Kristin Hitchcock, MSI

Evidence summary

Psychotic symptoms, including aggression, in patients with dementia are a leading cause of nursing home placement and pharmacologic treatment. RCTs have demonstrated the efficacy of atypical antipsychotics in aggressive nursing home patients.

Risperidone significantly reduces aggression
An RCT comparing risperidone with placebo in 345 patients found that low-dose risperidone (mean 0.95 mg/d) significantly improved aggression scores (number needed to treat [NNT][H11005]4; P<.001). Serious adverse events included injury, cerebrovascular events, pneumonia, and accidental overdose (number needed to harm [NNH][H11005]13).¹ Other RCTs also have found risperidone to be effective in reducing aggressive behavior.^2,3

Olanzapine is effective and well tolerated
Researchers have also studied olanzapine, another atypical antipsychotic. A 6-week RCT of 206 elderly nursing home patients with Alzheimer’s disease and psychotic or behavioral symptoms found that low-dose olanzapine (5 or 10 mg/d) decreased agitation and aggression scores (olanzapine 5 mg: NNT=5; olanzapine 10 mg: NNT=6) compared with placebo. Commonly reported adverse effects included somnolence (5 mg: NNH=5; 10 mg: NNH=5) and gait disturbance (5 mg: NNH=6; 10 mg: NNH=8).⁴ An open-label follow-up study also found low-dose olanzapine to be well tolerated and effective in decreasing agitation and aggression scores.⁵

Weigh the benefits against the risks
The US Food and Drug Administration issued a public health advisory regarding increased mortality risk after reviewing RCTs that evaluated atypical antipsychotics in patients with dementia.⁶ A meta-analysis of 15 RCTs (N=5110) that studied olanzapine, aripiprazole, risperidone, and quetiapine in patients with dementia demonstrated a small, but increased risk of death associated with their use when compared with placebo (3.5% vs 2.3%; odds ratio=1.54; 95% confidence interval [CI], 1.06-2.23; P=.02; NNH= 83).⁷

A population-based (community and long-term care facilities), retrospective cohort study of atypical and conventional antipsychotics involving 27,259 matched pairs also suggested an increased risk of death. Thirty days after beginning an atypical antipsychotic medication, increased mortality was noted when compared with no antipsychotic use in both the community cohort (adjusted hazard ratio [AHR]=1.31 [95% CI, 1.02-1.70]; NNH=500) and the long-term care cohort (AHR=1.55 [95% CI, 1.15-2.07]; absolute risk difference=1.2 percentage points; NNH=83). Conventional antipsychotics were associated with higher rates of death than atypical antipsychotics (absolute risk difference=2.6 percentage points in the community group [NNH=38] and 2.2 percentage points in the long-term care groups [NNH=45]).⁸

SSRIs may be an alternative
An RCT comparing citalopram and risperidone over 12 weeks in 103 patients with dementia demonstrated similar efficacy for the 2 drugs in treating agitation. Patients receiving citalopram experienced fewer adverse effects than those receiving risperidone.⁹ The study suggests that SSRIs may be an alternative to atypical antipsychotics.

Carbamazepine helps, valproate doesn’t
Evidence regarding the use of antiepileptic medications is conflicting. One RCT of 51 patients found carbamazepine 300 mg daily to be efficacious for short-term control of agitation with good safety and tolerability. Six weeks after beginning the study, Overt Aggression Scale scores decreased 6.7 points for carbamazepine compared with 1.9 points for placebo (P=.008). Adverse effects, including ataxia, drowsiness, postural instability, rash, weakness, and disorientation, were more common in the carbamazepine group than the placebo group (absolute risk increase=30%; NNH=3).¹⁰

When compared with placebo, 480 mg daily of sodium valproate for 8 weeks showed no differences in controlling aggressive behavior.¹¹ In an open-label follow-up study, aggressive behavior improved from 10.52 on the Social Dysfunction and Aggression Scale to 6.31 (P<.001), but no improvement was observed using the Clinical Global Impression Scale for aggressive behavior. Seven deaths that authors couldn’t attribute to the drug occurred. Three patients experienced drowsiness. No other adverse events were noted.¹²

A very small, double-blind crossover RCT (N=14) evaluated 250 to 1500 mg sodium valproate daily for 6 weeks compared with placebo. A 2-week period separated the valproate and placebo regimens. Neuropsychiatric Inventory agitation and aggression scores worsened significantly with valproate (increase of 1.43 points compared with a decrease of 2.08 points with placebo; P=.04). Adverse events related to valproate included falls, sedation, loss of appetite, thrombocytopenia, and loose stools (NNH=3).¹³

Recommendations

The Expert Consensus Guideline for the Treatment of Agitation in Older Persons with Dementia¹⁴ and treatment guidelines for Alzheimer’s disease and other dementias from the American Psychiatric Association (APA)¹⁵ offer different recommendations for first-line treatment.

The Expert Consensus Guideline recommends divalproate, risperidone, and conventional high-potency antipsychotics for patients with severe anger and physical aggression. Alternative treatments include olanzapine, carbamazepine, trazodone, and SSRIs.¹⁴

The APA recommends antipsychotics to treat agitation based on available evidence. If treatment fails, consider anticonvulsants, lithium, or beta-blockers. The APA notes that although evidence for SSRIs is limited, they may be appropriate for agitated nonpsychotic patients.¹⁵

Evidence summary

Psychotic symptoms, including aggression, in patients with dementia are a leading cause of nursing home placement and pharmacologic treatment. RCTs have demonstrated the efficacy of atypical antipsychotics in aggressive nursing home patients.

Risperidone significantly reduces aggression
An RCT comparing risperidone with placebo in 345 patients found that low-dose risperidone (mean 0.95 mg/d) significantly improved aggression scores (number needed to treat [NNT][H11005]4; P<.001). Serious adverse events included injury, cerebrovascular events, pneumonia, and accidental overdose (number needed to harm [NNH][H11005]13).¹ Other RCTs also have found risperidone to be effective in reducing aggressive behavior.^2,3

Olanzapine is effective and well tolerated
Researchers have also studied olanzapine, another atypical antipsychotic. A 6-week RCT of 206 elderly nursing home patients with Alzheimer’s disease and psychotic or behavioral symptoms found that low-dose olanzapine (5 or 10 mg/d) decreased agitation and aggression scores (olanzapine 5 mg: NNT=5; olanzapine 10 mg: NNT=6) compared with placebo. Commonly reported adverse effects included somnolence (5 mg: NNH=5; 10 mg: NNH=5) and gait disturbance (5 mg: NNH=6; 10 mg: NNH=8).⁴ An open-label follow-up study also found low-dose olanzapine to be well tolerated and effective in decreasing agitation and aggression scores.⁵

Weigh the benefits against the risks
The US Food and Drug Administration issued a public health advisory regarding increased mortality risk after reviewing RCTs that evaluated atypical antipsychotics in patients with dementia.⁶ A meta-analysis of 15 RCTs (N=5110) that studied olanzapine, aripiprazole, risperidone, and quetiapine in patients with dementia demonstrated a small, but increased risk of death associated with their use when compared with placebo (3.5% vs 2.3%; odds ratio=1.54; 95% confidence interval [CI], 1.06-2.23; P=.02; NNH= 83).⁷

A population-based (community and long-term care facilities), retrospective cohort study of atypical and conventional antipsychotics involving 27,259 matched pairs also suggested an increased risk of death. Thirty days after beginning an atypical antipsychotic medication, increased mortality was noted when compared with no antipsychotic use in both the community cohort (adjusted hazard ratio [AHR]=1.31 [95% CI, 1.02-1.70]; NNH=500) and the long-term care cohort (AHR=1.55 [95% CI, 1.15-2.07]; absolute risk difference=1.2 percentage points; NNH=83). Conventional antipsychotics were associated with higher rates of death than atypical antipsychotics (absolute risk difference=2.6 percentage points in the community group [NNH=38] and 2.2 percentage points in the long-term care groups [NNH=45]).⁸

SSRIs may be an alternative
An RCT comparing citalopram and risperidone over 12 weeks in 103 patients with dementia demonstrated similar efficacy for the 2 drugs in treating agitation. Patients receiving citalopram experienced fewer adverse effects than those receiving risperidone.⁹ The study suggests that SSRIs may be an alternative to atypical antipsychotics.

Carbamazepine helps, valproate doesn’t
Evidence regarding the use of antiepileptic medications is conflicting. One RCT of 51 patients found carbamazepine 300 mg daily to be efficacious for short-term control of agitation with good safety and tolerability. Six weeks after beginning the study, Overt Aggression Scale scores decreased 6.7 points for carbamazepine compared with 1.9 points for placebo (P=.008). Adverse effects, including ataxia, drowsiness, postural instability, rash, weakness, and disorientation, were more common in the carbamazepine group than the placebo group (absolute risk increase=30%; NNH=3).¹⁰

When compared with placebo, 480 mg daily of sodium valproate for 8 weeks showed no differences in controlling aggressive behavior.¹¹ In an open-label follow-up study, aggressive behavior improved from 10.52 on the Social Dysfunction and Aggression Scale to 6.31 (P<.001), but no improvement was observed using the Clinical Global Impression Scale for aggressive behavior. Seven deaths that authors couldn’t attribute to the drug occurred. Three patients experienced drowsiness. No other adverse events were noted.¹²

A very small, double-blind crossover RCT (N=14) evaluated 250 to 1500 mg sodium valproate daily for 6 weeks compared with placebo. A 2-week period separated the valproate and placebo regimens. Neuropsychiatric Inventory agitation and aggression scores worsened significantly with valproate (increase of 1.43 points compared with a decrease of 2.08 points with placebo; P=.04). Adverse events related to valproate included falls, sedation, loss of appetite, thrombocytopenia, and loose stools (NNH=3).¹³

Recommendations

The Expert Consensus Guideline for the Treatment of Agitation in Older Persons with Dementia¹⁴ and treatment guidelines for Alzheimer’s disease and other dementias from the American Psychiatric Association (APA)¹⁵ offer different recommendations for first-line treatment.

The Expert Consensus Guideline recommends divalproate, risperidone, and conventional high-potency antipsychotics for patients with severe anger and physical aggression. Alternative treatments include olanzapine, carbamazepine, trazodone, and SSRIs.¹⁴

The APA recommends antipsychotics to treat agitation based on available evidence. If treatment fails, consider anticonvulsants, lithium, or beta-blockers. The APA notes that although evidence for SSRIs is limited, they may be appropriate for agitated nonpsychotic patients.¹⁵

Evidence summary

Psychotic symptoms, including aggression, in patients with dementia are a leading cause of nursing home placement and pharmacologic treatment. RCTs have demonstrated the efficacy of atypical antipsychotics in aggressive nursing home patients.

