, data were combined from of 2 trials, 1 comparing the use of ciprofloxacin with placebo, and the other comparing ciprofloxacin with tobramycin. Details about the nature of the allocation process for this study are lacking, but exclusion of this study does not significantly change the results. The greatest limitation of this study is its applicability to the primary care setting. The majority of the patients come from hospital-based clinics, and 2 of the 3 studies used subjects with culture-confirmed bacterial conjunctivitis, while most patients in primary care are treated empirically without culture confirmation.

OUTCOMES MEASURED: Outcomes included clinical cure (not otherwise described) or microbiologic cure (by culture) at 2 time frames: early (2-5 days) and late (6-10 days). One of the 3 studies measured microbiologic remission only at day 3. results By clinical cure, conjunctivitis was resolved by day 2 to 5 in 64% of patients using placebo and in 83% of those using topical antibiotics (relative risk [RR]=1.31; 95% confidence interval [CI], 1.11-1.55; number needed to treat [NNT]=5.3). This relative benefit was not statistically significant after 5 days (RR=1.27; 95% CI, 1.00-1.61) in the 1 study providing evaluation at this time. The relative benefit was also smaller in the study that used clinical assessment to diagnose bacterial infection (RR=1.31; 95% CI, 1.11-1.55; NNT=6.25). Microbiologic remission was also more often attained in the patients receiving antibiotics than in those on placebo, with a relative benefit of 1.71 (95% CI, 1.32-2.21), which remained stable at 6 to 10 days as well. No serious adverse reactions were reported in either the treatment groups or the placebo groups.

BACKGROUND: Acute conjunctivitis (pinkeye) accounts for 1% to 4% of primary care office visits. Although often viral, common bacterial pathogens include Streptococcus pneumoniae, Haemophilus influenza, and Staphylococcus aureus. Antibiotics are commonly prescribed in the belief that they hasten recovery and reduce complications, although little data are available to support this assertion.

POPULATION STUDIED: The authors of this meta-analysis performed a comprehensive search of MEDLINE, The Cochrane Library, the Cochrane Eyes and Vision Group Register, Science Citation Index, the bibliographies of retrieved reports, and inquiry to authors and pharmaceutical companies producing relevant ophthalmic preparations. They identified 5 randomized controlled trials comparing topical antibiotics with placebo for the treatment of bacterial conjunctivitis. Two trials were excluded because of incomplete blinding or deficient reporting of data. The remaining 3 trials involved 527 patients of various ages (1 studied children only, 1 did not specify, and 1 studied adults) treated with: (1) polymyxin and bacitracin, (2) ciprofloxacin or tobramycin, or (3) norfloxacin.

STUDY DESIGN AND VALIDITY: Two authors determined whether studies met inclusion criteria and graded eligible studies for quality. Relative benefit (relative risk of clinical or microbial remission) was calculated using Review Manager software (Cochrane Collaboration).The 3 included studies were not homogeneous in their populations studied (children vs adults), the method of diagnosis (culture vs clinical assessment), and the outcomes measured (clinical vs microbiologic resolution, time to resolution measured). However, the results of the 3 studies were statistically homogenous, supporting the combination of the results by meta-analysis. The criteria used to make clinical assessments for inclusion or for evaluating outcomes are not discussed, making it difficult to assess their validity. In 1 study, data were combined from of 2 trials, 1 comparing the use of ciprofloxacin with placebo, and the other comparing ciprofloxacin with tobramycin. Details about the nature of the allocation process for this study are lacking, but exclusion of this study does not significantly change the results. The greatest limitation of this study is its applicability to the primary care setting. The majority of the patients come from hospital-based clinics, and 2 of the 3 studies used subjects with culture-confirmed bacterial conjunctivitis, while most patients in primary care are treated empirically without culture confirmation.

OUTCOMES MEASURED: Outcomes included clinical cure (not otherwise described) or microbiologic cure (by culture) at 2 time frames: early (2-5 days) and late (6-10 days). One of the 3 studies measured microbiologic remission only at day 3. results By clinical cure, conjunctivitis was resolved by day 2 to 5 in 64% of patients using placebo and in 83% of those using topical antibiotics (relative risk [RR]=1.31; 95% confidence interval [CI], 1.11-1.55; number needed to treat [NNT]=5.3). This relative benefit was not statistically significant after 5 days (RR=1.27; 95% CI, 1.00-1.61) in the 1 study providing evaluation at this time. The relative benefit was also smaller in the study that used clinical assessment to diagnose bacterial infection (RR=1.31; 95% CI, 1.11-1.55; NNT=6.25). Microbiologic remission was also more often attained in the patients receiving antibiotics than in those on placebo, with a relative benefit of 1.71 (95% CI, 1.32-2.21), which remained stable at 6 to 10 days as well. No serious adverse reactions were reported in either the treatment groups or the placebo groups.

