Clinical Inquiries

EVIDENCE SUMMARY

A Cochrane review of interventions for preventing rickets in children born at term found 2 studies, a controlled clinical trial and a cluster-randomized controlled trial, that included 905 breastfed infants.¹ In these trials, oral vitamin D (300 or 400 IU per day) starting between one and 36 months of age reduced the risk of rickets when compared with no supplementation (TABLE). The authors concluded that it was reasonable to offer preventive measures (vitamin D or calcium) to all children 2 years or younger.

400 IU of vitamin D daily increases blood levels the most

A study done in north and south China investigated vitamin D dose by randomizing 312 infants to receive supplements of 100, 200, or 400 IU daily.² Although no infant developed rickets, a dose of 400 IU per day achieved higher serum levels of 25-hydroxy vitamin D (25[OH]-D) than the lower doses.

In the northern location, doses of 100, 200, or 400 IU daily increased 25(OH)-D levels from 5 ng/mL at birth to an average of 12, 15, and 25 ng/mL, respectively, at 6 months. In the southern location, 25(OH)-D levels increased from 14 ng/mL at birth to 20, 22, and 25 ng/mL at 6 months for the 100, 200, and 400 IU per day doses, respectively.

Recommendations

The guidelines from the American Academy of Pediatrics (AAP) on preventing rickets and vitamin D deficiency in infants, children, and adolescents recommends that exclusively breastfed neonates receive 400 IU of vitamin D daily, starting in the first days of life—a revision of the previous recommendation of 200 IU daily beginning at 2 months. The AAP doesn’t recommend giving vitamin D supplements to formula-fed infants because formula contains 400 IU/L of vitamin D; infants who don’t drink at least 1 liter of formula per day should receive supplementation. The AAP advocates a serum 25(OH)-D level of at least 20 ng/mL.³

The Pediatric Endocrine Society (PES) defines vitamin D deficiency as a serum 25(OH)-D level below 15 ng/mL and recommends mends maintaining the level above 20 ng/mL to prevent rickets. The PES also recommends that breastfed infants receive 400 IU of vitamin D daily starting at birth.⁴

EVIDENCE SUMMARY

A Cochrane review of interventions for preventing rickets in children born at term found 2 studies, a controlled clinical trial and a cluster-randomized controlled trial, that included 905 breastfed infants.¹ In these trials, oral vitamin D (300 or 400 IU per day) starting between one and 36 months of age reduced the risk of rickets when compared with no supplementation (TABLE). The authors concluded that it was reasonable to offer preventive measures (vitamin D or calcium) to all children 2 years or younger.

400 IU of vitamin D daily increases blood levels the most

A study done in north and south China investigated vitamin D dose by randomizing 312 infants to receive supplements of 100, 200, or 400 IU daily.² Although no infant developed rickets, a dose of 400 IU per day achieved higher serum levels of 25-hydroxy vitamin D (25[OH]-D) than the lower doses.

In the northern location, doses of 100, 200, or 400 IU daily increased 25(OH)-D levels from 5 ng/mL at birth to an average of 12, 15, and 25 ng/mL, respectively, at 6 months. In the southern location, 25(OH)-D levels increased from 14 ng/mL at birth to 20, 22, and 25 ng/mL at 6 months for the 100, 200, and 400 IU per day doses, respectively.

Recommendations

The guidelines from the American Academy of Pediatrics (AAP) on preventing rickets and vitamin D deficiency in infants, children, and adolescents recommends that exclusively breastfed neonates receive 400 IU of vitamin D daily, starting in the first days of life—a revision of the previous recommendation of 200 IU daily beginning at 2 months. The AAP doesn’t recommend giving vitamin D supplements to formula-fed infants because formula contains 400 IU/L of vitamin D; infants who don’t drink at least 1 liter of formula per day should receive supplementation. The AAP advocates a serum 25(OH)-D level of at least 20 ng/mL.³

The Pediatric Endocrine Society (PES) defines vitamin D deficiency as a serum 25(OH)-D level below 15 ng/mL and recommends mends maintaining the level above 20 ng/mL to prevent rickets. The PES also recommends that breastfed infants receive 400 IU of vitamin D daily starting at birth.⁴

EVIDENCE SUMMARY

A Cochrane review of interventions for preventing rickets in children born at term found 2 studies, a controlled clinical trial and a cluster-randomized controlled trial, that included 905 breastfed infants.¹ In these trials, oral vitamin D (300 or 400 IU per day) starting between one and 36 months of age reduced the risk of rickets when compared with no supplementation (TABLE). The authors concluded that it was reasonable to offer preventive measures (vitamin D or calcium) to all children 2 years or younger.

400 IU of vitamin D daily increases blood levels the most

A study done in north and south China investigated vitamin D dose by randomizing 312 infants to receive supplements of 100, 200, or 400 IU daily.² Although no infant developed rickets, a dose of 400 IU per day achieved higher serum levels of 25-hydroxy vitamin D (25[OH]-D) than the lower doses.

In the northern location, doses of 100, 200, or 400 IU daily increased 25(OH)-D levels from 5 ng/mL at birth to an average of 12, 15, and 25 ng/mL, respectively, at 6 months. In the southern location, 25(OH)-D levels increased from 14 ng/mL at birth to 20, 22, and 25 ng/mL at 6 months for the 100, 200, and 400 IU per day doses, respectively.

Recommendations

The guidelines from the American Academy of Pediatrics (AAP) on preventing rickets and vitamin D deficiency in infants, children, and adolescents recommends that exclusively breastfed neonates receive 400 IU of vitamin D daily, starting in the first days of life—a revision of the previous recommendation of 200 IU daily beginning at 2 months. The AAP doesn’t recommend giving vitamin D supplements to formula-fed infants because formula contains 400 IU/L of vitamin D; infants who don’t drink at least 1 liter of formula per day should receive supplementation. The AAP advocates a serum 25(OH)-D level of at least 20 ng/mL.³

The Pediatric Endocrine Society (PES) defines vitamin D deficiency as a serum 25(OH)-D level below 15 ng/mL and recommends mends maintaining the level above 20 ng/mL to prevent rickets. The PES also recommends that breastfed infants receive 400 IU of vitamin D daily starting at birth.⁴

EVIDENCE SUMMARY

Clinical signs and symptoms define headache types. The International Headache Society (IHS)’s definition of migraine (which is considered the gold standard) includes many of the same symptoms associated with headaches attributed to rhinosinusitis (TABLE 1).¹ In order for a headache to be attributed to rhinosinusitis, the patient must meet the definition of acute rhinosinusitis as defined by the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS). The definition includes purulent discharge, nasal obstruction, and facial pain-pressure-fullness.

Migraine headache symptoms include nasal discharge but not purulent discharge or nasal obstruction. The IHS doesn’t accept chronic sinusitis as a cause of headaches unless the patient meets the criteria for acute rhinosinusitis.^1,2

When a “sinus” headache isn’t

A cross-sectional study enrolled 100 patients (78 female, 22 male) 18 to 81 years of age who responded to an advertisement seeking people with self-diagnosed “sinus” headaches.³ A neurologist used the 2004 IHS criteria to classify the correct headache type. In 86% of patients, the investigators reclassified the patients with a migraine or probable migraine. Only 3 patients retained the sinus headache diagnosis. All 3 had at least one of the following: thick nasal discharge, fever, chills, sweats, or abnormally malodorous breath. The remaining 11 patients suffered from other headache subtypes.

The big 5 migraine symptoms

A prospective cohort study of 166 French railway employees evaluated the sensitivity and specificity of individual components of the IHS criteria. Patients enrolled had an average age of 39 years and a female-to-male ratio of 1:2. A neurologist diagnosed the headache type and placed patients into either a migraine or nonmigraine cohort. Researchers asked participants about IHS defined migraine symptoms and then compared the frequency of positive responses from migraineurs vs nonmigraineurs.

Five specific IHS criteria were found to be useful in identifying patients with migraine: duration between 4 and 72 hours (odds ratio [OR]=2.5; P=.02), unilateral location (OR=2.3; P=.03), pulsating quality (OR=2.4; P=.02), disturbance of daily activity (OR=2.5; P=.02), and nausea or vomiting (OR=2.8; P=.009). Any 4 of these features indicated a probability of migraine headache of ≥70%. The presence of photophobia and phonophobia (OR=0.5; P=.11) and aggravation by physical activity (OR=1.7; P=.14) didn’t improve diagnostic accuracy.⁴

Patients with sinus headaches have thick nasal discharge, fever, chills, sweats, or abnormally malodorous breath.A systematic review of retrospective cohort studies later analyzed the data.⁵ The authors derived the POUND mnemonic (TABLE 2)⁵ to aid clinicians in using the 5 clinical features to determine the likelihood of migraine headache. When any 4 of the 5 screening questions are positively, the likelihood ratio (LR) for migraine is 24 (95% confidence interval [CI], 1.5-388). Conversely, when 2 or fewer screening questions elicit positive responses, migraine is less likely (LR=0.41; 95% CI, 0.32-0.52).⁵

Most “sinus” headaches found to be migraine

A multicenter cross-sectional study evaluated 2991 male and female primary care patients, 18 to 65 years of age, who reported at least 6 self-described or physician-diagnosed sinus headaches within the preceding 6 months.6 At baseline, patients reported the following symptoms: pulsing or throbbing pain (89%), pain that worsened with physical activity (85%), sinus pressure (84%), sinus pain (82%), nasal congestion (63%), photophobia (79%), nausea (73%), and phonophobia (67%). Patients were excluded if they had a previous diagnosis of migraine, used a triptan, had a radiologic diagnosis of sinusitis, or had purulent drainage or fever.