Risperidone significantly reduces aggression
An RCT comparing risperidone with placebo in 345 patients found that low-dose risperidone (mean 0.95 mg/d) significantly improved aggression scores (number needed to treat [NNT][H11005]4; P<.001). Serious adverse events included injury, cerebrovascular events, pneumonia, and accidental overdose (number needed to harm [NNH][H11005]13).¹ Other RCTs also have found risperidone to be effective in reducing aggressive behavior.^2,3

Olanzapine is effective and well tolerated
Researchers have also studied olanzapine, another atypical antipsychotic. A 6-week RCT of 206 elderly nursing home patients with Alzheimer’s disease and psychotic or behavioral symptoms found that low-dose olanzapine (5 or 10 mg/d) decreased agitation and aggression scores (olanzapine 5 mg: NNT=5; olanzapine 10 mg: NNT=6) compared with placebo. Commonly reported adverse effects included somnolence (5 mg: NNH=5; 10 mg: NNH=5) and gait disturbance (5 mg: NNH=6; 10 mg: NNH=8).⁴ An open-label follow-up study also found low-dose olanzapine to be well tolerated and effective in decreasing agitation and aggression scores.⁵

Weigh the benefits against the risks
The US Food and Drug Administration issued a public health advisory regarding increased mortality risk after reviewing RCTs that evaluated atypical antipsychotics in patients with dementia.⁶ A meta-analysis of 15 RCTs (N=5110) that studied olanzapine, aripiprazole, risperidone, and quetiapine in patients with dementia demonstrated a small, but increased risk of death associated with their use when compared with placebo (3.5% vs 2.3%; odds ratio=1.54; 95% confidence interval [CI], 1.06-2.23; P=.02; NNH= 83).⁷

A population-based (community and long-term care facilities), retrospective cohort study of atypical and conventional antipsychotics involving 27,259 matched pairs also suggested an increased risk of death. Thirty days after beginning an atypical antipsychotic medication, increased mortality was noted when compared with no antipsychotic use in both the community cohort (adjusted hazard ratio [AHR]=1.31 [95% CI, 1.02-1.70]; NNH=500) and the long-term care cohort (AHR=1.55 [95% CI, 1.15-2.07]; absolute risk difference=1.2 percentage points; NNH=83). Conventional antipsychotics were associated with higher rates of death than atypical antipsychotics (absolute risk difference=2.6 percentage points in the community group [NNH=38] and 2.2 percentage points in the long-term care groups [NNH=45]).⁸

SSRIs may be an alternative
An RCT comparing citalopram and risperidone over 12 weeks in 103 patients with dementia demonstrated similar efficacy for the 2 drugs in treating agitation. Patients receiving citalopram experienced fewer adverse effects than those receiving risperidone.⁹ The study suggests that SSRIs may be an alternative to atypical antipsychotics.

Carbamazepine helps, valproate doesn’t
Evidence regarding the use of antiepileptic medications is conflicting. One RCT of 51 patients found carbamazepine 300 mg daily to be efficacious for short-term control of agitation with good safety and tolerability. Six weeks after beginning the study, Overt Aggression Scale scores decreased 6.7 points for carbamazepine compared with 1.9 points for placebo (P=.008). Adverse effects, including ataxia, drowsiness, postural instability, rash, weakness, and disorientation, were more common in the carbamazepine group than the placebo group (absolute risk increase=30%; NNH=3).¹⁰

When compared with placebo, 480 mg daily of sodium valproate for 8 weeks showed no differences in controlling aggressive behavior.¹¹ In an open-label follow-up study, aggressive behavior improved from 10.52 on the Social Dysfunction and Aggression Scale to 6.31 (P<.001), but no improvement was observed using the Clinical Global Impression Scale for aggressive behavior. Seven deaths that authors couldn’t attribute to the drug occurred. Three patients experienced drowsiness. No other adverse events were noted.¹²

A very small, double-blind crossover RCT (N=14) evaluated 250 to 1500 mg sodium valproate daily for 6 weeks compared with placebo. A 2-week period separated the valproate and placebo regimens. Neuropsychiatric Inventory agitation and aggression scores worsened significantly with valproate (increase of 1.43 points compared with a decrease of 2.08 points with placebo; P=.04). Adverse events related to valproate included falls, sedation, loss of appetite, thrombocytopenia, and loose stools (NNH=3).¹³

Recommendations

The Expert Consensus Guideline for the Treatment of Agitation in Older Persons with Dementia¹⁴ and treatment guidelines for Alzheimer’s disease and other dementias from the American Psychiatric Association (APA)¹⁵ offer different recommendations for first-line treatment.

The Expert Consensus Guideline recommends divalproate, risperidone, and conventional high-potency antipsychotics for patients with severe anger and physical aggression. Alternative treatments include olanzapine, carbamazepine, trazodone, and SSRIs.¹⁴

The APA recommends antipsychotics to treat agitation based on available evidence. If treatment fails, consider anticonvulsants, lithium, or beta-blockers. The APA notes that although evidence for SSRIs is limited, they may be appropriate for agitated nonpsychotic patients.¹⁵

Evidence summary

The National Cholesterol Education Program’s definition of “very high risk” for coronary heart disease (CHD) encompasses established CHD and CHD equivalents, including diabetes, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, and multiple cardiac risk factors that confer a 10-year calculated cardiac risk greater than 20%.¹

Statin dosage: Bigger is better

The Treating to New Targets (TNT) study showed that in patients with stable CHD, intensive lipid lowering with atorvastatin 80 mg daily delivered significant clinical benefit beyond that provided by atorvastatin 10 mg daily.² The mean LDL achieved in TNT was 77 mg/dL on 80 mg atorvastatin, compared with 101 mg/dL on 10 mg.

Patients with diabetes who took 80 mg had a 2.26% absolute risk reduction for major cardiovascular events (number needed to treat=43). Secondary outcomes—including all cardiovascular events, cerebrovascular events, and congestive heart failure with hospitalization—also improved on 80 mg atorvastatin.

Although this study enrolled a total of 10,001 patients with clinically evident CHD, it was not sufficiently powered to demonstrate differences in overall mortality between the 2 groups. While it is clear that patients in the 80-mg group had better outcomes than patients in the lower-dose group, the exact role of LDL lowering cannot be easily separated from other potentially beneficial effects of the higher dose of atorvastatin.

How low should LDL go? What the studies show

In the Heart Protection Study, patients with CHD, other occlusive arterial disease, or diabetes were randomized to 40 mg simvastatin or placebo.³ Simvastatin reduced relative risk of CHD—regardless of baseline LDL—even in patients with a baseline LDL <116 mg/dL.

Further analysis showed that among the many types of high-risk patients, 5 years of simvastatin at 40 mg daily would prevent about 70 to 100 people in 1000 from suffering at least 1 major vascular event (myocardial infarction, stroke, or the need for revascularization). Interestingly, patients with relatively smaller reductions in LDL (those in the lowest third) showed the same decrease in CHD events as patients in the highest third—although the overall difference in LDL wasn’t large.

A meta-analysis of these and other studies concluded that intensive lipid lowering with high-dose statin therapy confers a significant benefit over standard-dose therapy for preventing predominantly nonfatal cardiovascular events.⁴ The safety and tolerability of higher and standard statin doses are similar.² Two additional meta-analyses supported the use of intensive statin regimens to reduce cardiovascular risk, but didn’t find evidence for lowering LDL to a particular target level.^5,6

Meta-analysis: The lower the LDL, the lower the risk of CHD

The ENHANCE study, a double-blind, randomized trial conducted over a period of 24 months, compared the effects of 80 mg per day of simvastatin with either placebo or 10 mg per day of ezetimibe in 720 patients with familial hypercholesterolemia. The primary outcome measure was a change in intimamedia thickness of the walls of the carotid and femoral arteries. The results of the study have raised the question of whether it is appropriate to target LDL cholesterol primarily to reduce CHD risk, because ezetimibe did not affect carotid artery intima-media thickness, despite its effectiveness in reducing LDL cholesterol.⁷

However, an earlier 19-trial metaregression analysis (81,859 patients with stable CHD) demonstrated that each 1% reduction in LDL cholesterol corresponded to a 1% decrease in risk for CHD. This result held true regardless of different approaches to treatment, which included diet, bile-acid sequestrant, statins, or ileal bypass surgery.⁸

Recommendations

The Adult Treatment Panel (ATP) III guidelines recommend an LDL level <100 mg/dL for high-risk patients (CHD or a CHD risk equivalent)^.9 An update to the ATP III guidelines states that the LDL goal of <100 mg/dL was as low as could be supported by clinical trial evidence at the time of publication and was also the practical limit of LDL reduction that could be achieved with standard treatment in most high-risk patients.¹ The ATP III update offers the option of treating high-risk patients to a target LDL <70 mg/dL and clarifies that recent trials have shown no significant side effects associated with very low LDL levels.

Recent American Diabetes Association guidelines state that the LDL target should be <100 mg/dL in patients with diabetes, with the option of treating patients with both overt CHD and diabetes to an LDL of <70 mg/dL.¹⁰

Evidence summary

The National Cholesterol Education Program’s definition of “very high risk” for coronary heart disease (CHD) encompasses established CHD and CHD equivalents, including diabetes, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, and multiple cardiac risk factors that confer a 10-year calculated cardiac risk greater than 20%.¹

Statin dosage: Bigger is better

The Treating to New Targets (TNT) study showed that in patients with stable CHD, intensive lipid lowering with atorvastatin 80 mg daily delivered significant clinical benefit beyond that provided by atorvastatin 10 mg daily.² The mean LDL achieved in TNT was 77 mg/dL on 80 mg atorvastatin, compared with 101 mg/dL on 10 mg.

Patients with diabetes who took 80 mg had a 2.26% absolute risk reduction for major cardiovascular events (number needed to treat=43). Secondary outcomes—including all cardiovascular events, cerebrovascular events, and congestive heart failure with hospitalization—also improved on 80 mg atorvastatin.

Although this study enrolled a total of 10,001 patients with clinically evident CHD, it was not sufficiently powered to demonstrate differences in overall mortality between the 2 groups. While it is clear that patients in the 80-mg group had better outcomes than patients in the lower-dose group, the exact role of LDL lowering cannot be easily separated from other potentially beneficial effects of the higher dose of atorvastatin.

How low should LDL go? What the studies show

In the Heart Protection Study, patients with CHD, other occlusive arterial disease, or diabetes were randomized to 40 mg simvastatin or placebo.³ Simvastatin reduced relative risk of CHD—regardless of baseline LDL—even in patients with a baseline LDL <116 mg/dL.