In the June 2001 issue of The Journal of Family Practice, the diagnostic approach to the patient with dyspepsia was presented.¹ In that analysis, gastroesophageal reflux disease (GERD), gastric ulcers, and duodenal ulcers emerged as the most common identifiable causes of dyspepsia. However, most patients with dyspepsia do not have one of these conditions, and are considered to have functional or nonulcer dyspepsia. The diagnosis and management of adults with GERD was recently described in detail.² Therefore, this paper reviews the treatment of undifferentiated dyspepsia, gastric ulcer caused by nonsteroidal anti-inflammatory drugs (NSAIDs), peptic ulcer disease not associated with NSAID use, and nonulcer dyspepsia (dyspepsia in a patient who has no evidence of ulcer or GERD on endoscopy). An algorithm for the management of the patient with known ulcer disease is shown in the Figure 1. (J Fam Pract 2001; 50:614-619)

Undifferentiated dyspepsia

In primary care, the typical patient presenting with dyspepsia will not have had endoscopy. Therefore, the presence of an underlying lesion will be unknown, a situation known as undifferentiated dyspepsia. As described by Smucny,² randomized trials and economic analyses have demonstrated the cost-effectiveness of a test-and-treat strategy^3,4 in which patients with dyspepsia are tested for Helicobacter pylori and treated with eradication therapy if positive. This strategy would reserve endoscopy for those patients with alarm signs Table1 or those who have persistent symptoms despite appropriate empiric therapy. Certainly a physician must weigh the potential for complications during endoscopy with the risks of adverse reactions to eradication therapy, including the development of antimicrobial resistant organisms. All patients with dyspepsia should be counseled to avoid factors that exacerbate their symptoms or disrupt the integrity of the mucosal lining of the stomach, such as NSAID use and cigarette smoking. Both of these have been identified as risk factors for the development of peptic ulcers and delayed ulcer healing.^5,6

NSAID-related gastric ulcers

NSAIDs are associated with a 5- to 7-fold increased risk of gastric ulceration in the first 3 months of use. In a meta-analysis of observational studies of gastrointestinal bleeding risk due to various NSAIDs, a 4-fold increased risk associated with NSAID-use persisted throughout therapy and fell to baseline within 2 months of discontinuation of the NSAID.⁷ This study demonstrated a clear dose-response relationship; the difference between NSAIDs, however, was minimal.

Table 2 summarizes treatments for NSAID-related gastric ulcers. Misoprostol is an effective prophylaxis against ulcers when used with NSAIDs, but is associated with diarrhea, even at lower than optimal doses.⁸ Standard doses of H2-receptor agonists (H2RAs) are ineffective at preventing NSAID-related gastric ulcers, but double doses of H2RAs (eg, ranitidine 300 mg twice daily) and standard doses of proton-pump inhibitors (PPIs; eg, omeprazole 20 mg 4 times per day) are effective prophylactic agents for the duration of NSAID use according to the results of endoscopic studies. New COX-2 specific anti-inflammatory agents are associated with a significantly lower risk of ulcers as seen by endoscopy (4.7% with rofecoxib vs 27.7% with ibuprofen).⁹ The benefit in terms of actual adverse clinical outcomes and ulcer complications, however, is much smaller; the risk of symptomatic ulcer, perforation, symptomatic ulcer, and clinically significant bleeding was 1.3% for rofecoxib (Vioxx) and 1.8% with ibuprofen, diclofenac, or nabumetone taken for 1 year (P <.05).¹⁰ Thus, one would have to treat 200 patients for 1 year to prevent 1 adverse outcome. Similarly, the annual risk of bleeding, perforation, or gastric outlet obstruction was lower with celecoxib (Celebrex) than with naproxen, diclofenac, or ibuprofen (0.2% vs. 1.68%; P <.002; number needed to treat=60).11 COX-2 inhibitors have not been studied as an alternative therapy in patients with a history of NSAID-induced ulcers. While no trial data are available, a consensus-based recommendation has been made for dyspeptic patients with no alarm symptoms who are regular NSAID-users: The first step in management is to stop the NSAID use if possible, and determine if the symptoms improve.¹² If symptoms persist after NSAID use is discontinued, the patient should be managed as others with undifferentiated dyspepsia.

Non–NSAID-related duodenal and gastric ulcers

Helicobacter pylori is now well recognized as a major risk factor for the development of peptic ulcer disease. Although most H pylori–infected patients do not develop an ulcer, as many as 95% of patients with duodenal ulcers and 80% of those with gastric ulcers are infected. These rates may be lower in the United States because of greater use of NSAIDs and a lower rate of H pylori infection than in other parts of the world.¹³ Successful eradication of the organism following treatment heals ulcers and reduces the risk of recurrence from 67% to 6% for patients with duodenal ulcers, and from 59% to 4% for patients with gastric ulcers.¹⁴ A meta-analysis of North American randomized controlled trials of H pylori eradication for duodenal ulcer found that one ulcer recurrence (by endoscopy) would be prevented for every 2.8 patients successfully treated.¹⁵

However, a multi-drug regimen and an adequate length of treatment are required for eradication. Because antimicrobial resistance and incomplete treatment are major reasons for treatment failure,^16,17 convenience and tolerability become important considerations in choosing a treatment plan.