Using the patients’ headache histories, reported symptoms, and the IHS criteria, researchers reclassified 88% of these “sinus headache” patients as having migraine type headaches.

Recommendations

IHS recommends using strict criteria for diagnosing migraines and headaches attributed to rhinosinusitis.¹

EVIDENCE SUMMARY

Clinical signs and symptoms define headache types. The International Headache Society (IHS)’s definition of migraine (which is considered the gold standard) includes many of the same symptoms associated with headaches attributed to rhinosinusitis (TABLE 1).¹ In order for a headache to be attributed to rhinosinusitis, the patient must meet the definition of acute rhinosinusitis as defined by the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS). The definition includes purulent discharge, nasal obstruction, and facial pain-pressure-fullness.

Migraine headache symptoms include nasal discharge but not purulent discharge or nasal obstruction. The IHS doesn’t accept chronic sinusitis as a cause of headaches unless the patient meets the criteria for acute rhinosinusitis.^1,2

When a “sinus” headache isn’t

A cross-sectional study enrolled 100 patients (78 female, 22 male) 18 to 81 years of age who responded to an advertisement seeking people with self-diagnosed “sinus” headaches.³ A neurologist used the 2004 IHS criteria to classify the correct headache type. In 86% of patients, the investigators reclassified the patients with a migraine or probable migraine. Only 3 patients retained the sinus headache diagnosis. All 3 had at least one of the following: thick nasal discharge, fever, chills, sweats, or abnormally malodorous breath. The remaining 11 patients suffered from other headache subtypes.

The big 5 migraine symptoms

A prospective cohort study of 166 French railway employees evaluated the sensitivity and specificity of individual components of the IHS criteria. Patients enrolled had an average age of 39 years and a female-to-male ratio of 1:2. A neurologist diagnosed the headache type and placed patients into either a migraine or nonmigraine cohort. Researchers asked participants about IHS defined migraine symptoms and then compared the frequency of positive responses from migraineurs vs nonmigraineurs.

Five specific IHS criteria were found to be useful in identifying patients with migraine: duration between 4 and 72 hours (odds ratio [OR]=2.5; P=.02), unilateral location (OR=2.3; P=.03), pulsating quality (OR=2.4; P=.02), disturbance of daily activity (OR=2.5; P=.02), and nausea or vomiting (OR=2.8; P=.009). Any 4 of these features indicated a probability of migraine headache of ≥70%. The presence of photophobia and phonophobia (OR=0.5; P=.11) and aggravation by physical activity (OR=1.7; P=.14) didn’t improve diagnostic accuracy.⁴

Patients with sinus headaches have thick nasal discharge, fever, chills, sweats, or abnormally malodorous breath.A systematic review of retrospective cohort studies later analyzed the data.⁵ The authors derived the POUND mnemonic (TABLE 2)⁵ to aid clinicians in using the 5 clinical features to determine the likelihood of migraine headache. When any 4 of the 5 screening questions are positively, the likelihood ratio (LR) for migraine is 24 (95% confidence interval [CI], 1.5-388). Conversely, when 2 or fewer screening questions elicit positive responses, migraine is less likely (LR=0.41; 95% CI, 0.32-0.52).⁵

Most “sinus” headaches found to be migraine

A multicenter cross-sectional study evaluated 2991 male and female primary care patients, 18 to 65 years of age, who reported at least 6 self-described or physician-diagnosed sinus headaches within the preceding 6 months.6 At baseline, patients reported the following symptoms: pulsing or throbbing pain (89%), pain that worsened with physical activity (85%), sinus pressure (84%), sinus pain (82%), nasal congestion (63%), photophobia (79%), nausea (73%), and phonophobia (67%). Patients were excluded if they had a previous diagnosis of migraine, used a triptan, had a radiologic diagnosis of sinusitis, or had purulent drainage or fever.

Using the patients’ headache histories, reported symptoms, and the IHS criteria, researchers reclassified 88% of these “sinus headache” patients as having migraine type headaches.

Recommendations

IHS recommends using strict criteria for diagnosing migraines and headaches attributed to rhinosinusitis.¹

EVIDENCE SUMMARY

Clinical signs and symptoms define headache types. The International Headache Society (IHS)’s definition of migraine (which is considered the gold standard) includes many of the same symptoms associated with headaches attributed to rhinosinusitis (TABLE 1).¹ In order for a headache to be attributed to rhinosinusitis, the patient must meet the definition of acute rhinosinusitis as defined by the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS). The definition includes purulent discharge, nasal obstruction, and facial pain-pressure-fullness.

Migraine headache symptoms include nasal discharge but not purulent discharge or nasal obstruction. The IHS doesn’t accept chronic sinusitis as a cause of headaches unless the patient meets the criteria for acute rhinosinusitis.^1,2

When a “sinus” headache isn’t

A cross-sectional study enrolled 100 patients (78 female, 22 male) 18 to 81 years of age who responded to an advertisement seeking people with self-diagnosed “sinus” headaches.³ A neurologist used the 2004 IHS criteria to classify the correct headache type. In 86% of patients, the investigators reclassified the patients with a migraine or probable migraine. Only 3 patients retained the sinus headache diagnosis. All 3 had at least one of the following: thick nasal discharge, fever, chills, sweats, or abnormally malodorous breath. The remaining 11 patients suffered from other headache subtypes.

The big 5 migraine symptoms

A prospective cohort study of 166 French railway employees evaluated the sensitivity and specificity of individual components of the IHS criteria. Patients enrolled had an average age of 39 years and a female-to-male ratio of 1:2. A neurologist diagnosed the headache type and placed patients into either a migraine or nonmigraine cohort. Researchers asked participants about IHS defined migraine symptoms and then compared the frequency of positive responses from migraineurs vs nonmigraineurs.

Five specific IHS criteria were found to be useful in identifying patients with migraine: duration between 4 and 72 hours (odds ratio [OR]=2.5; P=.02), unilateral location (OR=2.3; P=.03), pulsating quality (OR=2.4; P=.02), disturbance of daily activity (OR=2.5; P=.02), and nausea or vomiting (OR=2.8; P=.009). Any 4 of these features indicated a probability of migraine headache of ≥70%. The presence of photophobia and phonophobia (OR=0.5; P=.11) and aggravation by physical activity (OR=1.7; P=.14) didn’t improve diagnostic accuracy.⁴

Patients with sinus headaches have thick nasal discharge, fever, chills, sweats, or abnormally malodorous breath.A systematic review of retrospective cohort studies later analyzed the data.⁵ The authors derived the POUND mnemonic (TABLE 2)⁵ to aid clinicians in using the 5 clinical features to determine the likelihood of migraine headache. When any 4 of the 5 screening questions are positively, the likelihood ratio (LR) for migraine is 24 (95% confidence interval [CI], 1.5-388). Conversely, when 2 or fewer screening questions elicit positive responses, migraine is less likely (LR=0.41; 95% CI, 0.32-0.52).⁵

Most “sinus” headaches found to be migraine

A multicenter cross-sectional study evaluated 2991 male and female primary care patients, 18 to 65 years of age, who reported at least 6 self-described or physician-diagnosed sinus headaches within the preceding 6 months.6 At baseline, patients reported the following symptoms: pulsing or throbbing pain (89%), pain that worsened with physical activity (85%), sinus pressure (84%), sinus pain (82%), nasal congestion (63%), photophobia (79%), nausea (73%), and phonophobia (67%). Patients were excluded if they had a previous diagnosis of migraine, used a triptan, had a radiologic diagnosis of sinusitis, or had purulent drainage or fever.

Using the patients’ headache histories, reported symptoms, and the IHS criteria, researchers reclassified 88% of these “sinus headache” patients as having migraine type headaches.

Recommendations

IHS recommends using strict criteria for diagnosing migraines and headaches attributed to rhinosinusitis.¹

EVIDENCE SUMMARY

Women with probable migraine with visual aura (PMVA) have an increased risk for ischemic stroke (odds ratio [OR]=2.1) but not hemorrhagic stroke.¹ Women with >12 PMVA episodes per year are at greatest risk (OR=2.2, compared with <12 PMVA episodes per year, OR=1.1).² Women taking oral contraceptive pills (OCPs) also have an increased risk for stroke, depending on the estrogen dose (OR=4.8 for 50 mcg; OR=2.7 for 30-40 mcg; OR=1.7 for 20 mcg; and OR=1.0 for progestin-only pills).³

Women with migraines who smoke and take OCPs have the highest risk

Four case-control studies evaluated the risk of ischemic stroke in women with migraines who take OCPs. The first study compared the OR among 135 women 15 to 49 years of age with PMVA and a first ischemic stroke with 614 controls (no history of stroke, matched for age and ethnicity).² Although women with PMVA overall had an increased risk of ischemic stroke (OR=1.5; 95% confidence interval [CI], 1.1-2.0), a subgroup of women with PMVA who also were taking OCPs didn’t have a significantly greater stroke risk than women with PMVA who were not taking OCPs (OR=1.6; 95% CI, not given but reported as not significant; P=.87). Investigators didn’t specify the type of OCPs.