Further analysis showed that among the many types of high-risk patients, 5 years of simvastatin at 40 mg daily would prevent about 70 to 100 people in 1000 from suffering at least 1 major vascular event (myocardial infarction, stroke, or the need for revascularization). Interestingly, patients with relatively smaller reductions in LDL (those in the lowest third) showed the same decrease in CHD events as patients in the highest third—although the overall difference in LDL wasn’t large.

A meta-analysis of these and other studies concluded that intensive lipid lowering with high-dose statin therapy confers a significant benefit over standard-dose therapy for preventing predominantly nonfatal cardiovascular events.⁴ The safety and tolerability of higher and standard statin doses are similar.² Two additional meta-analyses supported the use of intensive statin regimens to reduce cardiovascular risk, but didn’t find evidence for lowering LDL to a particular target level.^5,6

Meta-analysis: The lower the LDL, the lower the risk of CHD

The ENHANCE study, a double-blind, randomized trial conducted over a period of 24 months, compared the effects of 80 mg per day of simvastatin with either placebo or 10 mg per day of ezetimibe in 720 patients with familial hypercholesterolemia. The primary outcome measure was a change in intimamedia thickness of the walls of the carotid and femoral arteries. The results of the study have raised the question of whether it is appropriate to target LDL cholesterol primarily to reduce CHD risk, because ezetimibe did not affect carotid artery intima-media thickness, despite its effectiveness in reducing LDL cholesterol.⁷

However, an earlier 19-trial metaregression analysis (81,859 patients with stable CHD) demonstrated that each 1% reduction in LDL cholesterol corresponded to a 1% decrease in risk for CHD. This result held true regardless of different approaches to treatment, which included diet, bile-acid sequestrant, statins, or ileal bypass surgery.⁸

Recommendations

The Adult Treatment Panel (ATP) III guidelines recommend an LDL level <100 mg/dL for high-risk patients (CHD or a CHD risk equivalent)^.9 An update to the ATP III guidelines states that the LDL goal of <100 mg/dL was as low as could be supported by clinical trial evidence at the time of publication and was also the practical limit of LDL reduction that could be achieved with standard treatment in most high-risk patients.¹ The ATP III update offers the option of treating high-risk patients to a target LDL <70 mg/dL and clarifies that recent trials have shown no significant side effects associated with very low LDL levels.

Recent American Diabetes Association guidelines state that the LDL target should be <100 mg/dL in patients with diabetes, with the option of treating patients with both overt CHD and diabetes to an LDL of <70 mg/dL.¹⁰

Evidence summary

The National Cholesterol Education Program’s definition of “very high risk” for coronary heart disease (CHD) encompasses established CHD and CHD equivalents, including diabetes, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, and multiple cardiac risk factors that confer a 10-year calculated cardiac risk greater than 20%.¹

Statin dosage: Bigger is better

The Treating to New Targets (TNT) study showed that in patients with stable CHD, intensive lipid lowering with atorvastatin 80 mg daily delivered significant clinical benefit beyond that provided by atorvastatin 10 mg daily.² The mean LDL achieved in TNT was 77 mg/dL on 80 mg atorvastatin, compared with 101 mg/dL on 10 mg.

Patients with diabetes who took 80 mg had a 2.26% absolute risk reduction for major cardiovascular events (number needed to treat=43). Secondary outcomes—including all cardiovascular events, cerebrovascular events, and congestive heart failure with hospitalization—also improved on 80 mg atorvastatin.

Although this study enrolled a total of 10,001 patients with clinically evident CHD, it was not sufficiently powered to demonstrate differences in overall mortality between the 2 groups. While it is clear that patients in the 80-mg group had better outcomes than patients in the lower-dose group, the exact role of LDL lowering cannot be easily separated from other potentially beneficial effects of the higher dose of atorvastatin.

How low should LDL go? What the studies show

In the Heart Protection Study, patients with CHD, other occlusive arterial disease, or diabetes were randomized to 40 mg simvastatin or placebo.³ Simvastatin reduced relative risk of CHD—regardless of baseline LDL—even in patients with a baseline LDL <116 mg/dL.

Further analysis showed that among the many types of high-risk patients, 5 years of simvastatin at 40 mg daily would prevent about 70 to 100 people in 1000 from suffering at least 1 major vascular event (myocardial infarction, stroke, or the need for revascularization). Interestingly, patients with relatively smaller reductions in LDL (those in the lowest third) showed the same decrease in CHD events as patients in the highest third—although the overall difference in LDL wasn’t large.

A meta-analysis of these and other studies concluded that intensive lipid lowering with high-dose statin therapy confers a significant benefit over standard-dose therapy for preventing predominantly nonfatal cardiovascular events.⁴ The safety and tolerability of higher and standard statin doses are similar.² Two additional meta-analyses supported the use of intensive statin regimens to reduce cardiovascular risk, but didn’t find evidence for lowering LDL to a particular target level.^5,6

Meta-analysis: The lower the LDL, the lower the risk of CHD

The ENHANCE study, a double-blind, randomized trial conducted over a period of 24 months, compared the effects of 80 mg per day of simvastatin with either placebo or 10 mg per day of ezetimibe in 720 patients with familial hypercholesterolemia. The primary outcome measure was a change in intimamedia thickness of the walls of the carotid and femoral arteries. The results of the study have raised the question of whether it is appropriate to target LDL cholesterol primarily to reduce CHD risk, because ezetimibe did not affect carotid artery intima-media thickness, despite its effectiveness in reducing LDL cholesterol.⁷

However, an earlier 19-trial metaregression analysis (81,859 patients with stable CHD) demonstrated that each 1% reduction in LDL cholesterol corresponded to a 1% decrease in risk for CHD. This result held true regardless of different approaches to treatment, which included diet, bile-acid sequestrant, statins, or ileal bypass surgery.⁸

Recommendations

The Adult Treatment Panel (ATP) III guidelines recommend an LDL level <100 mg/dL for high-risk patients (CHD or a CHD risk equivalent)^.9 An update to the ATP III guidelines states that the LDL goal of <100 mg/dL was as low as could be supported by clinical trial evidence at the time of publication and was also the practical limit of LDL reduction that could be achieved with standard treatment in most high-risk patients.¹ The ATP III update offers the option of treating high-risk patients to a target LDL <70 mg/dL and clarifies that recent trials have shown no significant side effects associated with very low LDL levels.

Recent American Diabetes Association guidelines state that the LDL target should be <100 mg/dL in patients with diabetes, with the option of treating patients with both overt CHD and diabetes to an LDL of <70 mg/dL.¹⁰

Evidence summary

Initial treatments for cervical radiculopathy encompass:

• rest
• cervical immobilization
• NSAIDs
• analgesics (including muscle relaxants and antiepileptics)
• physical therapy.

Because few RCTs of these treatment options have been conducted,¹ recommendations are based primarily on cohort studies and clinical experience.

Analgesia: Try anticonvulsants last

No clinical trials have been published that look specifically at rest, immobilization, or oral analgesics for cervical radiculopathy. A Cochrane review of studies of anticonvulsants for treating acute and chronic pain found none that focused on cervical radiculopathy. The review concluded that “surprisingly few trials show analgesic effectiveness of anticonvulsants,” and “anticonvulsants should be withheld until other interventions have been tried.”²

Physical therapy seems to help

No RCTs of physical therapy for cervical radiculopathy been reported. However, a case series of patients treated specifically for cervical radiculopathy found that 10 of 11 patients who underwent physical therapy (including manual therapy, cervical traction, and strengthening exercises) were improved—defined as a self-report of being “quite a bit better”—at 6-month follow-up.³

A 1995 systematic, blinded review of RCTs of cervical traction found 3 studies. However, the inclusion criteria of these studies weren’t limited to cervical radiculopathy, limiting the applicability of the results. The 3 RCTs showed no advantages (2 studies) or modest advantages (1 study) for cervical traction over placebo or standard physical therapy without traction. Each study defined improvement differently, but most patients in all groups showed improvement.⁴

Epidural steroids appear effective

Epidural corticosteroid injections have demonstrated success in both retrospective and prospective studies. One case series of cortisone epidural injections reported 60% of patients (12 of 20) had good or excellent response at long-term follow-up (mean follow-up=21.2 months; range=2–45 months). Six of the 20 patients proceeded to surgery.⁵

Another series of 32 patients who had failed conventional treatment showed a 62% response—defined as “good or excellent” pain relief—to epidural steroid injection at 14 days. At 6 months, 53% continued to report good or excellent pain relief. No significant side effects occurred. The 44% of patients who didn’t report success also didn’t report any further deterioration.⁶

Surgery can relieve pain, but has risks

Laminectomy to reduce nerve compression may alleviate pain and improve function, but it has risks. Surgical procedures for cervical radiculomyelopathy have reported death rates of 0% to 1.8%; nonfatal complications occurred in 1% to 8% of patients.

A Cochrane review found only one RCT (N=81) that compared surgery with conservative treatment (physiotherapy and the cervical collar).⁷ Twenty patients crossed over to another treatment, including 3 surgical patients who improved before surgery and 11 who did postop physiotherapy.⁸ Patients were still analyzed by intention to treat, however.

The surgery group showed greater pain improvement at 3 months, as assessed by visual analogue scale (0 to 100), than the physiotherapy group (mean difference [MD]=–14; 95% confidence interval [CI], –27.84 to –0.16) and the cervical collar (MD=–21; 95% CI, –33.32 to –8.68). At 1 year, however, no difference was seen between surgery and physiotherapy (MD=–9; 95% CI, –23.39 to 5.39) or between surgery and the cervical collar (MD=–5; 95% CI, –18.84 to 8.84).⁷

Symptoms often resolve spontaneously

The natural course of cervical radiculopathy is uncertain, but symptoms often resolve with conservative measures or no treatment at all. A 1994 community-based epidemiological survey of 561 patients showed that 75% of patients had a spontaneous symptomatic improvement within 5 years. Earlier studies (6 studies from 1957 to 1972) concluded that untreated patients wouldn’t necessarily develop progressive disability and that patients with severe disability sometimes improve without treatment.⁷

Recommendations

Brigham and Women’s Hospital’s guideline recommends treating cervical radiculopathy with a soft collar, rest, nonsteroidal anti-inflammatory drugs, and physical therapy with cervical traction. If initial management isn’t effective after 6 weeks, the guideline advises referral to a specialist such as an orthopedic surgeon, neurologist, or rheumatologist. Surgical intervention is indicated if the patient shows signs of spinal cord compression or if pain is hindering function.⁹

An evidence-based practice guideline from The American Society of Interventional Pain Physicians states that moderate evidence supports the efficacy of interlaminar and transforaminal steroid injections.¹⁰

Evidence summary

Initial treatments for cervical radiculopathy encompass:

• rest
• cervical immobilization
• NSAIDs
• analgesics (including muscle relaxants and antiepileptics)
• physical therapy.