Effective H pylori treatment regimens include a combination of two antibiotics and acid suppression therapy, with or without a bismuth compound, taken for 10 to 14 days. Choosing a combination that can be taken in two daily doses may be easier for patients, although this option is also more costly.Table 3 provides a practical list of selected effective drug combinations used for treating H pylori infection. Triple therapies with reported eradication rates approaching 90% or more are included, though resistant strains may continue to emerge. Single and dual therapies, though FDA-approved for treatment of H pylori, have unacceptably low cure rates and are not recommended. PPI quadruple therapy or a regimen including furazolidone (a monoamine oxidase inhibitor) may serve as second-line treatment for eradication of initial failures and in case of metronidazole resistance.^18,19 Studies using ranitidine bismuth citrate in place of PPIs have also shown comparable results.

Patient education regarding the need for effective eradication therapy and to encourage adherence to the drug regimen is critical. Patients should have adequate follow-up, since further diagnostic testing may be needed to ensure eradication of the H pylori organism, particularly in the case of treatment failure or relapse. Because eradication usually cures peptic ulcer disease, chronic acid suppression therapy should not be needed in most patients who have cleared the H pylori infection and who are not taking NSAIDs. Among primary care patients with a history of peptic ulcer disease taking chronic acid suppressive therapy, 78% of those treated for H pylori were able to discontinue their therapy.²¹

Persistent or recurrent ulcers in patients treated for H pylori are strongly associated with persistent or recurrent infection.²² Because symptom relief is not always correlated with eradication, testing for cure following eradication therapy should be considered, particularly in high-risk patients, such as those with a history of bleeding or perforation.¹³ However, no randomized studies have been done to assess the outcomes associated with the decision to test for cure. If desired, noninvasive tests (eg stool antigen test or urea breath test) may be used for patients who become symptom-free following eradication therapy or for patients with persistent symptoms and a previously documented duodenal ulcer. Acid suppressive therapy with a PPI can result in false negative results, so this should be withheld for at least 2 weeks prior to testing for persistent infection.²³ Because of the risk of cancer associated with gastric ulcers, endoscopic documentation of gastric ulcer healing might be preferable to noninvasive testing, particularly in high-risk patients. In either case, patients with persistent or recurrent symptoms following eradication should have endoscopy to document ulcer healing and to obtain biopsies if necessary.

Nonulcer Dyspepsia

The pathophysiology of nonulcer dyspepsia (NUD) is not definitively known, though factors implicated include gastric acid secretion, gastro-duodenal dysmotility, visceral hypersensitivity, stress, and psychological factors.²⁴ A relationship with H pylori has not been established, though there is some evidence of an association.²⁵

Studies of drug treatments for NUD are limited by small samples, short duration of follow-up and the use of unvalidated outcome measures.²⁶ A recent meta-analysis found no significant benefit from the use of antacids or sucralfate for NUD, defined as dyspeptic symptoms with negative endoscopic or barium studies, excluding other organic (eg pancreato-biliary disease, oesophagitis) and drug-induced (NSAIDs) disease. The same study reported statistically significant benefits with the prokinetic drug cisapride, but there was evidence of a publication bias in these comparisons, making interpretation difficult (“positive” studies were more likely to be published than “negative” trials). Cisapride was also recently taken off the market, so is no longer available as a treatment option. No placebo-controlled studies of metoclopramide were identified in this systematic review.

Antisecretory treatments were more effective than placebo in the treatment of NUD, with a number needed to treat of 6 for H2-RAs and 11 for PPIs (ie, for every 11 patients who received a PPI instead of placebo, one benefited).²⁴ Thus, PPIs were actually less effective than H2-RAs in this meta-analysis of placebo-controlled trials. Long-term use of antisecretory therapy may be associated with hypergastrinemia, increased gastrointestinal bacterial counts, and altered absorption of nutrients, though the clinical significance of this is unclear.²⁷ For patients who do not respond to acid-suppressive therapy it might be necessary to entertain alternative diagnoses, and if no explanation for the symptoms can be identified, consider counseling or pain management strategies to help the patient cope with the discomfort. Studies of the use of antidepressants, though small and of questionable quality, consistently show improvement in symptoms of patients with functional gastrointestinal disorders, including NUD and irritable bowel syndrome.²⁸ Treatment recommendations for NUD are shown inTable 4.

To date there is no convincing evidence that empiric eradication of H pylori in patients with NUD improves symptoms. One recent meta-analysis of randomized controlled trials revealed no improvement with H pylori eradication for the symptoms of NUD,²⁹ while 2 others^25,30 showed a modest but statistically significant benefit, with 1 patient cured for every 19 treated (number needed to treat = 19).