Women with PMVA who smoked had a greater risk of ischemic stroke (OR=1.5; 95% CI, 1.1-2.3), and women with PMVA who both smoked and took OCPs had the highest risk of ischemic stroke (OR =7.0; 95% CI, 1.4-22.8).

In women younger than 45 years, OCPs are associated with higher stroke risk

The second study compared the odds ratio for ischemic stroke among 47 women younger than 45 years with PMVA who were taking combined OCPs with 63 controls.³ Most OCPs contained 30 to 40 mcg estrogen. Women with PMVA taking a combined OCP had a higher risk of ischemic stroke (OR=13.9; 95% CI, 5.5-35.1) than women with PMVA who didn’t take OCPs (OR=3.7; 95% CI, 1.5-9.1). Investigators didn’t report the number of PMVA episodes per year among the women.

The third study compared the odds ratio for ischemic stroke among 10 women 20 to 44 years of age with migraines who were taking combined OCPs with 23 controls.⁴ Investigators didn’t specify the type of migraine, although classic migraine was approximately twice as common as simple migraine among the women in the larger study population. Women with migraine taking OCPs were more likely to have an ischemic stroke overall (OR=16.9; 95% CI, 2.7-106), with the exception of those taking OCPs with <50 mcg estrogen (4 patients) (OR=0.59; 95 % CI, 0.79-54.8).

The fourth study compared the OR for ischemic stroke among 4 women 18 to 44 years old who had a history of migraine (type not specified) and used low-dose OCPs with 14 controls. Women with migraines taking OCPs had a higher risk of ischemic stroke (OR=2.08; 95% CI, 1.19-3.65).⁵

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists says that combined OCPs are contraindicated for women with migraine with focal neurologic symptoms such as aura.⁶ Although strokes are rare in women with migraine taking OCPs, the impact of a stroke is so devastating that clinicians should consider progestin-only, intrauterine, or barrier contraceptives for these women. However, physicians may consider combined OCPs for women younger than 35 years with migraine if they don’t have focal neurologic signs, don’t smoke, and are otherwise healthy.

The World Health Organization and Centers for Disease Control and Prevention state that women with a history of migraine who use combined OCPs are 2 to 4 times more likely to have an ischemic stroke than nonusers and conclude that combined OCP use in women older than 35 years with migraine, or migraine with aura at any age, represents an unacceptable health risk. However, the advantages of using combined OCPs in women younger than 35 years with migraine generally outweigh the theoretical or proven risks.^7,8

EVIDENCE SUMMARY

Women with probable migraine with visual aura (PMVA) have an increased risk for ischemic stroke (odds ratio [OR]=2.1) but not hemorrhagic stroke.¹ Women with >12 PMVA episodes per year are at greatest risk (OR=2.2, compared with <12 PMVA episodes per year, OR=1.1).² Women taking oral contraceptive pills (OCPs) also have an increased risk for stroke, depending on the estrogen dose (OR=4.8 for 50 mcg; OR=2.7 for 30-40 mcg; OR=1.7 for 20 mcg; and OR=1.0 for progestin-only pills).³

Women with migraines who smoke and take OCPs have the highest risk

Four case-control studies evaluated the risk of ischemic stroke in women with migraines who take OCPs. The first study compared the OR among 135 women 15 to 49 years of age with PMVA and a first ischemic stroke with 614 controls (no history of stroke, matched for age and ethnicity).² Although women with PMVA overall had an increased risk of ischemic stroke (OR=1.5; 95% confidence interval [CI], 1.1-2.0), a subgroup of women with PMVA who also were taking OCPs didn’t have a significantly greater stroke risk than women with PMVA who were not taking OCPs (OR=1.6; 95% CI, not given but reported as not significant; P=.87). Investigators didn’t specify the type of OCPs.

Women with PMVA who smoked had a greater risk of ischemic stroke (OR=1.5; 95% CI, 1.1-2.3), and women with PMVA who both smoked and took OCPs had the highest risk of ischemic stroke (OR =7.0; 95% CI, 1.4-22.8).

In women younger than 45 years, OCPs are associated with higher stroke risk

The second study compared the odds ratio for ischemic stroke among 47 women younger than 45 years with PMVA who were taking combined OCPs with 63 controls.³ Most OCPs contained 30 to 40 mcg estrogen. Women with PMVA taking a combined OCP had a higher risk of ischemic stroke (OR=13.9; 95% CI, 5.5-35.1) than women with PMVA who didn’t take OCPs (OR=3.7; 95% CI, 1.5-9.1). Investigators didn’t report the number of PMVA episodes per year among the women.

The third study compared the odds ratio for ischemic stroke among 10 women 20 to 44 years of age with migraines who were taking combined OCPs with 23 controls.⁴ Investigators didn’t specify the type of migraine, although classic migraine was approximately twice as common as simple migraine among the women in the larger study population. Women with migraine taking OCPs were more likely to have an ischemic stroke overall (OR=16.9; 95% CI, 2.7-106), with the exception of those taking OCPs with <50 mcg estrogen (4 patients) (OR=0.59; 95 % CI, 0.79-54.8).

The fourth study compared the OR for ischemic stroke among 4 women 18 to 44 years old who had a history of migraine (type not specified) and used low-dose OCPs with 14 controls. Women with migraines taking OCPs had a higher risk of ischemic stroke (OR=2.08; 95% CI, 1.19-3.65).⁵

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists says that combined OCPs are contraindicated for women with migraine with focal neurologic symptoms such as aura.⁶ Although strokes are rare in women with migraine taking OCPs, the impact of a stroke is so devastating that clinicians should consider progestin-only, intrauterine, or barrier contraceptives for these women. However, physicians may consider combined OCPs for women younger than 35 years with migraine if they don’t have focal neurologic signs, don’t smoke, and are otherwise healthy.

The World Health Organization and Centers for Disease Control and Prevention state that women with a history of migraine who use combined OCPs are 2 to 4 times more likely to have an ischemic stroke than nonusers and conclude that combined OCP use in women older than 35 years with migraine, or migraine with aura at any age, represents an unacceptable health risk. However, the advantages of using combined OCPs in women younger than 35 years with migraine generally outweigh the theoretical or proven risks.^7,8

EVIDENCE SUMMARY

Women with probable migraine with visual aura (PMVA) have an increased risk for ischemic stroke (odds ratio [OR]=2.1) but not hemorrhagic stroke.¹ Women with >12 PMVA episodes per year are at greatest risk (OR=2.2, compared with <12 PMVA episodes per year, OR=1.1).² Women taking oral contraceptive pills (OCPs) also have an increased risk for stroke, depending on the estrogen dose (OR=4.8 for 50 mcg; OR=2.7 for 30-40 mcg; OR=1.7 for 20 mcg; and OR=1.0 for progestin-only pills).³

Women with migraines who smoke and take OCPs have the highest risk

Four case-control studies evaluated the risk of ischemic stroke in women with migraines who take OCPs. The first study compared the OR among 135 women 15 to 49 years of age with PMVA and a first ischemic stroke with 614 controls (no history of stroke, matched for age and ethnicity).² Although women with PMVA overall had an increased risk of ischemic stroke (OR=1.5; 95% confidence interval [CI], 1.1-2.0), a subgroup of women with PMVA who also were taking OCPs didn’t have a significantly greater stroke risk than women with PMVA who were not taking OCPs (OR=1.6; 95% CI, not given but reported as not significant; P=.87). Investigators didn’t specify the type of OCPs.

Women with PMVA who smoked had a greater risk of ischemic stroke (OR=1.5; 95% CI, 1.1-2.3), and women with PMVA who both smoked and took OCPs had the highest risk of ischemic stroke (OR =7.0; 95% CI, 1.4-22.8).

In women younger than 45 years, OCPs are associated with higher stroke risk

The second study compared the odds ratio for ischemic stroke among 47 women younger than 45 years with PMVA who were taking combined OCPs with 63 controls.³ Most OCPs contained 30 to 40 mcg estrogen. Women with PMVA taking a combined OCP had a higher risk of ischemic stroke (OR=13.9; 95% CI, 5.5-35.1) than women with PMVA who didn’t take OCPs (OR=3.7; 95% CI, 1.5-9.1). Investigators didn’t report the number of PMVA episodes per year among the women.

The third study compared the odds ratio for ischemic stroke among 10 women 20 to 44 years of age with migraines who were taking combined OCPs with 23 controls.⁴ Investigators didn’t specify the type of migraine, although classic migraine was approximately twice as common as simple migraine among the women in the larger study population. Women with migraine taking OCPs were more likely to have an ischemic stroke overall (OR=16.9; 95% CI, 2.7-106), with the exception of those taking OCPs with <50 mcg estrogen (4 patients) (OR=0.59; 95 % CI, 0.79-54.8).