Because few RCTs of these treatment options have been conducted,¹ recommendations are based primarily on cohort studies and clinical experience.

Analgesia: Try anticonvulsants last

No clinical trials have been published that look specifically at rest, immobilization, or oral analgesics for cervical radiculopathy. A Cochrane review of studies of anticonvulsants for treating acute and chronic pain found none that focused on cervical radiculopathy. The review concluded that “surprisingly few trials show analgesic effectiveness of anticonvulsants,” and “anticonvulsants should be withheld until other interventions have been tried.”²

Physical therapy seems to help

No RCTs of physical therapy for cervical radiculopathy been reported. However, a case series of patients treated specifically for cervical radiculopathy found that 10 of 11 patients who underwent physical therapy (including manual therapy, cervical traction, and strengthening exercises) were improved—defined as a self-report of being “quite a bit better”—at 6-month follow-up.³

A 1995 systematic, blinded review of RCTs of cervical traction found 3 studies. However, the inclusion criteria of these studies weren’t limited to cervical radiculopathy, limiting the applicability of the results. The 3 RCTs showed no advantages (2 studies) or modest advantages (1 study) for cervical traction over placebo or standard physical therapy without traction. Each study defined improvement differently, but most patients in all groups showed improvement.⁴

Epidural steroids appear effective

Epidural corticosteroid injections have demonstrated success in both retrospective and prospective studies. One case series of cortisone epidural injections reported 60% of patients (12 of 20) had good or excellent response at long-term follow-up (mean follow-up=21.2 months; range=2–45 months). Six of the 20 patients proceeded to surgery.⁵

Another series of 32 patients who had failed conventional treatment showed a 62% response—defined as “good or excellent” pain relief—to epidural steroid injection at 14 days. At 6 months, 53% continued to report good or excellent pain relief. No significant side effects occurred. The 44% of patients who didn’t report success also didn’t report any further deterioration.⁶

Surgery can relieve pain, but has risks

Laminectomy to reduce nerve compression may alleviate pain and improve function, but it has risks. Surgical procedures for cervical radiculomyelopathy have reported death rates of 0% to 1.8%; nonfatal complications occurred in 1% to 8% of patients.

A Cochrane review found only one RCT (N=81) that compared surgery with conservative treatment (physiotherapy and the cervical collar).⁷ Twenty patients crossed over to another treatment, including 3 surgical patients who improved before surgery and 11 who did postop physiotherapy.⁸ Patients were still analyzed by intention to treat, however.

The surgery group showed greater pain improvement at 3 months, as assessed by visual analogue scale (0 to 100), than the physiotherapy group (mean difference [MD]=–14; 95% confidence interval [CI], –27.84 to –0.16) and the cervical collar (MD=–21; 95% CI, –33.32 to –8.68). At 1 year, however, no difference was seen between surgery and physiotherapy (MD=–9; 95% CI, –23.39 to 5.39) or between surgery and the cervical collar (MD=–5; 95% CI, –18.84 to 8.84).⁷

Symptoms often resolve spontaneously

The natural course of cervical radiculopathy is uncertain, but symptoms often resolve with conservative measures or no treatment at all. A 1994 community-based epidemiological survey of 561 patients showed that 75% of patients had a spontaneous symptomatic improvement within 5 years. Earlier studies (6 studies from 1957 to 1972) concluded that untreated patients wouldn’t necessarily develop progressive disability and that patients with severe disability sometimes improve without treatment.⁷

Recommendations

Brigham and Women’s Hospital’s guideline recommends treating cervical radiculopathy with a soft collar, rest, nonsteroidal anti-inflammatory drugs, and physical therapy with cervical traction. If initial management isn’t effective after 6 weeks, the guideline advises referral to a specialist such as an orthopedic surgeon, neurologist, or rheumatologist. Surgical intervention is indicated if the patient shows signs of spinal cord compression or if pain is hindering function.⁹

An evidence-based practice guideline from The American Society of Interventional Pain Physicians states that moderate evidence supports the efficacy of interlaminar and transforaminal steroid injections.¹⁰

Evidence summary

Initial treatments for cervical radiculopathy encompass:

• rest
• cervical immobilization
• NSAIDs
• analgesics (including muscle relaxants and antiepileptics)
• physical therapy.

Because few RCTs of these treatment options have been conducted,¹ recommendations are based primarily on cohort studies and clinical experience.

Analgesia: Try anticonvulsants last

No clinical trials have been published that look specifically at rest, immobilization, or oral analgesics for cervical radiculopathy. A Cochrane review of studies of anticonvulsants for treating acute and chronic pain found none that focused on cervical radiculopathy. The review concluded that “surprisingly few trials show analgesic effectiveness of anticonvulsants,” and “anticonvulsants should be withheld until other interventions have been tried.”²

Physical therapy seems to help

No RCTs of physical therapy for cervical radiculopathy been reported. However, a case series of patients treated specifically for cervical radiculopathy found that 10 of 11 patients who underwent physical therapy (including manual therapy, cervical traction, and strengthening exercises) were improved—defined as a self-report of being “quite a bit better”—at 6-month follow-up.³

A 1995 systematic, blinded review of RCTs of cervical traction found 3 studies. However, the inclusion criteria of these studies weren’t limited to cervical radiculopathy, limiting the applicability of the results. The 3 RCTs showed no advantages (2 studies) or modest advantages (1 study) for cervical traction over placebo or standard physical therapy without traction. Each study defined improvement differently, but most patients in all groups showed improvement.⁴

Epidural steroids appear effective

Epidural corticosteroid injections have demonstrated success in both retrospective and prospective studies. One case series of cortisone epidural injections reported 60% of patients (12 of 20) had good or excellent response at long-term follow-up (mean follow-up=21.2 months; range=2–45 months). Six of the 20 patients proceeded to surgery.⁵

Another series of 32 patients who had failed conventional treatment showed a 62% response—defined as “good or excellent” pain relief—to epidural steroid injection at 14 days. At 6 months, 53% continued to report good or excellent pain relief. No significant side effects occurred. The 44% of patients who didn’t report success also didn’t report any further deterioration.⁶

Surgery can relieve pain, but has risks

Laminectomy to reduce nerve compression may alleviate pain and improve function, but it has risks. Surgical procedures for cervical radiculomyelopathy have reported death rates of 0% to 1.8%; nonfatal complications occurred in 1% to 8% of patients.

A Cochrane review found only one RCT (N=81) that compared surgery with conservative treatment (physiotherapy and the cervical collar).⁷ Twenty patients crossed over to another treatment, including 3 surgical patients who improved before surgery and 11 who did postop physiotherapy.⁸ Patients were still analyzed by intention to treat, however.

The surgery group showed greater pain improvement at 3 months, as assessed by visual analogue scale (0 to 100), than the physiotherapy group (mean difference [MD]=–14; 95% confidence interval [CI], –27.84 to –0.16) and the cervical collar (MD=–21; 95% CI, –33.32 to –8.68). At 1 year, however, no difference was seen between surgery and physiotherapy (MD=–9; 95% CI, –23.39 to 5.39) or between surgery and the cervical collar (MD=–5; 95% CI, –18.84 to 8.84).⁷

Symptoms often resolve spontaneously

The natural course of cervical radiculopathy is uncertain, but symptoms often resolve with conservative measures or no treatment at all. A 1994 community-based epidemiological survey of 561 patients showed that 75% of patients had a spontaneous symptomatic improvement within 5 years. Earlier studies (6 studies from 1957 to 1972) concluded that untreated patients wouldn’t necessarily develop progressive disability and that patients with severe disability sometimes improve without treatment.⁷

Recommendations

Brigham and Women’s Hospital’s guideline recommends treating cervical radiculopathy with a soft collar, rest, nonsteroidal anti-inflammatory drugs, and physical therapy with cervical traction. If initial management isn’t effective after 6 weeks, the guideline advises referral to a specialist such as an orthopedic surgeon, neurologist, or rheumatologist. Surgical intervention is indicated if the patient shows signs of spinal cord compression or if pain is hindering function.⁹

An evidence-based practice guideline from The American Society of Interventional Pain Physicians states that moderate evidence supports the efficacy of interlaminar and transforaminal steroid injections.¹⁰

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

Significant macrocytosis is usually defined as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.^1-4 As many as 60% to 80% of primary care patients may not have anemia.^3,4

Because no study has looked specifically at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of macrocytosis (with and without anemia) must help guide evaluation.^1,3,5-7 The causes of macrocytosis vary depending on the population studied (TABLE). In primary care, alcohol use and vitamin deficiency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.³

TABLE
Causes of macrocytosis: What prospective studies show

Clues in the history, physical exam, and lab results

A history focusing specifically on alcohol use and medications—especially chemotherapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocytosis. During the physical examination, look for signs consistent with chronic liver disease.

Laboratory studies can help identify vitamin deficiencies, liver disease, and thyroid disease. A normal serum B₁₂ level may not rule out a true B₁₂ deficiency, but normal levels of the metabolites methylmalonic acid and homocysteine do essentially rule it out.⁸ In this era of folic acid fortification, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a deficiency when B₁₂ deficiency has been ruled out.^7,9

Liver disease—which may be confounded by alcohol abuse, medications, or cancer—is a common cause of macrocytosis.⁵ Hypothyroidism is rarely a cause, but may be more prevalent in the elderly.¹⁰

What these 2 tests may, or may not, tell you

Although several authorities recommend a peripheral smear and reticulocyte count to help evaluate macrocytic anemia, no specific recommendations exist for these tests in the absence of anemia. A peripheral smear can detect megaloblastic changes typical of B₁₂ and folate deficiency and other marrow disorders, especially myelodysplastic changes. Peripheral smear findings and reticulocytosis can also show evidence of hemolysis. However, megaloblastic changes and marrow-related changes on peripheral smear are typically seen with anemia.

In 2 prospective studies of primary care patients, 1 reported little diagnostic value for the peripheral smear,¹ and the other found that reticulocytosis rarely caused macrocytosis.⁵ A prospective study of 300 hospitalized patients with macrocytosis found that 100% of marrow disorders and hemolysis that caused macrocytosis also caused an associated anemia.⁷ A retrospective chart review of 113 cases of macrocytosis in outpatients found that general practitioners often didn’t order a peripheral smear and reticulocyte count to complete their diagnostic workups.⁴

Bone marrow biopsy may reveal dysplastic changes, but not a Dx

A prospective study of the utility of bone marrow biopsy in 124 elderly patients with macrocytosis found that as many as 60% were diagnosed by blood tests alone. All the remaining patients with unexplained macrocytosis underwent bone marrow biopsy, which showed early dysplastic changes in 39%, but did not provide a diagnosis in nearly 50%. Twelve percent were found to have myelodysplastic syndrome, but they had a mean hemoglobin of 8.5 g/dL.¹⁰

Recommendations

We were unable to find published guidelines for the evaluation of macrocytosis without anemia by the American Society of Hematology, the British Committee for Standards in Haematology, or in an authoritative hematology text.¹¹

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

Evidence summary

Significant macrocytosis is usually defined as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.^1-4 As many as 60% to 80% of primary care patients may not have anemia.^3,4

Because no study has looked specifically at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of macrocytosis (with and without anemia) must help guide evaluation.^1,3,5-7 The causes of macrocytosis vary depending on the population studied (TABLE). In primary care, alcohol use and vitamin deficiency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.³

TABLE
Causes of macrocytosis: What prospective studies show

Clues in the history, physical exam, and lab results

A history focusing specifically on alcohol use and medications—especially chemotherapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocytosis. During the physical examination, look for signs consistent with chronic liver disease.