Prognosis

Without treatment, peptic ulcer disease can lead to serious complications such as gastrointestinal bleeding and cancer. Acid suppression achieves ulcer healing rates of approximately 90%, but is associated with a 10% recurrence rate even with long-term treatment.²² Successful eradication of H pylori in the absence of NSAID use cures ulcer disease in 95% of cases; the recurrence rate is 33% to 41% if eradication is not achieved.¹⁴ Reinfection is rare once eradication has been accomplished, with a rate of about 1% per year,³¹ though rates can be much higher in endemic areas.³² Persistent infection requires re-treatment, ideally with a regimen not previously used, in case of antimicrobial resistance. Persistent gastric ulcers can harbor malignancy and therefore, evaluation with endoscopy might be prudent. H pylori itself is associated with a 2- to 6-fold increase in risk of gastric cancer.³³ Widespread screening or treatment to prevent cancer has not been recommended to date. A cost-benefit analysis suggests that the development and distribution of a vaccination for H pylori would be highly cost-effective,³⁴ but such a vaccine is not available as yet.

The prognosis of NUD is more discouraging. NUD is a chronic relapsing and remitting disorder, and treatment responses difficult to measure. For example, one systematic review of the literature found 56% of patients experienced an improvement in symptom scores when given placebo (range 5% - 90%). As with other functional gastrointestinal disorders, underlying psychosocial and lifestyle factors may be involved and must be addressed. Further research is needed in this area, particularly in the primary care setting.

Each Applied Evidence review article considers a common presenting complaint or disease and summarizes the best available evidence for clinicians. The collected reviews are published online at www.jfponline.com. Explanations of the Levels of Evidence can be found at http://cebm.jr2.ox.ac.uk/docs/levels.html.

In the June 2001 issue of The Journal of Family Practice, the diagnostic approach to the patient with dyspepsia was presented.¹ In that analysis, gastroesophageal reflux disease (GERD), gastric ulcers, and duodenal ulcers emerged as the most common identifiable causes of dyspepsia. However, most patients with dyspepsia do not have one of these conditions, and are considered to have functional or nonulcer dyspepsia. The diagnosis and management of adults with GERD was recently described in detail.² Therefore, this paper reviews the treatment of undifferentiated dyspepsia, gastric ulcer caused by nonsteroidal anti-inflammatory drugs (NSAIDs), peptic ulcer disease not associated with NSAID use, and nonulcer dyspepsia (dyspepsia in a patient who has no evidence of ulcer or GERD on endoscopy). An algorithm for the management of the patient with known ulcer disease is shown in the Figure 1. (J Fam Pract 2001; 50:614-619)

Undifferentiated dyspepsia

In primary care, the typical patient presenting with dyspepsia will not have had endoscopy. Therefore, the presence of an underlying lesion will be unknown, a situation known as undifferentiated dyspepsia. As described by Smucny,² randomized trials and economic analyses have demonstrated the cost-effectiveness of a test-and-treat strategy^3,4 in which patients with dyspepsia are tested for Helicobacter pylori and treated with eradication therapy if positive. This strategy would reserve endoscopy for those patients with alarm signs Table1 or those who have persistent symptoms despite appropriate empiric therapy. Certainly a physician must weigh the potential for complications during endoscopy with the risks of adverse reactions to eradication therapy, including the development of antimicrobial resistant organisms. All patients with dyspepsia should be counseled to avoid factors that exacerbate their symptoms or disrupt the integrity of the mucosal lining of the stomach, such as NSAID use and cigarette smoking. Both of these have been identified as risk factors for the development of peptic ulcers and delayed ulcer healing.^5,6

NSAID-related gastric ulcers

NSAIDs are associated with a 5- to 7-fold increased risk of gastric ulceration in the first 3 months of use. In a meta-analysis of observational studies of gastrointestinal bleeding risk due to various NSAIDs, a 4-fold increased risk associated with NSAID-use persisted throughout therapy and fell to baseline within 2 months of discontinuation of the NSAID.⁷ This study demonstrated a clear dose-response relationship; the difference between NSAIDs, however, was minimal.

Table 2 summarizes treatments for NSAID-related gastric ulcers. Misoprostol is an effective prophylaxis against ulcers when used with NSAIDs, but is associated with diarrhea, even at lower than optimal doses.⁸ Standard doses of H2-receptor agonists (H2RAs) are ineffective at preventing NSAID-related gastric ulcers, but double doses of H2RAs (eg, ranitidine 300 mg twice daily) and standard doses of proton-pump inhibitors (PPIs; eg, omeprazole 20 mg 4 times per day) are effective prophylactic agents for the duration of NSAID use according to the results of endoscopic studies. New COX-2 specific anti-inflammatory agents are associated with a significantly lower risk of ulcers as seen by endoscopy (4.7% with rofecoxib vs 27.7% with ibuprofen).⁹ The benefit in terms of actual adverse clinical outcomes and ulcer complications, however, is much smaller; the risk of symptomatic ulcer, perforation, symptomatic ulcer, and clinically significant bleeding was 1.3% for rofecoxib (Vioxx) and 1.8% with ibuprofen, diclofenac, or nabumetone taken for 1 year (P <.05).¹⁰ Thus, one would have to treat 200 patients for 1 year to prevent 1 adverse outcome. Similarly, the annual risk of bleeding, perforation, or gastric outlet obstruction was lower with celecoxib (Celebrex) than with naproxen, diclofenac, or ibuprofen (0.2% vs. 1.68%; P <.002; number needed to treat=60).11 COX-2 inhibitors have not been studied as an alternative therapy in patients with a history of NSAID-induced ulcers. While no trial data are available, a consensus-based recommendation has been made for dyspeptic patients with no alarm symptoms who are regular NSAID-users: The first step in management is to stop the NSAID use if possible, and determine if the symptoms improve.¹² If symptoms persist after NSAID use is discontinued, the patient should be managed as others with undifferentiated dyspepsia.