The fourth study compared the OR for ischemic stroke among 4 women 18 to 44 years old who had a history of migraine (type not specified) and used low-dose OCPs with 14 controls. Women with migraines taking OCPs had a higher risk of ischemic stroke (OR=2.08; 95% CI, 1.19-3.65).⁵

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists says that combined OCPs are contraindicated for women with migraine with focal neurologic symptoms such as aura.⁶ Although strokes are rare in women with migraine taking OCPs, the impact of a stroke is so devastating that clinicians should consider progestin-only, intrauterine, or barrier contraceptives for these women. However, physicians may consider combined OCPs for women younger than 35 years with migraine if they don’t have focal neurologic signs, don’t smoke, and are otherwise healthy.

The World Health Organization and Centers for Disease Control and Prevention state that women with a history of migraine who use combined OCPs are 2 to 4 times more likely to have an ischemic stroke than nonusers and conclude that combined OCP use in women older than 35 years with migraine, or migraine with aura at any age, represents an unacceptable health risk. However, the advantages of using combined OCPs in women younger than 35 years with migraine generally outweigh the theoretical or proven risks.^7,8

Evidence summary

Six studies (5 cohort studies and one randomized crossover study) attempted to isolate specific dietary components as risk factors for metabolic syndrome, by performing multivariate analyses to control for weight and exercise habits. The cohort studies all used the National Cholesterol Education Program Adult Treatment Panel III definition of metabolic syndrome. Overall, consumption of foods with a high glycemic index was associated with an increased risk of metabolic syndrome.

A cohort study that evaluated the diet, body habitus, and serum metabolic parameters of 2834 US adults using a validated, interviewer-administered food frequency questionnaire found that the rate of metabolic syndrome was significantly higher in patients with the highest glycemic index diets (highest vs lowest quintile adjusted odds ratio [aOR]=1.4; 95% confidence interval [CI], 1.04-1.9).¹ Conversely, metabolic syndrome was less common in subjects who ate diets rich in whole grains (aOR=0.67; 95% CI, 0.48-0.91) and cereal fiber (aOR=0.62; 95% CI, 0.45-0.86).

A second cohort study evaluated the diet, body habitus, and metabolic parameters in 2043 Asian women using the same food frequency questionnaire to obtain dietary history.² Metabolic syndrome was significantly more common among the women with a high refined carbohydrate intake (highest vs lowest quartile aOR=7.8; 95% CI, 4.7-13).

“Western” diet, lack of diversity associated with metabolic syndrome
Two studies from Iran evaluated the rates of metabolic syndrome according to different dietary patterns. The first evaluated a cohort of 486 female teachers 40 to 60 years of age.³ Investigators characterized dietary patterns as “healthy” (rich in fruits, vegetables, and whole grains) or “Western” (more meat and refined grains). The more “Western” the dietary pattern became, the more often metabolic syndrome was diagnosed (highest vs lowest quintile aOR=1.7; 95% CI, 1.1-1.9).

In the second study, 581 healthy adults received dietary surveys and were tested for metabolic syndrome.⁴ Diets were assessed and scored for their diversity. High levels of dietary diversity were inversely associated with metabolic syndrome (highest vs lowest quartile aOR=0.77; 95% CI, 0.59-0.93).

No short-term gain in switching to foods with low glycemic index
Switching to foods with a low glycemic index, however, may not provide much benefit, at least in the short term. An 11-week prospective, double-blind, crossover trial in which 15 overweight patients at risk of developing metabolic syndrome alternated eating foods with high and low glycemic indexes found no significant difference in the serum markers associated with metabolic syndrome (fasting glucose, insulin, and triglyceride levels).⁵

Recommendations

The 2010 Dietary Guidelines for Americans, jointly issued by the US Department of Agriculture and Health and Human Services, recommend increasing fruit and vegetable intake, eating a variety of vegetables, and consuming at least half of all grains as whole grains.⁶ The guidelines further recommend limiting consumption of foods that contain refined grains, “especially refined grain foods that contain solid fats, added sugars, and sodium.”

The American Diabetes Association (ADA) encourages consumption of low-glycemic index foods, especially foods rich in fiber and other nutrients. However, the ADA also states that there are “not sufficient, consistent” data to conclude that low-glycemic index diets reduce the risk of diabetes.⁷

Evidence summary

Six studies (5 cohort studies and one randomized crossover study) attempted to isolate specific dietary components as risk factors for metabolic syndrome, by performing multivariate analyses to control for weight and exercise habits. The cohort studies all used the National Cholesterol Education Program Adult Treatment Panel III definition of metabolic syndrome. Overall, consumption of foods with a high glycemic index was associated with an increased risk of metabolic syndrome.

A cohort study that evaluated the diet, body habitus, and serum metabolic parameters of 2834 US adults using a validated, interviewer-administered food frequency questionnaire found that the rate of metabolic syndrome was significantly higher in patients with the highest glycemic index diets (highest vs lowest quintile adjusted odds ratio [aOR]=1.4; 95% confidence interval [CI], 1.04-1.9).¹ Conversely, metabolic syndrome was less common in subjects who ate diets rich in whole grains (aOR=0.67; 95% CI, 0.48-0.91) and cereal fiber (aOR=0.62; 95% CI, 0.45-0.86).

A second cohort study evaluated the diet, body habitus, and metabolic parameters in 2043 Asian women using the same food frequency questionnaire to obtain dietary history.² Metabolic syndrome was significantly more common among the women with a high refined carbohydrate intake (highest vs lowest quartile aOR=7.8; 95% CI, 4.7-13).

“Western” diet, lack of diversity associated with metabolic syndrome
Two studies from Iran evaluated the rates of metabolic syndrome according to different dietary patterns. The first evaluated a cohort of 486 female teachers 40 to 60 years of age.³ Investigators characterized dietary patterns as “healthy” (rich in fruits, vegetables, and whole grains) or “Western” (more meat and refined grains). The more “Western” the dietary pattern became, the more often metabolic syndrome was diagnosed (highest vs lowest quintile aOR=1.7; 95% CI, 1.1-1.9).

In the second study, 581 healthy adults received dietary surveys and were tested for metabolic syndrome.⁴ Diets were assessed and scored for their diversity. High levels of dietary diversity were inversely associated with metabolic syndrome (highest vs lowest quartile aOR=0.77; 95% CI, 0.59-0.93).

No short-term gain in switching to foods with low glycemic index
Switching to foods with a low glycemic index, however, may not provide much benefit, at least in the short term. An 11-week prospective, double-blind, crossover trial in which 15 overweight patients at risk of developing metabolic syndrome alternated eating foods with high and low glycemic indexes found no significant difference in the serum markers associated with metabolic syndrome (fasting glucose, insulin, and triglyceride levels).⁵

Recommendations

The 2010 Dietary Guidelines for Americans, jointly issued by the US Department of Agriculture and Health and Human Services, recommend increasing fruit and vegetable intake, eating a variety of vegetables, and consuming at least half of all grains as whole grains.⁶ The guidelines further recommend limiting consumption of foods that contain refined grains, “especially refined grain foods that contain solid fats, added sugars, and sodium.”

The American Diabetes Association (ADA) encourages consumption of low-glycemic index foods, especially foods rich in fiber and other nutrients. However, the ADA also states that there are “not sufficient, consistent” data to conclude that low-glycemic index diets reduce the risk of diabetes.⁷

Evidence summary

Six studies (5 cohort studies and one randomized crossover study) attempted to isolate specific dietary components as risk factors for metabolic syndrome, by performing multivariate analyses to control for weight and exercise habits. The cohort studies all used the National Cholesterol Education Program Adult Treatment Panel III definition of metabolic syndrome. Overall, consumption of foods with a high glycemic index was associated with an increased risk of metabolic syndrome.

A cohort study that evaluated the diet, body habitus, and serum metabolic parameters of 2834 US adults using a validated, interviewer-administered food frequency questionnaire found that the rate of metabolic syndrome was significantly higher in patients with the highest glycemic index diets (highest vs lowest quintile adjusted odds ratio [aOR]=1.4; 95% confidence interval [CI], 1.04-1.9).¹ Conversely, metabolic syndrome was less common in subjects who ate diets rich in whole grains (aOR=0.67; 95% CI, 0.48-0.91) and cereal fiber (aOR=0.62; 95% CI, 0.45-0.86).

A second cohort study evaluated the diet, body habitus, and metabolic parameters in 2043 Asian women using the same food frequency questionnaire to obtain dietary history.² Metabolic syndrome was significantly more common among the women with a high refined carbohydrate intake (highest vs lowest quartile aOR=7.8; 95% CI, 4.7-13).

“Western” diet, lack of diversity associated with metabolic syndrome
Two studies from Iran evaluated the rates of metabolic syndrome according to different dietary patterns. The first evaluated a cohort of 486 female teachers 40 to 60 years of age.³ Investigators characterized dietary patterns as “healthy” (rich in fruits, vegetables, and whole grains) or “Western” (more meat and refined grains). The more “Western” the dietary pattern became, the more often metabolic syndrome was diagnosed (highest vs lowest quintile aOR=1.7; 95% CI, 1.1-1.9).