Laboratory studies can help identify vitamin deficiencies, liver disease, and thyroid disease. A normal serum B₁₂ level may not rule out a true B₁₂ deficiency, but normal levels of the metabolites methylmalonic acid and homocysteine do essentially rule it out.⁸ In this era of folic acid fortification, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a deficiency when B₁₂ deficiency has been ruled out.^7,9

Liver disease—which may be confounded by alcohol abuse, medications, or cancer—is a common cause of macrocytosis.⁵ Hypothyroidism is rarely a cause, but may be more prevalent in the elderly.¹⁰

What these 2 tests may, or may not, tell you

Although several authorities recommend a peripheral smear and reticulocyte count to help evaluate macrocytic anemia, no specific recommendations exist for these tests in the absence of anemia. A peripheral smear can detect megaloblastic changes typical of B₁₂ and folate deficiency and other marrow disorders, especially myelodysplastic changes. Peripheral smear findings and reticulocytosis can also show evidence of hemolysis. However, megaloblastic changes and marrow-related changes on peripheral smear are typically seen with anemia.

In 2 prospective studies of primary care patients, 1 reported little diagnostic value for the peripheral smear,¹ and the other found that reticulocytosis rarely caused macrocytosis.⁵ A prospective study of 300 hospitalized patients with macrocytosis found that 100% of marrow disorders and hemolysis that caused macrocytosis also caused an associated anemia.⁷ A retrospective chart review of 113 cases of macrocytosis in outpatients found that general practitioners often didn’t order a peripheral smear and reticulocyte count to complete their diagnostic workups.⁴

Bone marrow biopsy may reveal dysplastic changes, but not a Dx

A prospective study of the utility of bone marrow biopsy in 124 elderly patients with macrocytosis found that as many as 60% were diagnosed by blood tests alone. All the remaining patients with unexplained macrocytosis underwent bone marrow biopsy, which showed early dysplastic changes in 39%, but did not provide a diagnosis in nearly 50%. Twelve percent were found to have myelodysplastic syndrome, but they had a mean hemoglobin of 8.5 g/dL.¹⁰

Recommendations

We were unable to find published guidelines for the evaluation of macrocytosis without anemia by the American Society of Hematology, the British Committee for Standards in Haematology, or in an authoritative hematology text.¹¹

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

Evidence summary

Significant macrocytosis is usually defined as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.^1-4 As many as 60% to 80% of primary care patients may not have anemia.^3,4

Because no study has looked specifically at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of macrocytosis (with and without anemia) must help guide evaluation.^1,3,5-7 The causes of macrocytosis vary depending on the population studied (TABLE). In primary care, alcohol use and vitamin deficiency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.³

TABLE
Causes of macrocytosis: What prospective studies show

Clues in the history, physical exam, and lab results

A history focusing specifically on alcohol use and medications—especially chemotherapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocytosis. During the physical examination, look for signs consistent with chronic liver disease.

Laboratory studies can help identify vitamin deficiencies, liver disease, and thyroid disease. A normal serum B₁₂ level may not rule out a true B₁₂ deficiency, but normal levels of the metabolites methylmalonic acid and homocysteine do essentially rule it out.⁸ In this era of folic acid fortification, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a deficiency when B₁₂ deficiency has been ruled out.^7,9

Liver disease—which may be confounded by alcohol abuse, medications, or cancer—is a common cause of macrocytosis.⁵ Hypothyroidism is rarely a cause, but may be more prevalent in the elderly.¹⁰

What these 2 tests may, or may not, tell you

Although several authorities recommend a peripheral smear and reticulocyte count to help evaluate macrocytic anemia, no specific recommendations exist for these tests in the absence of anemia. A peripheral smear can detect megaloblastic changes typical of B₁₂ and folate deficiency and other marrow disorders, especially myelodysplastic changes. Peripheral smear findings and reticulocytosis can also show evidence of hemolysis. However, megaloblastic changes and marrow-related changes on peripheral smear are typically seen with anemia.

In 2 prospective studies of primary care patients, 1 reported little diagnostic value for the peripheral smear,¹ and the other found that reticulocytosis rarely caused macrocytosis.⁵ A prospective study of 300 hospitalized patients with macrocytosis found that 100% of marrow disorders and hemolysis that caused macrocytosis also caused an associated anemia.⁷ A retrospective chart review of 113 cases of macrocytosis in outpatients found that general practitioners often didn’t order a peripheral smear and reticulocyte count to complete their diagnostic workups.⁴

Bone marrow biopsy may reveal dysplastic changes, but not a Dx

A prospective study of the utility of bone marrow biopsy in 124 elderly patients with macrocytosis found that as many as 60% were diagnosed by blood tests alone. All the remaining patients with unexplained macrocytosis underwent bone marrow biopsy, which showed early dysplastic changes in 39%, but did not provide a diagnosis in nearly 50%. Twelve percent were found to have myelodysplastic syndrome, but they had a mean hemoglobin of 8.5 g/dL.¹⁰

Recommendations

We were unable to find published guidelines for the evaluation of macrocytosis without anemia by the American Society of Hematology, the British Committee for Standards in Haematology, or in an authoritative hematology text.¹¹

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

Evidence summary

Make sure it’s true hypercalcemia

Measuring calcium levels in asymptomatic patients often leads to false-positive elevations caused by random error or changes in the level of physiologically active calcium because of alterations in blood pH or serum albumin. Serum calcium levels between 10.0 and 12.0 mg/dL indicate mild hypercalcemia; levels >14.0 mg/dL are severe. Because changes in pH and serum albumin levels alter levels of physiologically active calcium, authoritative sources recommend measuring or calculating physiologically active calcium if blood pH or albumin is abnormal.^1,2 To determine the level, use the equation [4.0 – (plasma albumin)] × 0.8 + (serum calcium) or measure serum ionized calcium.² Normal levels of serum ionized calcium for adults older than 19 years are 1.13 to 1.32 mmol/L, although the exact range can vary from laboratory to laboratory. Elevated physiologically active calcium indicates true hypercalcemia.

Assess for the most common causes, PHPT and malignancy

Evaluation of the patient with true hypercalcemia should include a detailed history, physical examination, and assessment of risk factors for all causes of hypercalcemia.^1,2 PHPT and malignancy are the two most common causes of asymptomatic true hypercalcemia (TABLE).²

Laboratory evaluation targeting these causes, beginning with an intact PTH level, is a logical first step.^1,2 Persistent hypercalcemia in the presence of elevated or inappropriately normal PTH concentrations confirms the diagnosis of PHPT.³ When serum calcium rises, PTH is normally suppressed. Normal intact PTH and low 24-hour urinary calcium excretion distinguishes patients with PHPT from those with less common familial hypocalciuric hypercalcemia.^1,2

Most patients with PHPT are asymptomatic, although some eventually develop bone loss, nephrolithiasis, and renal colic.^4,5 A 10-year prospective cohort study of patients with PHPT found that 21% of asymptomatic patients developed decreased bone density at one or more sites.⁶ None acquired kidney stones, but hypercalcemia and hypercalciuria did worsen in 10 of 52 patients. A guideline and a review on PHPT recommend measuring creatinine clearance and obtaining a bone densitometry study of the distal third of the radius, hip, and lumbar spine to assess for end-organ changes related to the condition; declining renal function and osteoporosis may be indications for surgery.^3,5

Malignancy is the most common cause of low intact PTH and true hypercalcemia, especially when the calcium level is >14 mg/dL.¹ A PTHrP >1.0 pmol/L is highly specific for malignancy because this level does not occur in healthy people.¹ In a prospective case series of patients with hypercalcemia and malignancy, 54% had elevated PTHrP levels.⁷ The authors found that an elevated PTHrP in patients younger than 65 years of age doubles the risk of death from malignancy compared to patients the same age with normal PTHrP (hazard ratio=1.9; 95% CI, 1.1-3.4).

TABLE
Causes of hypercalcemia

Identify less common causes

Serum calcitriol in association with a low intact PTH level and elevated calcium lower than 14 mg/dL helps differentiate the less common causes of hypercalcemia. Calcitriol is high in granulomatous diseases such as sarcoidosis, tuberculosis, and histoplasmosis, and normal in hyperthyroidism and Addison’s disease.¹

Immobilization as a cause of hypercalcemia can be distinguished from PHPT by history and normal PTH levels and from malignancy by a normal alkaline phosphatase level.¹

Recommendations

In addition to the recommendations discussed previously, Williams Textbook of Endocrinology advises repeating the initial calcium level twice and measuring serum BUN, creatinine, electrolytes, albumin, globulin, and phosphate.⁸ The authors recommend a generalized work-up for malignancy, including mammography, chest radiography with or without CT, abdominal CT, serum and urine immunoelectrophoresis, and temporary discontinuation of lithium for patients taking the drug. They also recommend using PTHrP only when PTH is suppressed but an underlying malignancy can’t be found.

Evidence summary

Make sure it’s true hypercalcemia

Measuring calcium levels in asymptomatic patients often leads to false-positive elevations caused by random error or changes in the level of physiologically active calcium because of alterations in blood pH or serum albumin. Serum calcium levels between 10.0 and 12.0 mg/dL indicate mild hypercalcemia; levels >14.0 mg/dL are severe. Because changes in pH and serum albumin levels alter levels of physiologically active calcium, authoritative sources recommend measuring or calculating physiologically active calcium if blood pH or albumin is abnormal.^1,2 To determine the level, use the equation [4.0 – (plasma albumin)] × 0.8 + (serum calcium) or measure serum ionized calcium.² Normal levels of serum ionized calcium for adults older than 19 years are 1.13 to 1.32 mmol/L, although the exact range can vary from laboratory to laboratory. Elevated physiologically active calcium indicates true hypercalcemia.