Non–NSAID-related duodenal and gastric ulcers

Helicobacter pylori is now well recognized as a major risk factor for the development of peptic ulcer disease. Although most H pylori–infected patients do not develop an ulcer, as many as 95% of patients with duodenal ulcers and 80% of those with gastric ulcers are infected. These rates may be lower in the United States because of greater use of NSAIDs and a lower rate of H pylori infection than in other parts of the world.¹³ Successful eradication of the organism following treatment heals ulcers and reduces the risk of recurrence from 67% to 6% for patients with duodenal ulcers, and from 59% to 4% for patients with gastric ulcers.¹⁴ A meta-analysis of North American randomized controlled trials of H pylori eradication for duodenal ulcer found that one ulcer recurrence (by endoscopy) would be prevented for every 2.8 patients successfully treated.¹⁵

However, a multi-drug regimen and an adequate length of treatment are required for eradication. Because antimicrobial resistance and incomplete treatment are major reasons for treatment failure,^16,17 convenience and tolerability become important considerations in choosing a treatment plan.

Effective H pylori treatment regimens include a combination of two antibiotics and acid suppression therapy, with or without a bismuth compound, taken for 10 to 14 days. Choosing a combination that can be taken in two daily doses may be easier for patients, although this option is also more costly.Table 3 provides a practical list of selected effective drug combinations used for treating H pylori infection. Triple therapies with reported eradication rates approaching 90% or more are included, though resistant strains may continue to emerge. Single and dual therapies, though FDA-approved for treatment of H pylori, have unacceptably low cure rates and are not recommended. PPI quadruple therapy or a regimen including furazolidone (a monoamine oxidase inhibitor) may serve as second-line treatment for eradication of initial failures and in case of metronidazole resistance.^18,19 Studies using ranitidine bismuth citrate in place of PPIs have also shown comparable results.

Patient education regarding the need for effective eradication therapy and to encourage adherence to the drug regimen is critical. Patients should have adequate follow-up, since further diagnostic testing may be needed to ensure eradication of the H pylori organism, particularly in the case of treatment failure or relapse. Because eradication usually cures peptic ulcer disease, chronic acid suppression therapy should not be needed in most patients who have cleared the H pylori infection and who are not taking NSAIDs. Among primary care patients with a history of peptic ulcer disease taking chronic acid suppressive therapy, 78% of those treated for H pylori were able to discontinue their therapy.²¹

Persistent or recurrent ulcers in patients treated for H pylori are strongly associated with persistent or recurrent infection.²² Because symptom relief is not always correlated with eradication, testing for cure following eradication therapy should be considered, particularly in high-risk patients, such as those with a history of bleeding or perforation.¹³ However, no randomized studies have been done to assess the outcomes associated with the decision to test for cure. If desired, noninvasive tests (eg stool antigen test or urea breath test) may be used for patients who become symptom-free following eradication therapy or for patients with persistent symptoms and a previously documented duodenal ulcer. Acid suppressive therapy with a PPI can result in false negative results, so this should be withheld for at least 2 weeks prior to testing for persistent infection.²³ Because of the risk of cancer associated with gastric ulcers, endoscopic documentation of gastric ulcer healing might be preferable to noninvasive testing, particularly in high-risk patients. In either case, patients with persistent or recurrent symptoms following eradication should have endoscopy to document ulcer healing and to obtain biopsies if necessary.

Nonulcer Dyspepsia

The pathophysiology of nonulcer dyspepsia (NUD) is not definitively known, though factors implicated include gastric acid secretion, gastro-duodenal dysmotility, visceral hypersensitivity, stress, and psychological factors.²⁴ A relationship with H pylori has not been established, though there is some evidence of an association.²⁵

Studies of drug treatments for NUD are limited by small samples, short duration of follow-up and the use of unvalidated outcome measures.²⁶ A recent meta-analysis found no significant benefit from the use of antacids or sucralfate for NUD, defined as dyspeptic symptoms with negative endoscopic or barium studies, excluding other organic (eg pancreato-biliary disease, oesophagitis) and drug-induced (NSAIDs) disease. The same study reported statistically significant benefits with the prokinetic drug cisapride, but there was evidence of a publication bias in these comparisons, making interpretation difficult (“positive” studies were more likely to be published than “negative” trials). Cisapride was also recently taken off the market, so is no longer available as a treatment option. No placebo-controlled studies of metoclopramide were identified in this systematic review.