In the second study, 581 healthy adults received dietary surveys and were tested for metabolic syndrome.⁴ Diets were assessed and scored for their diversity. High levels of dietary diversity were inversely associated with metabolic syndrome (highest vs lowest quartile aOR=0.77; 95% CI, 0.59-0.93).

No short-term gain in switching to foods with low glycemic index
Switching to foods with a low glycemic index, however, may not provide much benefit, at least in the short term. An 11-week prospective, double-blind, crossover trial in which 15 overweight patients at risk of developing metabolic syndrome alternated eating foods with high and low glycemic indexes found no significant difference in the serum markers associated with metabolic syndrome (fasting glucose, insulin, and triglyceride levels).⁵

Recommendations

The 2010 Dietary Guidelines for Americans, jointly issued by the US Department of Agriculture and Health and Human Services, recommend increasing fruit and vegetable intake, eating a variety of vegetables, and consuming at least half of all grains as whole grains.⁶ The guidelines further recommend limiting consumption of foods that contain refined grains, “especially refined grain foods that contain solid fats, added sugars, and sodium.”

The American Diabetes Association (ADA) encourages consumption of low-glycemic index foods, especially foods rich in fiber and other nutrients. However, the ADA also states that there are “not sufficient, consistent” data to conclude that low-glycemic index diets reduce the risk of diabetes.⁷

Evidence summary

The US Pooling Project divided EKG abnormalities into major and minor findings.¹ A number of large cohort studies have shown that both major and minor findings are associated with an elevated odds ratio for mortality (TABLE).^1-5 However, these studies, completed before the development of modern medical management of acute coronary syndrome and stable coronary artery disease, may no longer estimate mortality accurately. Moreover, no studies have examined the effect of screening EKGs on coronary heart disease (CHD) outcomes.

Neither major nor minor EKG abnormalities linked to higher mortality
A 2012 cohort study—which included Q-waves as major criteria and examined fewer minor abnormalities than previous studies—followed 2192 patients 70 to 79 years of age for 8 years.⁶ The study enrolled a higher percentage of women and blacks than earlier investigations had.

Major EKG abnormalities predicted an increase in CHD events (hazard ratio [HR]=1.51; 95% confidence interval [CI], 1.20-1.90) as did minor abnormalities (HR=1.35; 95% CI, 1.02-1.81). In contrast to earlier studies, which tended to enroll younger patients, neither type of abnormality was associated with a significantly increased risk of all-cause mortality.⁶

Including EKG abnormalities in a regression model of traditional risk factors improved stratification (overall net reclassification improvement [NRI]=7.4%; 95% CI, 3.1%-19.0%).⁶ No low-risk patients were reclassified as high risk and no high-risk patients were reclassified as low risk. Overall, 156 intermediate risk patients were correctly reclassified and an equal number were incorrectly reclassified. Adding EKG abnormalities to the Framingham Risk Score (which hasn’t been validated in adults >75 years) didn’t significantly improve stratification (NRI=5.7%; 95% CI, −0.4% to 11.8%).⁶

Comparing ED with baseline EKGs has little effect on management
A 1980 retrospective study looked at 236 patients with acute chest pain and no known CHD who were seen in the ED. Comparing routine baseline EKGs obtained before ED presentation for 6 of 41 patients with equivocal EKGs in the ED—including T-wave inversions, nonspecific T-wave and ST-segment abnormalities, and bundle branch blocks—prevented 2 admissions (no EKG change from baseline) and caused 4 unnecessary admissions (EKG changed from baseline with no subsequent evidence of acute coronary syndromes).⁷

A 1985 prospective study of 84 ED patients, in which treating physicians were given baseline EKGs after committing to an initial disposition plan, showed that the baseline EKG altered the decision to admit or discharge in only one case.⁸

A 1990 prospective multicenter study of 5673 patients older than 30 years—41% of whom had known CHD—reported that when the current EKG was consistent with ischemia or infarction, a baseline EKG showing the changes to be old (10% of study population) increased the likelihood that the patient would be discharged from the ED to home (26% vs 12%; risk difference=14%; 95% CI, 7%-23%). Unlike previous studies, however, the exact role of the baseline EKG in the admission decision was isolated not by study design but rather by multivariate logistic regression modeling.⁹

Recommendations

The 2010 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for assessment of cardiovascular risk in asymptomatic adults states that a resting EKG is probably indicated in patients with diabetes and hypertension and that its usefulness in patients without these conditions isn’t well established.²

The US Preventive Services Task Force recommends against screening EKGs in adults at low risk for CHD events (grade D recommendation).¹⁰

Evidence summary

The US Pooling Project divided EKG abnormalities into major and minor findings.¹ A number of large cohort studies have shown that both major and minor findings are associated with an elevated odds ratio for mortality (TABLE).^1-5 However, these studies, completed before the development of modern medical management of acute coronary syndrome and stable coronary artery disease, may no longer estimate mortality accurately. Moreover, no studies have examined the effect of screening EKGs on coronary heart disease (CHD) outcomes.

Neither major nor minor EKG abnormalities linked to higher mortality
A 2012 cohort study—which included Q-waves as major criteria and examined fewer minor abnormalities than previous studies—followed 2192 patients 70 to 79 years of age for 8 years.⁶ The study enrolled a higher percentage of women and blacks than earlier investigations had.

Major EKG abnormalities predicted an increase in CHD events (hazard ratio [HR]=1.51; 95% confidence interval [CI], 1.20-1.90) as did minor abnormalities (HR=1.35; 95% CI, 1.02-1.81). In contrast to earlier studies, which tended to enroll younger patients, neither type of abnormality was associated with a significantly increased risk of all-cause mortality.⁶

Including EKG abnormalities in a regression model of traditional risk factors improved stratification (overall net reclassification improvement [NRI]=7.4%; 95% CI, 3.1%-19.0%).⁶ No low-risk patients were reclassified as high risk and no high-risk patients were reclassified as low risk. Overall, 156 intermediate risk patients were correctly reclassified and an equal number were incorrectly reclassified. Adding EKG abnormalities to the Framingham Risk Score (which hasn’t been validated in adults >75 years) didn’t significantly improve stratification (NRI=5.7%; 95% CI, −0.4% to 11.8%).⁶

Comparing ED with baseline EKGs has little effect on management
A 1980 retrospective study looked at 236 patients with acute chest pain and no known CHD who were seen in the ED. Comparing routine baseline EKGs obtained before ED presentation for 6 of 41 patients with equivocal EKGs in the ED—including T-wave inversions, nonspecific T-wave and ST-segment abnormalities, and bundle branch blocks—prevented 2 admissions (no EKG change from baseline) and caused 4 unnecessary admissions (EKG changed from baseline with no subsequent evidence of acute coronary syndromes).⁷

A 1985 prospective study of 84 ED patients, in which treating physicians were given baseline EKGs after committing to an initial disposition plan, showed that the baseline EKG altered the decision to admit or discharge in only one case.⁸

A 1990 prospective multicenter study of 5673 patients older than 30 years—41% of whom had known CHD—reported that when the current EKG was consistent with ischemia or infarction, a baseline EKG showing the changes to be old (10% of study population) increased the likelihood that the patient would be discharged from the ED to home (26% vs 12%; risk difference=14%; 95% CI, 7%-23%). Unlike previous studies, however, the exact role of the baseline EKG in the admission decision was isolated not by study design but rather by multivariate logistic regression modeling.⁹

Recommendations

The 2010 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for assessment of cardiovascular risk in asymptomatic adults states that a resting EKG is probably indicated in patients with diabetes and hypertension and that its usefulness in patients without these conditions isn’t well established.²

The US Preventive Services Task Force recommends against screening EKGs in adults at low risk for CHD events (grade D recommendation).¹⁰

Evidence summary

The US Pooling Project divided EKG abnormalities into major and minor findings.¹ A number of large cohort studies have shown that both major and minor findings are associated with an elevated odds ratio for mortality (TABLE).^1-5 However, these studies, completed before the development of modern medical management of acute coronary syndrome and stable coronary artery disease, may no longer estimate mortality accurately. Moreover, no studies have examined the effect of screening EKGs on coronary heart disease (CHD) outcomes.

Neither major nor minor EKG abnormalities linked to higher mortality
A 2012 cohort study—which included Q-waves as major criteria and examined fewer minor abnormalities than previous studies—followed 2192 patients 70 to 79 years of age for 8 years.⁶ The study enrolled a higher percentage of women and blacks than earlier investigations had.