Assess for the most common causes, PHPT and malignancy

Evaluation of the patient with true hypercalcemia should include a detailed history, physical examination, and assessment of risk factors for all causes of hypercalcemia.^1,2 PHPT and malignancy are the two most common causes of asymptomatic true hypercalcemia (TABLE).²

Laboratory evaluation targeting these causes, beginning with an intact PTH level, is a logical first step.^1,2 Persistent hypercalcemia in the presence of elevated or inappropriately normal PTH concentrations confirms the diagnosis of PHPT.³ When serum calcium rises, PTH is normally suppressed. Normal intact PTH and low 24-hour urinary calcium excretion distinguishes patients with PHPT from those with less common familial hypocalciuric hypercalcemia.^1,2

Most patients with PHPT are asymptomatic, although some eventually develop bone loss, nephrolithiasis, and renal colic.^4,5 A 10-year prospective cohort study of patients with PHPT found that 21% of asymptomatic patients developed decreased bone density at one or more sites.⁶ None acquired kidney stones, but hypercalcemia and hypercalciuria did worsen in 10 of 52 patients. A guideline and a review on PHPT recommend measuring creatinine clearance and obtaining a bone densitometry study of the distal third of the radius, hip, and lumbar spine to assess for end-organ changes related to the condition; declining renal function and osteoporosis may be indications for surgery.^3,5

Malignancy is the most common cause of low intact PTH and true hypercalcemia, especially when the calcium level is >14 mg/dL.¹ A PTHrP >1.0 pmol/L is highly specific for malignancy because this level does not occur in healthy people.¹ In a prospective case series of patients with hypercalcemia and malignancy, 54% had elevated PTHrP levels.⁷ The authors found that an elevated PTHrP in patients younger than 65 years of age doubles the risk of death from malignancy compared to patients the same age with normal PTHrP (hazard ratio=1.9; 95% CI, 1.1-3.4).

TABLE
Causes of hypercalcemia

Identify less common causes

Serum calcitriol in association with a low intact PTH level and elevated calcium lower than 14 mg/dL helps differentiate the less common causes of hypercalcemia. Calcitriol is high in granulomatous diseases such as sarcoidosis, tuberculosis, and histoplasmosis, and normal in hyperthyroidism and Addison’s disease.¹

Immobilization as a cause of hypercalcemia can be distinguished from PHPT by history and normal PTH levels and from malignancy by a normal alkaline phosphatase level.¹

Recommendations

In addition to the recommendations discussed previously, Williams Textbook of Endocrinology advises repeating the initial calcium level twice and measuring serum BUN, creatinine, electrolytes, albumin, globulin, and phosphate.⁸ The authors recommend a generalized work-up for malignancy, including mammography, chest radiography with or without CT, abdominal CT, serum and urine immunoelectrophoresis, and temporary discontinuation of lithium for patients taking the drug. They also recommend using PTHrP only when PTH is suppressed but an underlying malignancy can’t be found.

Evidence summary

Make sure it’s true hypercalcemia

Measuring calcium levels in asymptomatic patients often leads to false-positive elevations caused by random error or changes in the level of physiologically active calcium because of alterations in blood pH or serum albumin. Serum calcium levels between 10.0 and 12.0 mg/dL indicate mild hypercalcemia; levels >14.0 mg/dL are severe. Because changes in pH and serum albumin levels alter levels of physiologically active calcium, authoritative sources recommend measuring or calculating physiologically active calcium if blood pH or albumin is abnormal.^1,2 To determine the level, use the equation [4.0 – (plasma albumin)] × 0.8 + (serum calcium) or measure serum ionized calcium.² Normal levels of serum ionized calcium for adults older than 19 years are 1.13 to 1.32 mmol/L, although the exact range can vary from laboratory to laboratory. Elevated physiologically active calcium indicates true hypercalcemia.

Assess for the most common causes, PHPT and malignancy

Evaluation of the patient with true hypercalcemia should include a detailed history, physical examination, and assessment of risk factors for all causes of hypercalcemia.^1,2 PHPT and malignancy are the two most common causes of asymptomatic true hypercalcemia (TABLE).²

Laboratory evaluation targeting these causes, beginning with an intact PTH level, is a logical first step.^1,2 Persistent hypercalcemia in the presence of elevated or inappropriately normal PTH concentrations confirms the diagnosis of PHPT.³ When serum calcium rises, PTH is normally suppressed. Normal intact PTH and low 24-hour urinary calcium excretion distinguishes patients with PHPT from those with less common familial hypocalciuric hypercalcemia.^1,2

Most patients with PHPT are asymptomatic, although some eventually develop bone loss, nephrolithiasis, and renal colic.^4,5 A 10-year prospective cohort study of patients with PHPT found that 21% of asymptomatic patients developed decreased bone density at one or more sites.⁶ None acquired kidney stones, but hypercalcemia and hypercalciuria did worsen in 10 of 52 patients. A guideline and a review on PHPT recommend measuring creatinine clearance and obtaining a bone densitometry study of the distal third of the radius, hip, and lumbar spine to assess for end-organ changes related to the condition; declining renal function and osteoporosis may be indications for surgery.^3,5

Malignancy is the most common cause of low intact PTH and true hypercalcemia, especially when the calcium level is >14 mg/dL.¹ A PTHrP >1.0 pmol/L is highly specific for malignancy because this level does not occur in healthy people.¹ In a prospective case series of patients with hypercalcemia and malignancy, 54% had elevated PTHrP levels.⁷ The authors found that an elevated PTHrP in patients younger than 65 years of age doubles the risk of death from malignancy compared to patients the same age with normal PTHrP (hazard ratio=1.9; 95% CI, 1.1-3.4).

TABLE
Causes of hypercalcemia

Identify less common causes

Serum calcitriol in association with a low intact PTH level and elevated calcium lower than 14 mg/dL helps differentiate the less common causes of hypercalcemia. Calcitriol is high in granulomatous diseases such as sarcoidosis, tuberculosis, and histoplasmosis, and normal in hyperthyroidism and Addison’s disease.¹

Immobilization as a cause of hypercalcemia can be distinguished from PHPT by history and normal PTH levels and from malignancy by a normal alkaline phosphatase level.¹

Recommendations

In addition to the recommendations discussed previously, Williams Textbook of Endocrinology advises repeating the initial calcium level twice and measuring serum BUN, creatinine, electrolytes, albumin, globulin, and phosphate.⁸ The authors recommend a generalized work-up for malignancy, including mammography, chest radiography with or without CT, abdominal CT, serum and urine immunoelectrophoresis, and temporary discontinuation of lithium for patients taking the drug. They also recommend using PTHrP only when PTH is suppressed but an underlying malignancy can’t be found.

Evidence summary

Although most patients undergo surgery for hip fracture, family physicians often serve as consultants for perioperative management and rehabilitation. Several interventions have been studied that influence outcomes for hip fracture patients.

Surgical interventions: Timing is critical

Most ambulatory, medically stable patients elect to have surgical repair of their fractures. A meta-analysis found few randomized trials comparing operative with nonoperative therapy; it concluded that surgical treatment seems to be associated with a reduced length of hospital stay and improved rehabilitation.¹

The timing of surgery appears to be an important variable, particularly whether patients should undergo surgery within 24 hours of the fracture. Some studies found decreased mortality with earlier surgical intervention,² while others have not.³ A 2006 observational study⁴ found that delay in operating was associated with an increased risk of death in the hospital, even after adjusting for comorbidities. For all deaths in the hospital, the odds ratio [OR] for delaying more than 1 day, relative to 1 day or less, was 1.27 (95% confidence interval [CI], 1.23–1.32). Despite the inconsistency regarding mortality rates, complication rates (such as decubitus ulcers) do increase with a delay in surgery.³

Unfractionated vs LMW heparin

After a hip fracture, patients are at very high risk for VTE. For untreated patients, the rate of deep vein thromboses (DVT) may be as high as 50%, with an associated fatal pulmonary embolism rate as high as 7.5%.⁵

The effectiveness of unfractionated and low-molecular-weight heparin was evaluated in a 2002 Cochrane systematic review.⁶ While evidence was insufficient to recommend 1 agent over another, both were found to significantly decrease the incidence of lower-extremity DVT over placebo (for unfractionated heparin, relative risk [RR]=0.59 [95% CI, 0.49–0.72]; for low-molecular-weight heparin, RR=0.60 [95% CI, 0.50–0.71]). Number needed to treat [NNT] with either agent was 7.

Reduce infections with antibiotic prophylaxis

Antibiotic prophylaxis has been supported by a Cochrane review, which concluded that single-dose antibiotic prophylaxis before surgery significantly reduced the risk of deep wound infections (RR=0.40; 95% CI, 0.24–0.67; NNT=55), as well as superficial wound, urinary, and respiratory tract infections.⁷

Patients should receive antibiotics less than 2 hours before surgery to reduce the risk of infection.⁸ Classen et al found that patients treated less than 2 hours before surgery had a 0.6% rate of infection (10/1208), compared with a 3.85% rate for those treated 2 to 24 hours ahead (14/369) (NNT=31).⁸ It is unclear whether multiple-dose therapy provides additional benefit when administered over the first 24 to 36 hours after surgery⁹ (OR=0.60; 95% CI, 0.18–2.02). First- or second-generation cephalosporins were used in most studies.

Delirium: A common but avoidable complication

Delirium is a common complication seen after hip fracture, affecting approximately 10% to 16% of patients.^10,11 Delirium may increase the duration of hospitalization, and may be associated with an increased mortality at 1 year.¹² Delirium can be avoided by looking at each patient’s risk factors.¹³ Studies suggest avoiding use of meperidine, benzodiazepines, and medications with anticholinergic side effects.^11,13 Sleep deprivation, delayed mobility, and inadequate pain control are also associated with the development of delirium.¹³

One study showed that prophylaxis with haloperidol for hip fracture patients did not decrease the incidence of postoperative delirium but did reduce its duration and severity.¹⁴ Haloperidol prophylaxis was also associated with shorter hospital stays. Treatment with haloperidol or risperidone for the agitation of postoperative delirium has been recommended when behavioral interventions fail.¹³

Pain control improves recovery

Providing adequate analgesia is of the utmost importance. In a 2003 prospective cohort study, patients without sufficient analgesia had an increased risk of poor functional recovery and longer hospitalization.¹⁵ In another cohort study, those patients whose pain was inadequately controlled also had an increased risk for delirium (RR=9.0; 95% CI, 1.8–45.2).¹¹ Meperidine use increased the risk for delirium compared with other opioid analgesics (RR=2.4; 95% CI, 1.3–4.5).¹¹

Recommendations of others

The American College of Physicians provides a comprehensive evidence-based guideline for the management of hip fracture patients in their PIER series (Physicians’ Information and Education Resource) (TABLE).¹⁶

The American College of Chest Physicians has published evidence-based guidelines for the prevention of VTE.⁵ For patients undergoing hip fracture surgery, they recommend routine use of fondaparinux, low-molecular-weight heparin at high-risk dosing, adjusted-dose warfarin (at a target international normalized ratio [INR] of 2.5, range 2.0–3.0), or unfractionated heparin. They recommend against routine use of aspirin alone. If surgery must be delayed, physicians should initiate prophylaxis with unfractionated or low-molecular-weight heparin at the time of hospital admission. Anticoagulation should routinely continue for 10 days after surgery or until the patient is ambulatory. If anticoagulation is contraindicated, mechanical prophylaxis of VTE with foot and calf pumping devices is recommended.^5,6

TABLE
6 steps for managing hip fracture from the American College of Physicians

Evidence summary

Although most patients undergo surgery for hip fracture, family physicians often serve as consultants for perioperative management and rehabilitation. Several interventions have been studied that influence outcomes for hip fracture patients.