Antisecretory treatments were more effective than placebo in the treatment of NUD, with a number needed to treat of 6 for H2-RAs and 11 for PPIs (ie, for every 11 patients who received a PPI instead of placebo, one benefited).²⁴ Thus, PPIs were actually less effective than H2-RAs in this meta-analysis of placebo-controlled trials. Long-term use of antisecretory therapy may be associated with hypergastrinemia, increased gastrointestinal bacterial counts, and altered absorption of nutrients, though the clinical significance of this is unclear.²⁷ For patients who do not respond to acid-suppressive therapy it might be necessary to entertain alternative diagnoses, and if no explanation for the symptoms can be identified, consider counseling or pain management strategies to help the patient cope with the discomfort. Studies of the use of antidepressants, though small and of questionable quality, consistently show improvement in symptoms of patients with functional gastrointestinal disorders, including NUD and irritable bowel syndrome.²⁸ Treatment recommendations for NUD are shown inTable 4.

To date there is no convincing evidence that empiric eradication of H pylori in patients with NUD improves symptoms. One recent meta-analysis of randomized controlled trials revealed no improvement with H pylori eradication for the symptoms of NUD,²⁹ while 2 others^25,30 showed a modest but statistically significant benefit, with 1 patient cured for every 19 treated (number needed to treat = 19).

Prognosis

Without treatment, peptic ulcer disease can lead to serious complications such as gastrointestinal bleeding and cancer. Acid suppression achieves ulcer healing rates of approximately 90%, but is associated with a 10% recurrence rate even with long-term treatment.²² Successful eradication of H pylori in the absence of NSAID use cures ulcer disease in 95% of cases; the recurrence rate is 33% to 41% if eradication is not achieved.¹⁴ Reinfection is rare once eradication has been accomplished, with a rate of about 1% per year,³¹ though rates can be much higher in endemic areas.³² Persistent infection requires re-treatment, ideally with a regimen not previously used, in case of antimicrobial resistance. Persistent gastric ulcers can harbor malignancy and therefore, evaluation with endoscopy might be prudent. H pylori itself is associated with a 2- to 6-fold increase in risk of gastric cancer.³³ Widespread screening or treatment to prevent cancer has not been recommended to date. A cost-benefit analysis suggests that the development and distribution of a vaccination for H pylori would be highly cost-effective,³⁴ but such a vaccine is not available as yet.

The prognosis of NUD is more discouraging. NUD is a chronic relapsing and remitting disorder, and treatment responses difficult to measure. For example, one systematic review of the literature found 56% of patients experienced an improvement in symptom scores when given placebo (range 5% - 90%). As with other functional gastrointestinal disorders, underlying psychosocial and lifestyle factors may be involved and must be addressed. Further research is needed in this area, particularly in the primary care setting.

Each Applied Evidence review article considers a common presenting complaint or disease and summarizes the best available evidence for clinicians. The collected reviews are published online at www.jfponline.com. Explanations of the Levels of Evidence can be found at http://cebm.jr2.ox.ac.uk/docs/levels.html.

In the June 2001 issue of The Journal of Family Practice, the diagnostic approach to the patient with dyspepsia was presented.¹ In that analysis, gastroesophageal reflux disease (GERD), gastric ulcers, and duodenal ulcers emerged as the most common identifiable causes of dyspepsia. However, most patients with dyspepsia do not have one of these conditions, and are considered to have functional or nonulcer dyspepsia. The diagnosis and management of adults with GERD was recently described in detail.² Therefore, this paper reviews the treatment of undifferentiated dyspepsia, gastric ulcer caused by nonsteroidal anti-inflammatory drugs (NSAIDs), peptic ulcer disease not associated with NSAID use, and nonulcer dyspepsia (dyspepsia in a patient who has no evidence of ulcer or GERD on endoscopy). An algorithm for the management of the patient with known ulcer disease is shown in the Figure 1. (J Fam Pract 2001; 50:614-619)

Undifferentiated dyspepsia

In primary care, the typical patient presenting with dyspepsia will not have had endoscopy. Therefore, the presence of an underlying lesion will be unknown, a situation known as undifferentiated dyspepsia. As described by Smucny,² randomized trials and economic analyses have demonstrated the cost-effectiveness of a test-and-treat strategy^3,4 in which patients with dyspepsia are tested for Helicobacter pylori and treated with eradication therapy if positive. This strategy would reserve endoscopy for those patients with alarm signs Table1 or those who have persistent symptoms despite appropriate empiric therapy. Certainly a physician must weigh the potential for complications during endoscopy with the risks of adverse reactions to eradication therapy, including the development of antimicrobial resistant organisms. All patients with dyspepsia should be counseled to avoid factors that exacerbate their symptoms or disrupt the integrity of the mucosal lining of the stomach, such as NSAID use and cigarette smoking. Both of these have been identified as risk factors for the development of peptic ulcers and delayed ulcer healing.^5,6

NSAID-related gastric ulcers

NSAIDs are associated with a 5- to 7-fold increased risk of gastric ulceration in the first 3 months of use. In a meta-analysis of observational studies of gastrointestinal bleeding risk due to various NSAIDs, a 4-fold increased risk associated with NSAID-use persisted throughout therapy and fell to baseline within 2 months of discontinuation of the NSAID.⁷ This study demonstrated a clear dose-response relationship; the difference between NSAIDs, however, was minimal.