Major EKG abnormalities predicted an increase in CHD events (hazard ratio [HR]=1.51; 95% confidence interval [CI], 1.20-1.90) as did minor abnormalities (HR=1.35; 95% CI, 1.02-1.81). In contrast to earlier studies, which tended to enroll younger patients, neither type of abnormality was associated with a significantly increased risk of all-cause mortality.⁶

Including EKG abnormalities in a regression model of traditional risk factors improved stratification (overall net reclassification improvement [NRI]=7.4%; 95% CI, 3.1%-19.0%).⁶ No low-risk patients were reclassified as high risk and no high-risk patients were reclassified as low risk. Overall, 156 intermediate risk patients were correctly reclassified and an equal number were incorrectly reclassified. Adding EKG abnormalities to the Framingham Risk Score (which hasn’t been validated in adults >75 years) didn’t significantly improve stratification (NRI=5.7%; 95% CI, −0.4% to 11.8%).⁶

Comparing ED with baseline EKGs has little effect on management
A 1980 retrospective study looked at 236 patients with acute chest pain and no known CHD who were seen in the ED. Comparing routine baseline EKGs obtained before ED presentation for 6 of 41 patients with equivocal EKGs in the ED—including T-wave inversions, nonspecific T-wave and ST-segment abnormalities, and bundle branch blocks—prevented 2 admissions (no EKG change from baseline) and caused 4 unnecessary admissions (EKG changed from baseline with no subsequent evidence of acute coronary syndromes).⁷

A 1985 prospective study of 84 ED patients, in which treating physicians were given baseline EKGs after committing to an initial disposition plan, showed that the baseline EKG altered the decision to admit or discharge in only one case.⁸

A 1990 prospective multicenter study of 5673 patients older than 30 years—41% of whom had known CHD—reported that when the current EKG was consistent with ischemia or infarction, a baseline EKG showing the changes to be old (10% of study population) increased the likelihood that the patient would be discharged from the ED to home (26% vs 12%; risk difference=14%; 95% CI, 7%-23%). Unlike previous studies, however, the exact role of the baseline EKG in the admission decision was isolated not by study design but rather by multivariate logistic regression modeling.⁹

Recommendations

The 2010 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for assessment of cardiovascular risk in asymptomatic adults states that a resting EKG is probably indicated in patients with diabetes and hypertension and that its usefulness in patients without these conditions isn’t well established.²

The US Preventive Services Task Force recommends against screening EKGs in adults at low risk for CHD events (grade D recommendation).¹⁰

Evidence summary

Three meta-analyses of studies lasting from 2 months to 5 years found that metformin reduced the risk of developing overt diabetes in at-risk adults when compared with placebo (TABLE).^1-3

Metformin is likely effective for as long as 10 years, based on long-term follow-up of patients in the Diabetes Prevention Program (DPP). In this trial, investigators randomized 3234 at-risk patients to 3 groups: metformin 850 mg twice daily; lifestyle modification (7% weight loss, 150 minutes of physical activity per week, and a one-to-one 16-lesson curriculum covering diet, exercise, and behavior modification); or placebo.⁴ At a mean 2.8-year follow-up, the incidence of diabetes was 31% lower in the metformin group (95% confidence interval [CI], 17%-43%) and 58% lower in the lifestyle modification group than in the placebo group (95% CI, 48%-66%; P<.001 for both comparisons).

At the close of the DPP trial, investigators offered lifestyle intervention to all 3 groups. Patients in the original metformin group continued to take metformin (with participants unblinded to assignment); patients in the original lifestyle intervention group were offered additional lifestyle support.⁵ At a median follow-up of 10 years after initial enrollment in the DPP trial, metformin reduced the incidence of overt diabetes by 18% compared with placebo (95% CI, 7%-28%), and lifestyle intervention reduced it by 34% (95% CI, 24%-42%; no statistic of comparison supplied).

Lifestyle modification works better than metformin in older adults
Another analysis found that metformin was equally effective in preventing diabetes in older and younger patients, whereas lifestyle modification was more effective in older patients. Investigators followed the patients in the DPP trial for an additional 5 months and stratified the effect of metformin and lifestyle modification by age.⁶

Metformin’s effectiveness didn’t change significantly in older adults compared with younger adults (hazard ratio [HR] for developing diabetes at age 60-85 years vs 25-44 years=1.45; 95% CI, 0.98-2.16; P=.06). In contrast, lifestyle modification worked better in older adults than younger adults (HR at age 60-85 years vs 25-44 years=0.47; 95% CI, 0.28- 0.78;P<.01).

Recommendations

The American Diabetes Association says that physicians may consider using metformin to prevent type 2 diabetes in patients at the highest risk, such as patients with multiple risk factors, especially if they show progression of hyperglycemia (HbA1c ≥6%, for example) despite lifestyle intervention.⁷

Evidence summary

Three meta-analyses of studies lasting from 2 months to 5 years found that metformin reduced the risk of developing overt diabetes in at-risk adults when compared with placebo (TABLE).^1-3

Metformin is likely effective for as long as 10 years, based on long-term follow-up of patients in the Diabetes Prevention Program (DPP). In this trial, investigators randomized 3234 at-risk patients to 3 groups: metformin 850 mg twice daily; lifestyle modification (7% weight loss, 150 minutes of physical activity per week, and a one-to-one 16-lesson curriculum covering diet, exercise, and behavior modification); or placebo.⁴ At a mean 2.8-year follow-up, the incidence of diabetes was 31% lower in the metformin group (95% confidence interval [CI], 17%-43%) and 58% lower in the lifestyle modification group than in the placebo group (95% CI, 48%-66%; P<.001 for both comparisons).

At the close of the DPP trial, investigators offered lifestyle intervention to all 3 groups. Patients in the original metformin group continued to take metformin (with participants unblinded to assignment); patients in the original lifestyle intervention group were offered additional lifestyle support.⁵ At a median follow-up of 10 years after initial enrollment in the DPP trial, metformin reduced the incidence of overt diabetes by 18% compared with placebo (95% CI, 7%-28%), and lifestyle intervention reduced it by 34% (95% CI, 24%-42%; no statistic of comparison supplied).

Lifestyle modification works better than metformin in older adults
Another analysis found that metformin was equally effective in preventing diabetes in older and younger patients, whereas lifestyle modification was more effective in older patients. Investigators followed the patients in the DPP trial for an additional 5 months and stratified the effect of metformin and lifestyle modification by age.⁶

Metformin’s effectiveness didn’t change significantly in older adults compared with younger adults (hazard ratio [HR] for developing diabetes at age 60-85 years vs 25-44 years=1.45; 95% CI, 0.98-2.16; P=.06). In contrast, lifestyle modification worked better in older adults than younger adults (HR at age 60-85 years vs 25-44 years=0.47; 95% CI, 0.28- 0.78;P<.01).

Recommendations

The American Diabetes Association says that physicians may consider using metformin to prevent type 2 diabetes in patients at the highest risk, such as patients with multiple risk factors, especially if they show progression of hyperglycemia (HbA1c ≥6%, for example) despite lifestyle intervention.⁷

Evidence summary

Three meta-analyses of studies lasting from 2 months to 5 years found that metformin reduced the risk of developing overt diabetes in at-risk adults when compared with placebo (TABLE).^1-3

Metformin is likely effective for as long as 10 years, based on long-term follow-up of patients in the Diabetes Prevention Program (DPP). In this trial, investigators randomized 3234 at-risk patients to 3 groups: metformin 850 mg twice daily; lifestyle modification (7% weight loss, 150 minutes of physical activity per week, and a one-to-one 16-lesson curriculum covering diet, exercise, and behavior modification); or placebo.⁴ At a mean 2.8-year follow-up, the incidence of diabetes was 31% lower in the metformin group (95% confidence interval [CI], 17%-43%) and 58% lower in the lifestyle modification group than in the placebo group (95% CI, 48%-66%; P<.001 for both comparisons).

At the close of the DPP trial, investigators offered lifestyle intervention to all 3 groups. Patients in the original metformin group continued to take metformin (with participants unblinded to assignment); patients in the original lifestyle intervention group were offered additional lifestyle support.⁵ At a median follow-up of 10 years after initial enrollment in the DPP trial, metformin reduced the incidence of overt diabetes by 18% compared with placebo (95% CI, 7%-28%), and lifestyle intervention reduced it by 34% (95% CI, 24%-42%; no statistic of comparison supplied).

Lifestyle modification works better than metformin in older adults
Another analysis found that metformin was equally effective in preventing diabetes in older and younger patients, whereas lifestyle modification was more effective in older patients. Investigators followed the patients in the DPP trial for an additional 5 months and stratified the effect of metformin and lifestyle modification by age.⁶

Metformin’s effectiveness didn’t change significantly in older adults compared with younger adults (hazard ratio [HR] for developing diabetes at age 60-85 years vs 25-44 years=1.45; 95% CI, 0.98-2.16; P=.06). In contrast, lifestyle modification worked better in older adults than younger adults (HR at age 60-85 years vs 25-44 years=0.47; 95% CI, 0.28- 0.78;P<.01).

Recommendations

The American Diabetes Association says that physicians may consider using metformin to prevent type 2 diabetes in patients at the highest risk, such as patients with multiple risk factors, especially if they show progression of hyperglycemia (HbA1c ≥6%, for example) despite lifestyle intervention.⁷

Evidence summary

A systematic review found 7 RCTs with a total of 686 subjects that compared compression with no compression for venous leg ulcers.¹  Although the outcome data were too heterogeneous for a meta-analysis, the 4 studies in which statistical analysis was possible showed that compression healed venous leg ulcers faster than no compression (relative risk [RR] range=1.2 to 4 in favor of compression), as detailed in the TABLE. Notably, only 2 of the studies achieved statistical significance (P<.05).

Two other studies in this review, with 20 and 245 patients, compared 4-component with single-component compression. In the smaller study, multicomponent compression produced more completely healed ulcers at 12 weeks, but the difference wasn’t statistically significant.