Surgical interventions: Timing is critical

Most ambulatory, medically stable patients elect to have surgical repair of their fractures. A meta-analysis found few randomized trials comparing operative with nonoperative therapy; it concluded that surgical treatment seems to be associated with a reduced length of hospital stay and improved rehabilitation.¹

The timing of surgery appears to be an important variable, particularly whether patients should undergo surgery within 24 hours of the fracture. Some studies found decreased mortality with earlier surgical intervention,² while others have not.³ A 2006 observational study⁴ found that delay in operating was associated with an increased risk of death in the hospital, even after adjusting for comorbidities. For all deaths in the hospital, the odds ratio [OR] for delaying more than 1 day, relative to 1 day or less, was 1.27 (95% confidence interval [CI], 1.23–1.32). Despite the inconsistency regarding mortality rates, complication rates (such as decubitus ulcers) do increase with a delay in surgery.³

Unfractionated vs LMW heparin

After a hip fracture, patients are at very high risk for VTE. For untreated patients, the rate of deep vein thromboses (DVT) may be as high as 50%, with an associated fatal pulmonary embolism rate as high as 7.5%.⁵

The effectiveness of unfractionated and low-molecular-weight heparin was evaluated in a 2002 Cochrane systematic review.⁶ While evidence was insufficient to recommend 1 agent over another, both were found to significantly decrease the incidence of lower-extremity DVT over placebo (for unfractionated heparin, relative risk [RR]=0.59 [95% CI, 0.49–0.72]; for low-molecular-weight heparin, RR=0.60 [95% CI, 0.50–0.71]). Number needed to treat [NNT] with either agent was 7.

Reduce infections with antibiotic prophylaxis

Antibiotic prophylaxis has been supported by a Cochrane review, which concluded that single-dose antibiotic prophylaxis before surgery significantly reduced the risk of deep wound infections (RR=0.40; 95% CI, 0.24–0.67; NNT=55), as well as superficial wound, urinary, and respiratory tract infections.⁷

Patients should receive antibiotics less than 2 hours before surgery to reduce the risk of infection.⁸ Classen et al found that patients treated less than 2 hours before surgery had a 0.6% rate of infection (10/1208), compared with a 3.85% rate for those treated 2 to 24 hours ahead (14/369) (NNT=31).⁸ It is unclear whether multiple-dose therapy provides additional benefit when administered over the first 24 to 36 hours after surgery⁹ (OR=0.60; 95% CI, 0.18–2.02). First- or second-generation cephalosporins were used in most studies.

Delirium: A common but avoidable complication

Delirium is a common complication seen after hip fracture, affecting approximately 10% to 16% of patients.^10,11 Delirium may increase the duration of hospitalization, and may be associated with an increased mortality at 1 year.¹² Delirium can be avoided by looking at each patient’s risk factors.¹³ Studies suggest avoiding use of meperidine, benzodiazepines, and medications with anticholinergic side effects.^11,13 Sleep deprivation, delayed mobility, and inadequate pain control are also associated with the development of delirium.¹³

One study showed that prophylaxis with haloperidol for hip fracture patients did not decrease the incidence of postoperative delirium but did reduce its duration and severity.¹⁴ Haloperidol prophylaxis was also associated with shorter hospital stays. Treatment with haloperidol or risperidone for the agitation of postoperative delirium has been recommended when behavioral interventions fail.¹³

Pain control improves recovery

Providing adequate analgesia is of the utmost importance. In a 2003 prospective cohort study, patients without sufficient analgesia had an increased risk of poor functional recovery and longer hospitalization.¹⁵ In another cohort study, those patients whose pain was inadequately controlled also had an increased risk for delirium (RR=9.0; 95% CI, 1.8–45.2).¹¹ Meperidine use increased the risk for delirium compared with other opioid analgesics (RR=2.4; 95% CI, 1.3–4.5).¹¹

Recommendations of others

The American College of Physicians provides a comprehensive evidence-based guideline for the management of hip fracture patients in their PIER series (Physicians’ Information and Education Resource) (TABLE).¹⁶

The American College of Chest Physicians has published evidence-based guidelines for the prevention of VTE.⁵ For patients undergoing hip fracture surgery, they recommend routine use of fondaparinux, low-molecular-weight heparin at high-risk dosing, adjusted-dose warfarin (at a target international normalized ratio [INR] of 2.5, range 2.0–3.0), or unfractionated heparin. They recommend against routine use of aspirin alone. If surgery must be delayed, physicians should initiate prophylaxis with unfractionated or low-molecular-weight heparin at the time of hospital admission. Anticoagulation should routinely continue for 10 days after surgery or until the patient is ambulatory. If anticoagulation is contraindicated, mechanical prophylaxis of VTE with foot and calf pumping devices is recommended.^5,6

TABLE
6 steps for managing hip fracture from the American College of Physicians

Evidence summary

Although most patients undergo surgery for hip fracture, family physicians often serve as consultants for perioperative management and rehabilitation. Several interventions have been studied that influence outcomes for hip fracture patients.

Surgical interventions: Timing is critical

Most ambulatory, medically stable patients elect to have surgical repair of their fractures. A meta-analysis found few randomized trials comparing operative with nonoperative therapy; it concluded that surgical treatment seems to be associated with a reduced length of hospital stay and improved rehabilitation.¹

The timing of surgery appears to be an important variable, particularly whether patients should undergo surgery within 24 hours of the fracture. Some studies found decreased mortality with earlier surgical intervention,² while others have not.³ A 2006 observational study⁴ found that delay in operating was associated with an increased risk of death in the hospital, even after adjusting for comorbidities. For all deaths in the hospital, the odds ratio [OR] for delaying more than 1 day, relative to 1 day or less, was 1.27 (95% confidence interval [CI], 1.23–1.32). Despite the inconsistency regarding mortality rates, complication rates (such as decubitus ulcers) do increase with a delay in surgery.³

Unfractionated vs LMW heparin

After a hip fracture, patients are at very high risk for VTE. For untreated patients, the rate of deep vein thromboses (DVT) may be as high as 50%, with an associated fatal pulmonary embolism rate as high as 7.5%.⁵

The effectiveness of unfractionated and low-molecular-weight heparin was evaluated in a 2002 Cochrane systematic review.⁶ While evidence was insufficient to recommend 1 agent over another, both were found to significantly decrease the incidence of lower-extremity DVT over placebo (for unfractionated heparin, relative risk [RR]=0.59 [95% CI, 0.49–0.72]; for low-molecular-weight heparin, RR=0.60 [95% CI, 0.50–0.71]). Number needed to treat [NNT] with either agent was 7.

Reduce infections with antibiotic prophylaxis

Antibiotic prophylaxis has been supported by a Cochrane review, which concluded that single-dose antibiotic prophylaxis before surgery significantly reduced the risk of deep wound infections (RR=0.40; 95% CI, 0.24–0.67; NNT=55), as well as superficial wound, urinary, and respiratory tract infections.⁷

Patients should receive antibiotics less than 2 hours before surgery to reduce the risk of infection.⁸ Classen et al found that patients treated less than 2 hours before surgery had a 0.6% rate of infection (10/1208), compared with a 3.85% rate for those treated 2 to 24 hours ahead (14/369) (NNT=31).⁸ It is unclear whether multiple-dose therapy provides additional benefit when administered over the first 24 to 36 hours after surgery⁹ (OR=0.60; 95% CI, 0.18–2.02). First- or second-generation cephalosporins were used in most studies.

Delirium: A common but avoidable complication

Delirium is a common complication seen after hip fracture, affecting approximately 10% to 16% of patients.^10,11 Delirium may increase the duration of hospitalization, and may be associated with an increased mortality at 1 year.¹² Delirium can be avoided by looking at each patient’s risk factors.¹³ Studies suggest avoiding use of meperidine, benzodiazepines, and medications with anticholinergic side effects.^11,13 Sleep deprivation, delayed mobility, and inadequate pain control are also associated with the development of delirium.¹³

One study showed that prophylaxis with haloperidol for hip fracture patients did not decrease the incidence of postoperative delirium but did reduce its duration and severity.¹⁴ Haloperidol prophylaxis was also associated with shorter hospital stays. Treatment with haloperidol or risperidone for the agitation of postoperative delirium has been recommended when behavioral interventions fail.¹³

Pain control improves recovery

Providing adequate analgesia is of the utmost importance. In a 2003 prospective cohort study, patients without sufficient analgesia had an increased risk of poor functional recovery and longer hospitalization.¹⁵ In another cohort study, those patients whose pain was inadequately controlled also had an increased risk for delirium (RR=9.0; 95% CI, 1.8–45.2).¹¹ Meperidine use increased the risk for delirium compared with other opioid analgesics (RR=2.4; 95% CI, 1.3–4.5).¹¹

Recommendations of others

The American College of Physicians provides a comprehensive evidence-based guideline for the management of hip fracture patients in their PIER series (Physicians’ Information and Education Resource) (TABLE).¹⁶

The American College of Chest Physicians has published evidence-based guidelines for the prevention of VTE.⁵ For patients undergoing hip fracture surgery, they recommend routine use of fondaparinux, low-molecular-weight heparin at high-risk dosing, adjusted-dose warfarin (at a target international normalized ratio [INR] of 2.5, range 2.0–3.0), or unfractionated heparin. They recommend against routine use of aspirin alone. If surgery must be delayed, physicians should initiate prophylaxis with unfractionated or low-molecular-weight heparin at the time of hospital admission. Anticoagulation should routinely continue for 10 days after surgery or until the patient is ambulatory. If anticoagulation is contraindicated, mechanical prophylaxis of VTE with foot and calf pumping devices is recommended.^5,6

TABLE
6 steps for managing hip fracture from the American College of Physicians

Evidence summary

VVC is a common cause of vaginitis; Candida albicans accounts for 85% to 90% of cases. Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics.¹ Incidence increases with onset of sexual activity, but there is no direct evidence it is sexually transmitted.¹ About 75% of women experience 1 VVC episode during their lifetime, 40% to 45% have 2 or more, and 5% to 8% have recurrent VVC (defined as 4 or more annually).^1,2

The candidiasis/antibiotics link

A 2003 systematic review found the evidence supporting the association between antibiotics and VVC limited and contradictory.³ Most were case-control or cohort studies with small sample sizes. No RCTs compare the incidence of culture-confirmed VVC among women receiving antibiotics or placebo.