Table 2 summarizes treatments for NSAID-related gastric ulcers. Misoprostol is an effective prophylaxis against ulcers when used with NSAIDs, but is associated with diarrhea, even at lower than optimal doses.⁸ Standard doses of H2-receptor agonists (H2RAs) are ineffective at preventing NSAID-related gastric ulcers, but double doses of H2RAs (eg, ranitidine 300 mg twice daily) and standard doses of proton-pump inhibitors (PPIs; eg, omeprazole 20 mg 4 times per day) are effective prophylactic agents for the duration of NSAID use according to the results of endoscopic studies. New COX-2 specific anti-inflammatory agents are associated with a significantly lower risk of ulcers as seen by endoscopy (4.7% with rofecoxib vs 27.7% with ibuprofen).⁹ The benefit in terms of actual adverse clinical outcomes and ulcer complications, however, is much smaller; the risk of symptomatic ulcer, perforation, symptomatic ulcer, and clinically significant bleeding was 1.3% for rofecoxib (Vioxx) and 1.8% with ibuprofen, diclofenac, or nabumetone taken for 1 year (P <.05).¹⁰ Thus, one would have to treat 200 patients for 1 year to prevent 1 adverse outcome. Similarly, the annual risk of bleeding, perforation, or gastric outlet obstruction was lower with celecoxib (Celebrex) than with naproxen, diclofenac, or ibuprofen (0.2% vs. 1.68%; P <.002; number needed to treat=60).11 COX-2 inhibitors have not been studied as an alternative therapy in patients with a history of NSAID-induced ulcers. While no trial data are available, a consensus-based recommendation has been made for dyspeptic patients with no alarm symptoms who are regular NSAID-users: The first step in management is to stop the NSAID use if possible, and determine if the symptoms improve.¹² If symptoms persist after NSAID use is discontinued, the patient should be managed as others with undifferentiated dyspepsia.

Non–NSAID-related duodenal and gastric ulcers

Helicobacter pylori is now well recognized as a major risk factor for the development of peptic ulcer disease. Although most H pylori–infected patients do not develop an ulcer, as many as 95% of patients with duodenal ulcers and 80% of those with gastric ulcers are infected. These rates may be lower in the United States because of greater use of NSAIDs and a lower rate of H pylori infection than in other parts of the world.¹³ Successful eradication of the organism following treatment heals ulcers and reduces the risk of recurrence from 67% to 6% for patients with duodenal ulcers, and from 59% to 4% for patients with gastric ulcers.¹⁴ A meta-analysis of North American randomized controlled trials of H pylori eradication for duodenal ulcer found that one ulcer recurrence (by endoscopy) would be prevented for every 2.8 patients successfully treated.¹⁵

However, a multi-drug regimen and an adequate length of treatment are required for eradication. Because antimicrobial resistance and incomplete treatment are major reasons for treatment failure,^16,17 convenience and tolerability become important considerations in choosing a treatment plan.

Effective H pylori treatment regimens include a combination of two antibiotics and acid suppression therapy, with or without a bismuth compound, taken for 10 to 14 days. Choosing a combination that can be taken in two daily doses may be easier for patients, although this option is also more costly.Table 3 provides a practical list of selected effective drug combinations used for treating H pylori infection. Triple therapies with reported eradication rates approaching 90% or more are included, though resistant strains may continue to emerge. Single and dual therapies, though FDA-approved for treatment of H pylori, have unacceptably low cure rates and are not recommended. PPI quadruple therapy or a regimen including furazolidone (a monoamine oxidase inhibitor) may serve as second-line treatment for eradication of initial failures and in case of metronidazole resistance.^18,19 Studies using ranitidine bismuth citrate in place of PPIs have also shown comparable results.