In the larger study, nonhealing at 24 weeks was much less common among patients treated with multicomponent compression than single-component therapy (RR=0.74; 95% confidence interval [CI], 0.59-0.92; number needed to treat [NNT]=5.7; P=.009), and median time to healing was shorter(78 vs 168 days; statistical significance not reported).

The reviewers concluded that compression increases ulcer healing rates compared with no compression and that multicomponent systems are more effective than single component systems.¹

Similar results, different costs among dressing types
A systematic review and meta-analysis of 42 RCTs that included 3001 patients compared multiple dressing types, including hydrocolloid, foam, alginate, and low-adherent dressings, used beneath compression.² The study found no significant differences in healing rates among the dressings, although costs varied widely.

Systemic therapy: Aspirin and pentoxifylline help
Systemic or topical treatments are an alternative for patients with contraindications or intolerance to compression. An RCT of 20 patients that compared aspirin 300 mg/day with placebo found higher ulcer healing rates in the aspirin group after 4 months (38% vs 0%; NNT=2.6; P<.007). Improvement, defined as reduction in ulcer size, occurred in 52%of patients treated with aspirin but only 26%treated with placebo(NNT=3.8;P<.007).³

A systematic review of 11 trials (N=841) found that pentoxifylline accelerated healing rates vs placebo (NNT=4; 95% CI, 3-6); the authors recommended its use in conjunction with compression therapy when possible.⁴

Another systematic review of 5 RCTs (N=232) found that systemic antibiotics didn’t improve outcomes significantly more than placebo.⁵

Topical cadexomer iodine: Effective, but is it feasible?
One of the 5 reviewed RCTs (60 patients) found that topical cadexomer iodine produced more frequent healing than standard care at 6 weeks (NNT=3;95%CI,2-19).⁵ However, the cadexomer regimen involved daily dressing changes, which might limit feasibility in many clinical settings.

Systemic aspirin and pentoxifylline improve healing rates, but systemic antibiotics don’t. Other interventions to consider for venous ulcers include hyperbaric oxygen and venous surgery. 

Recommendations

The Association for the Advancement of Wound Care recommends compression therapy and limb elevation to reduce edema.  They also recommend cleaning the ulcer with a safe cleanser, debriding nonvital tissue, maintaining a moist wound environment, and managing pain and odor.⁶

The Wound, Ostomy, and Continence Nurses Society and the American Society of Plastic Surgeons make similar recommendations: ulcer debridement, edema management, infection control, and pain management.^7,8

Evidence summary

A systematic review found 7 RCTs with a total of 686 subjects that compared compression with no compression for venous leg ulcers.¹  Although the outcome data were too heterogeneous for a meta-analysis, the 4 studies in which statistical analysis was possible showed that compression healed venous leg ulcers faster than no compression (relative risk [RR] range=1.2 to 4 in favor of compression), as detailed in the TABLE. Notably, only 2 of the studies achieved statistical significance (P<.05).

Two other studies in this review, with 20 and 245 patients, compared 4-component with single-component compression. In the smaller study, multicomponent compression produced more completely healed ulcers at 12 weeks, but the difference wasn’t statistically significant.

In the larger study, nonhealing at 24 weeks was much less common among patients treated with multicomponent compression than single-component therapy (RR=0.74; 95% confidence interval [CI], 0.59-0.92; number needed to treat [NNT]=5.7; P=.009), and median time to healing was shorter(78 vs 168 days; statistical significance not reported).

The reviewers concluded that compression increases ulcer healing rates compared with no compression and that multicomponent systems are more effective than single component systems.¹

Similar results, different costs among dressing types
A systematic review and meta-analysis of 42 RCTs that included 3001 patients compared multiple dressing types, including hydrocolloid, foam, alginate, and low-adherent dressings, used beneath compression.² The study found no significant differences in healing rates among the dressings, although costs varied widely.

Systemic therapy: Aspirin and pentoxifylline help
Systemic or topical treatments are an alternative for patients with contraindications or intolerance to compression. An RCT of 20 patients that compared aspirin 300 mg/day with placebo found higher ulcer healing rates in the aspirin group after 4 months (38% vs 0%; NNT=2.6; P<.007). Improvement, defined as reduction in ulcer size, occurred in 52%of patients treated with aspirin but only 26%treated with placebo(NNT=3.8;P<.007).³

A systematic review of 11 trials (N=841) found that pentoxifylline accelerated healing rates vs placebo (NNT=4; 95% CI, 3-6); the authors recommended its use in conjunction with compression therapy when possible.⁴

Another systematic review of 5 RCTs (N=232) found that systemic antibiotics didn’t improve outcomes significantly more than placebo.⁵

Topical cadexomer iodine: Effective, but is it feasible?
One of the 5 reviewed RCTs (60 patients) found that topical cadexomer iodine produced more frequent healing than standard care at 6 weeks (NNT=3;95%CI,2-19).⁵ However, the cadexomer regimen involved daily dressing changes, which might limit feasibility in many clinical settings.

Systemic aspirin and pentoxifylline improve healing rates, but systemic antibiotics don’t. Other interventions to consider for venous ulcers include hyperbaric oxygen and venous surgery. 

Recommendations

The Association for the Advancement of Wound Care recommends compression therapy and limb elevation to reduce edema.  They also recommend cleaning the ulcer with a safe cleanser, debriding nonvital tissue, maintaining a moist wound environment, and managing pain and odor.⁶

The Wound, Ostomy, and Continence Nurses Society and the American Society of Plastic Surgeons make similar recommendations: ulcer debridement, edema management, infection control, and pain management.^7,8

Evidence summary

A systematic review found 7 RCTs with a total of 686 subjects that compared compression with no compression for venous leg ulcers.¹  Although the outcome data were too heterogeneous for a meta-analysis, the 4 studies in which statistical analysis was possible showed that compression healed venous leg ulcers faster than no compression (relative risk [RR] range=1.2 to 4 in favor of compression), as detailed in the TABLE. Notably, only 2 of the studies achieved statistical significance (P<.05).

Two other studies in this review, with 20 and 245 patients, compared 4-component with single-component compression. In the smaller study, multicomponent compression produced more completely healed ulcers at 12 weeks, but the difference wasn’t statistically significant.

In the larger study, nonhealing at 24 weeks was much less common among patients treated with multicomponent compression than single-component therapy (RR=0.74; 95% confidence interval [CI], 0.59-0.92; number needed to treat [NNT]=5.7; P=.009), and median time to healing was shorter(78 vs 168 days; statistical significance not reported).

The reviewers concluded that compression increases ulcer healing rates compared with no compression and that multicomponent systems are more effective than single component systems.¹

Similar results, different costs among dressing types
A systematic review and meta-analysis of 42 RCTs that included 3001 patients compared multiple dressing types, including hydrocolloid, foam, alginate, and low-adherent dressings, used beneath compression.² The study found no significant differences in healing rates among the dressings, although costs varied widely.

Systemic therapy: Aspirin and pentoxifylline help
Systemic or topical treatments are an alternative for patients with contraindications or intolerance to compression. An RCT of 20 patients that compared aspirin 300 mg/day with placebo found higher ulcer healing rates in the aspirin group after 4 months (38% vs 0%; NNT=2.6; P<.007). Improvement, defined as reduction in ulcer size, occurred in 52%of patients treated with aspirin but only 26%treated with placebo(NNT=3.8;P<.007).³

A systematic review of 11 trials (N=841) found that pentoxifylline accelerated healing rates vs placebo (NNT=4; 95% CI, 3-6); the authors recommended its use in conjunction with compression therapy when possible.⁴

Another systematic review of 5 RCTs (N=232) found that systemic antibiotics didn’t improve outcomes significantly more than placebo.⁵

Topical cadexomer iodine: Effective, but is it feasible?
One of the 5 reviewed RCTs (60 patients) found that topical cadexomer iodine produced more frequent healing than standard care at 6 weeks (NNT=3;95%CI,2-19).⁵ However, the cadexomer regimen involved daily dressing changes, which might limit feasibility in many clinical settings.

Systemic aspirin and pentoxifylline improve healing rates, but systemic antibiotics don’t. Other interventions to consider for venous ulcers include hyperbaric oxygen and venous surgery. 

Recommendations

The Association for the Advancement of Wound Care recommends compression therapy and limb elevation to reduce edema.  They also recommend cleaning the ulcer with a safe cleanser, debriding nonvital tissue, maintaining a moist wound environment, and managing pain and odor.⁶

The Wound, Ostomy, and Continence Nurses Society and the American Society of Plastic Surgeons make similar recommendations: ulcer debridement, edema management, infection control, and pain management.^7,8

Evidence summary

A meta-analysis by the Agency for Healthcare Research and Quality of 37 RCTs examined off-label use of atypical antipsychotics in a total of 5364 patients.¹ Pooled results from 17 RCTs showed a statistically significant but clinically modest difference between atypical antipsychotics and placebo for agitation; the standard mean difference was 0.22 (95% confidence interval [CI], 0.09-0.35). Investigators found statistically significant but small effect sizes for aripiprazole, olanzapine, and risperidone.

Atypical antipsychotics are associated with serious adverse cerebrovascular events and extrapyramidal symptoms. A meta-analysis of 17 RCTs (N= 5106) demonstrated that patients who received antipsychotics had higher mortality than patients who received placebo (3.5% vs 2.3%).²

Haloperidol has significant adverse effects without significant results
A systematic review of 5 RCTs compared haloperidol with placebo over 3 to 16 weeks in 856 patients ages 72 to 81 years with dementia and agitation.³ When investigators pooled results from 3 RCTs (N=690) using an intention-to-treat analysis and 3 assessment tools, they found that haloperidol produced a statistically significant, but not clinically meaningful, standard mean difference in aggression.

Adverse effects included extrapyramidal symptoms (odds ratio [OR]=2.34; 95% CI, 1.25-4.38; number needed to harm [NNH]=6), somnolence (OR=4.20; 95% CI, 1.78-9.91; NNH=8), and fatigue (OR=5.39; 95% CI, 2.04-14.22; NNH=3). Most studies were underpowered, didn’t document randomization, and had dropout rates as high as 20%.

Antidepressants have no effect
A systematic review of 9 RCTs involving 692 patients with dementia compared antidepressants with placebo, other antidepressants, and antipsychotics using various neuropsychiatric symptom scales.⁴ Investigators performed meta-analyses for numerous outcomes but found none of clinical or statistical significance.

Pooled analysis of 2 RCTs that examined a total of 250 outpatients with Alzheimer’s disease found that sertraline and fluoxetine produced a statistically, but not clinically, significant difference in the Cohen Mansfield Agitation Inventory total score. One RCT (N=52) demonstrated that citalopram improved the Neurobehavioral Rating Scale total score after adjusting for baseline severity.

Investigators found no difference in withdrawal rates between SSRIs and placebo (relative risk=1.07; 95% CI, 0.55-2.11). All studies had multiple methodological limitations.

Melatonin has no adverse effects, but no benefit either
A systematic review that included 2 RCTs compared melatonin with placebo for agitation in 121 patients ages 77 to 79 years with dementia.⁵ Investigators prescribed melatonin for periods of 4 to 7 weeks and found reductions in agitation that were statistically significant, but not clinically meaningful. They reported no adverse events. The studies had a low risk of bias.

Recommendations

The American Psychiatric Association (APA) advocates evaluating and treating secondary causes of agitation and using environmental and behavioral measures to reduce agitation.⁶ The APA advocates using the lowest effective dosages of antipsychotics after considering adverse effect profiles and the risks of not treating.

The APA recommends benzodiazepines to treat prominent anxiety or infrequent agitation, preferably lorazepam and oxazepam rather than diazepam or clonazepam and suggests trazodone or SSRIs as alternative therapy for agitation in patients without psychosis or those who are intolerant to antipsychotics.⁶

Evidence summary

A meta-analysis by the Agency for Healthcare Research and Quality of 37 RCTs examined off-label use of atypical antipsychotics in a total of 5364 patients.¹ Pooled results from 17 RCTs showed a statistically significant but clinically modest difference between atypical antipsychotics and placebo for agitation; the standard mean difference was 0.22 (95% confidence interval [CI], 0.09-0.35). Investigators found statistically significant but small effect sizes for aripiprazole, olanzapine, and risperidone.

Atypical antipsychotics are associated with serious adverse cerebrovascular events and extrapyramidal symptoms. A meta-analysis of 17 RCTs (N= 5106) demonstrated that patients who received antipsychotics had higher mortality than patients who received placebo (3.5% vs 2.3%).²

Haloperidol has significant adverse effects without significant results
A systematic review of 5 RCTs compared haloperidol with placebo over 3 to 16 weeks in 856 patients ages 72 to 81 years with dementia and agitation.³ When investigators pooled results from 3 RCTs (N=690) using an intention-to-treat analysis and 3 assessment tools, they found that haloperidol produced a statistically significant, but not clinically meaningful, standard mean difference in aggression.

Adverse effects included extrapyramidal symptoms (odds ratio [OR]=2.34; 95% CI, 1.25-4.38; number needed to harm [NNH]=6), somnolence (OR=4.20; 95% CI, 1.78-9.91; NNH=8), and fatigue (OR=5.39; 95% CI, 2.04-14.22; NNH=3). Most studies were underpowered, didn’t document randomization, and had dropout rates as high as 20%.

Antidepressants have no effect
A systematic review of 9 RCTs involving 692 patients with dementia compared antidepressants with placebo, other antidepressants, and antipsychotics using various neuropsychiatric symptom scales.⁴ Investigators performed meta-analyses for numerous outcomes but found none of clinical or statistical significance.

Pooled analysis of 2 RCTs that examined a total of 250 outpatients with Alzheimer’s disease found that sertraline and fluoxetine produced a statistically, but not clinically, significant difference in the Cohen Mansfield Agitation Inventory total score. One RCT (N=52) demonstrated that citalopram improved the Neurobehavioral Rating Scale total score after adjusting for baseline severity.

Investigators found no difference in withdrawal rates between SSRIs and placebo (relative risk=1.07; 95% CI, 0.55-2.11). All studies had multiple methodological limitations.

Melatonin has no adverse effects, but no benefit either
A systematic review that included 2 RCTs compared melatonin with placebo for agitation in 121 patients ages 77 to 79 years with dementia.⁵ Investigators prescribed melatonin for periods of 4 to 7 weeks and found reductions in agitation that were statistically significant, but not clinically meaningful. They reported no adverse events. The studies had a low risk of bias.

Recommendations

The American Psychiatric Association (APA) advocates evaluating and treating secondary causes of agitation and using environmental and behavioral measures to reduce agitation.⁶ The APA advocates using the lowest effective dosages of antipsychotics after considering adverse effect profiles and the risks of not treating.

The APA recommends benzodiazepines to treat prominent anxiety or infrequent agitation, preferably lorazepam and oxazepam rather than diazepam or clonazepam and suggests trazodone or SSRIs as alternative therapy for agitation in patients without psychosis or those who are intolerant to antipsychotics.⁶

Evidence summary

A meta-analysis by the Agency for Healthcare Research and Quality of 37 RCTs examined off-label use of atypical antipsychotics in a total of 5364 patients.¹ Pooled results from 17 RCTs showed a statistically significant but clinically modest difference between atypical antipsychotics and placebo for agitation; the standard mean difference was 0.22 (95% confidence interval [CI], 0.09-0.35). Investigators found statistically significant but small effect sizes for aripiprazole, olanzapine, and risperidone.

Atypical antipsychotics are associated with serious adverse cerebrovascular events and extrapyramidal symptoms. A meta-analysis of 17 RCTs (N= 5106) demonstrated that patients who received antipsychotics had higher mortality than patients who received placebo (3.5% vs 2.3%).²

Haloperidol has significant adverse effects without significant results
A systematic review of 5 RCTs compared haloperidol with placebo over 3 to 16 weeks in 856 patients ages 72 to 81 years with dementia and agitation.³ When investigators pooled results from 3 RCTs (N=690) using an intention-to-treat analysis and 3 assessment tools, they found that haloperidol produced a statistically significant, but not clinically meaningful, standard mean difference in aggression.

Adverse effects included extrapyramidal symptoms (odds ratio [OR]=2.34; 95% CI, 1.25-4.38; number needed to harm [NNH]=6), somnolence (OR=4.20; 95% CI, 1.78-9.91; NNH=8), and fatigue (OR=5.39; 95% CI, 2.04-14.22; NNH=3). Most studies were underpowered, didn’t document randomization, and had dropout rates as high as 20%.

Antidepressants have no effect
A systematic review of 9 RCTs involving 692 patients with dementia compared antidepressants with placebo, other antidepressants, and antipsychotics using various neuropsychiatric symptom scales.⁴ Investigators performed meta-analyses for numerous outcomes but found none of clinical or statistical significance.

Pooled analysis of 2 RCTs that examined a total of 250 outpatients with Alzheimer’s disease found that sertraline and fluoxetine produced a statistically, but not clinically, significant difference in the Cohen Mansfield Agitation Inventory total score. One RCT (N=52) demonstrated that citalopram improved the Neurobehavioral Rating Scale total score after adjusting for baseline severity.

Investigators found no difference in withdrawal rates between SSRIs and placebo (relative risk=1.07; 95% CI, 0.55-2.11). All studies had multiple methodological limitations.

Melatonin has no adverse effects, but no benefit either
A systematic review that included 2 RCTs compared melatonin with placebo for agitation in 121 patients ages 77 to 79 years with dementia.⁵ Investigators prescribed melatonin for periods of 4 to 7 weeks and found reductions in agitation that were statistically significant, but not clinically meaningful. They reported no adverse events. The studies had a low risk of bias.

Recommendations

The American Psychiatric Association (APA) advocates evaluating and treating secondary causes of agitation and using environmental and behavioral measures to reduce agitation.⁶ The APA advocates using the lowest effective dosages of antipsychotics after considering adverse effect profiles and the risks of not treating.

The APA recommends benzodiazepines to treat prominent anxiety or infrequent agitation, preferably lorazepam and oxazepam rather than diazepam or clonazepam and suggests trazodone or SSRIs as alternative therapy for agitation in patients without psychosis or those who are intolerant to antipsychotics.⁶