Patient education regarding the need for effective eradication therapy and to encourage adherence to the drug regimen is critical. Patients should have adequate follow-up, since further diagnostic testing may be needed to ensure eradication of the H pylori organism, particularly in the case of treatment failure or relapse. Because eradication usually cures peptic ulcer disease, chronic acid suppression therapy should not be needed in most patients who have cleared the H pylori infection and who are not taking NSAIDs. Among primary care patients with a history of peptic ulcer disease taking chronic acid suppressive therapy, 78% of those treated for H pylori were able to discontinue their therapy.²¹

Persistent or recurrent ulcers in patients treated for H pylori are strongly associated with persistent or recurrent infection.²² Because symptom relief is not always correlated with eradication, testing for cure following eradication therapy should be considered, particularly in high-risk patients, such as those with a history of bleeding or perforation.¹³ However, no randomized studies have been done to assess the outcomes associated with the decision to test for cure. If desired, noninvasive tests (eg stool antigen test or urea breath test) may be used for patients who become symptom-free following eradication therapy or for patients with persistent symptoms and a previously documented duodenal ulcer. Acid suppressive therapy with a PPI can result in false negative results, so this should be withheld for at least 2 weeks prior to testing for persistent infection.²³ Because of the risk of cancer associated with gastric ulcers, endoscopic documentation of gastric ulcer healing might be preferable to noninvasive testing, particularly in high-risk patients. In either case, patients with persistent or recurrent symptoms following eradication should have endoscopy to document ulcer healing and to obtain biopsies if necessary.

Nonulcer Dyspepsia

The pathophysiology of nonulcer dyspepsia (NUD) is not definitively known, though factors implicated include gastric acid secretion, gastro-duodenal dysmotility, visceral hypersensitivity, stress, and psychological factors.²⁴ A relationship with H pylori has not been established, though there is some evidence of an association.²⁵

Studies of drug treatments for NUD are limited by small samples, short duration of follow-up and the use of unvalidated outcome measures.²⁶ A recent meta-analysis found no significant benefit from the use of antacids or sucralfate for NUD, defined as dyspeptic symptoms with negative endoscopic or barium studies, excluding other organic (eg pancreato-biliary disease, oesophagitis) and drug-induced (NSAIDs) disease. The same study reported statistically significant benefits with the prokinetic drug cisapride, but there was evidence of a publication bias in these comparisons, making interpretation difficult (“positive” studies were more likely to be published than “negative” trials). Cisapride was also recently taken off the market, so is no longer available as a treatment option. No placebo-controlled studies of metoclopramide were identified in this systematic review.

Antisecretory treatments were more effective than placebo in the treatment of NUD, with a number needed to treat of 6 for H2-RAs and 11 for PPIs (ie, for every 11 patients who received a PPI instead of placebo, one benefited).²⁴ Thus, PPIs were actually less effective than H2-RAs in this meta-analysis of placebo-controlled trials. Long-term use of antisecretory therapy may be associated with hypergastrinemia, increased gastrointestinal bacterial counts, and altered absorption of nutrients, though the clinical significance of this is unclear.²⁷ For patients who do not respond to acid-suppressive therapy it might be necessary to entertain alternative diagnoses, and if no explanation for the symptoms can be identified, consider counseling or pain management strategies to help the patient cope with the discomfort. Studies of the use of antidepressants, though small and of questionable quality, consistently show improvement in symptoms of patients with functional gastrointestinal disorders, including NUD and irritable bowel syndrome.²⁸ Treatment recommendations for NUD are shown inTable 4.

To date there is no convincing evidence that empiric eradication of H pylori in patients with NUD improves symptoms. One recent meta-analysis of randomized controlled trials revealed no improvement with H pylori eradication for the symptoms of NUD,²⁹ while 2 others^25,30 showed a modest but statistically significant benefit, with 1 patient cured for every 19 treated (number needed to treat = 19).

Prognosis

Without treatment, peptic ulcer disease can lead to serious complications such as gastrointestinal bleeding and cancer. Acid suppression achieves ulcer healing rates of approximately 90%, but is associated with a 10% recurrence rate even with long-term treatment.²² Successful eradication of H pylori in the absence of NSAID use cures ulcer disease in 95% of cases; the recurrence rate is 33% to 41% if eradication is not achieved.¹⁴ Reinfection is rare once eradication has been accomplished, with a rate of about 1% per year,³¹ though rates can be much higher in endemic areas.³² Persistent infection requires re-treatment, ideally with a regimen not previously used, in case of antimicrobial resistance. Persistent gastric ulcers can harbor malignancy and therefore, evaluation with endoscopy might be prudent. H pylori itself is associated with a 2- to 6-fold increase in risk of gastric cancer.³³ Widespread screening or treatment to prevent cancer has not been recommended to date. A cost-benefit analysis suggests that the development and distribution of a vaccination for H pylori would be highly cost-effective,³⁴ but such a vaccine is not available as yet.

The prognosis of NUD is more discouraging. NUD is a chronic relapsing and remitting disorder, and treatment responses difficult to measure. For example, one systematic review of the literature found 56% of patients experienced an improvement in symptom scores when given placebo (range 5% - 90%). As with other functional gastrointestinal disorders, underlying psychosocial and lifestyle factors may be involved and must be addressed. Further research is needed in this area, particularly in the primary care setting.

Each Applied Evidence review article considers a common presenting complaint or disease and summarizes the best available evidence for clinicians. The collected reviews are published online at www.jfponline.com. Explanations of the Levels of Evidence can be found at http://cebm.jr2.ox.ac.uk/docs/levels.html.