Nineteen reports of 18 original studies had sufficient data to calculate a relative risk or odds ratio for antibiotic-associated VVC. Thirteen of the 19 reports showed an increase (around twofold; range, 0.43–5) in vaginal Candida prevalence; however, 3 of the 13 reports had no mycological culture data. Six studies did not show significant association between antibiotics and vaginal yeast.³

Antibiotics are thought to increase risk of VVC by killing endogenous vaginal flora (particularly Lactobacillus), allowing microorganisms resistant to the antibiotics, like Candida, to flourish.¹ Yet there is evidence that numbers of genital Lactobacillus are similar for women with and without symptomatic VVC.⁴ Further, decreasing Lactobacillus does not increase the risk of VVC.⁵

Topical and oral antifungals—both do the job

For the treatment of uncomplicated VVC, both topical and oral antifungals are clinically and mycologically effective, with comparable clinical cure rates >80%.⁶ No difference in persistent symptoms between single and multiple doses, or different durations of multiple dose regimens have been found, but samples may have been too small to detect clinically significant effects. An RCT found less nausea, headache, and abdominal pain with intravaginal imidazoles, but more vulvar irritation and vaginal discharge than oral fluconazole.⁶

For treatment of recurrent VVC, RCTs have shown the effectiveness of oral fluconazole and itraconazole maintenance therapy taken for 6 months after an initial regimen.^7,8 Treating male sexual partners did not significantly improve resolution of the woman’s symptoms or reduce the rate of symptomatic relapse.⁹

Yogurt may not live up to its rep

Two poor-quality crossover RCTs provided insufficient evidence regarding effectiveness of a diet containing oral Lactobacillus yogurt to prevent recurrent VVC.⁹ A recent RCT of 278 women on short courses of antibiotics were randomized to oral lactobacilli or placebo and vaginal lactobacilli or placebo.¹⁰ The study was stopped early because there was no effect seen. Overall, 23% developed symptomatic vulvovaginitis.

Recommendations from others

The Infectious Diseases Society of America¹¹ recommends treating uncomplicated VVC with short-course of oral or topical antifungals; treating complicated VVC with antimycotic therapy for 7 days, either daily as topical therapy or as two 150-mg doses of fluconazole 72 hours apart; treating non-albicans species of Candida with topical boric acid (600 mg/day for 14 days) or topical flucytosine; and treating recurrent VVC with induction therapy with 2 weeks of a topical or oral azole followed by a maintenance regimen for 6 months (fluconazole once a week or itraconazole twice a week).¹¹

Evidence summary

VVC is a common cause of vaginitis; Candida albicans accounts for 85% to 90% of cases. Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics.¹ Incidence increases with onset of sexual activity, but there is no direct evidence it is sexually transmitted.¹ About 75% of women experience 1 VVC episode during their lifetime, 40% to 45% have 2 or more, and 5% to 8% have recurrent VVC (defined as 4 or more annually).^1,2

The candidiasis/antibiotics link

A 2003 systematic review found the evidence supporting the association between antibiotics and VVC limited and contradictory.³ Most were case-control or cohort studies with small sample sizes. No RCTs compare the incidence of culture-confirmed VVC among women receiving antibiotics or placebo.

Nineteen reports of 18 original studies had sufficient data to calculate a relative risk or odds ratio for antibiotic-associated VVC. Thirteen of the 19 reports showed an increase (around twofold; range, 0.43–5) in vaginal Candida prevalence; however, 3 of the 13 reports had no mycological culture data. Six studies did not show significant association between antibiotics and vaginal yeast.³

Antibiotics are thought to increase risk of VVC by killing endogenous vaginal flora (particularly Lactobacillus), allowing microorganisms resistant to the antibiotics, like Candida, to flourish.¹ Yet there is evidence that numbers of genital Lactobacillus are similar for women with and without symptomatic VVC.⁴ Further, decreasing Lactobacillus does not increase the risk of VVC.⁵

Topical and oral antifungals—both do the job

For the treatment of uncomplicated VVC, both topical and oral antifungals are clinically and mycologically effective, with comparable clinical cure rates >80%.⁶ No difference in persistent symptoms between single and multiple doses, or different durations of multiple dose regimens have been found, but samples may have been too small to detect clinically significant effects. An RCT found less nausea, headache, and abdominal pain with intravaginal imidazoles, but more vulvar irritation and vaginal discharge than oral fluconazole.⁶

For treatment of recurrent VVC, RCTs have shown the effectiveness of oral fluconazole and itraconazole maintenance therapy taken for 6 months after an initial regimen.^7,8 Treating male sexual partners did not significantly improve resolution of the woman’s symptoms or reduce the rate of symptomatic relapse.⁹

Yogurt may not live up to its rep

Two poor-quality crossover RCTs provided insufficient evidence regarding effectiveness of a diet containing oral Lactobacillus yogurt to prevent recurrent VVC.⁹ A recent RCT of 278 women on short courses of antibiotics were randomized to oral lactobacilli or placebo and vaginal lactobacilli or placebo.¹⁰ The study was stopped early because there was no effect seen. Overall, 23% developed symptomatic vulvovaginitis.

Recommendations from others

The Infectious Diseases Society of America¹¹ recommends treating uncomplicated VVC with short-course of oral or topical antifungals; treating complicated VVC with antimycotic therapy for 7 days, either daily as topical therapy or as two 150-mg doses of fluconazole 72 hours apart; treating non-albicans species of Candida with topical boric acid (600 mg/day for 14 days) or topical flucytosine; and treating recurrent VVC with induction therapy with 2 weeks of a topical or oral azole followed by a maintenance regimen for 6 months (fluconazole once a week or itraconazole twice a week).¹¹

Evidence summary

VVC is a common cause of vaginitis; Candida albicans accounts for 85% to 90% of cases. Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics.¹ Incidence increases with onset of sexual activity, but there is no direct evidence it is sexually transmitted.¹ About 75% of women experience 1 VVC episode during their lifetime, 40% to 45% have 2 or more, and 5% to 8% have recurrent VVC (defined as 4 or more annually).^1,2

The candidiasis/antibiotics link

A 2003 systematic review found the evidence supporting the association between antibiotics and VVC limited and contradictory.³ Most were case-control or cohort studies with small sample sizes. No RCTs compare the incidence of culture-confirmed VVC among women receiving antibiotics or placebo.

Nineteen reports of 18 original studies had sufficient data to calculate a relative risk or odds ratio for antibiotic-associated VVC. Thirteen of the 19 reports showed an increase (around twofold; range, 0.43–5) in vaginal Candida prevalence; however, 3 of the 13 reports had no mycological culture data. Six studies did not show significant association between antibiotics and vaginal yeast.³

Antibiotics are thought to increase risk of VVC by killing endogenous vaginal flora (particularly Lactobacillus), allowing microorganisms resistant to the antibiotics, like Candida, to flourish.¹ Yet there is evidence that numbers of genital Lactobacillus are similar for women with and without symptomatic VVC.⁴ Further, decreasing Lactobacillus does not increase the risk of VVC.⁵

Topical and oral antifungals—both do the job

For the treatment of uncomplicated VVC, both topical and oral antifungals are clinically and mycologically effective, with comparable clinical cure rates >80%.⁶ No difference in persistent symptoms between single and multiple doses, or different durations of multiple dose regimens have been found, but samples may have been too small to detect clinically significant effects. An RCT found less nausea, headache, and abdominal pain with intravaginal imidazoles, but more vulvar irritation and vaginal discharge than oral fluconazole.⁶

For treatment of recurrent VVC, RCTs have shown the effectiveness of oral fluconazole and itraconazole maintenance therapy taken for 6 months after an initial regimen.^7,8 Treating male sexual partners did not significantly improve resolution of the woman’s symptoms or reduce the rate of symptomatic relapse.⁹

Yogurt may not live up to its rep

Two poor-quality crossover RCTs provided insufficient evidence regarding effectiveness of a diet containing oral Lactobacillus yogurt to prevent recurrent VVC.⁹ A recent RCT of 278 women on short courses of antibiotics were randomized to oral lactobacilli or placebo and vaginal lactobacilli or placebo.¹⁰ The study was stopped early because there was no effect seen. Overall, 23% developed symptomatic vulvovaginitis.

Recommendations from others

The Infectious Diseases Society of America¹¹ recommends treating uncomplicated VVC with short-course of oral or topical antifungals; treating complicated VVC with antimycotic therapy for 7 days, either daily as topical therapy or as two 150-mg doses of fluconazole 72 hours apart; treating non-albicans species of Candida with topical boric acid (600 mg/day for 14 days) or topical flucytosine; and treating recurrent VVC with induction therapy with 2 weeks of a topical or oral azole followed by a maintenance regimen for 6 months (fluconazole once a week or itraconazole twice a week).¹¹

Evidence summary

Fungal infections of the nail (onychomycosis) are often treated for relief of local symptoms and cosmetic reasons. Griseofulvin, fluconazole, itraconazole, and terbinafine have all been used orally.

A meta-analysis comparing the efficacy of terbinafine (Lamisil), pulse-dosed and continuous-dosed itraconazole (Sporanox), fluconazole (Diflucan), and griseofulvin showed mycological cure rates of varying degrees for each treatment (TABLE).¹ Another meta-analysis of 6 studies comparing terbinafine with itraconazole reported odds ratios ranging from 1.8 (95% confidence interval [CI], 1.1–2.8) to 2.9 (95% CI, 1.9–4.1), indicating an 80% to 190% increased likelihood of clinical cure with terbinafine compared with itraconazole.²

Lower relapse rates with terbinafine

Longer-term mycologic cure and clinical relapse rates have also been reported. A 5-year blinded prospective study found long-term mycologic cures of 46% for terbinafine vs 13% for itraconazole (number needed to treat [NNT]=4.3). This study also showed a lower clinical relapse for terbinafine (21% vs 48%; NNT=3.7).³ A cost-efficacy analysis of terbinafine, itraconazole, and griseofulvin found terbinafine to be the most cost-effective (TABLE).⁴

A randomized, double-blind, controlled trial compared daily terbinafine with pulse-dose terbinafine.⁵ Daily terbinafine (250 mg for 3 months) had a 70.9% mycologic cure, while pulse-dose terbinafine (500 mg daily for 1 week per month for 3 months) had only a 58.7% mycologic cure (relative risk [RR]=1.21 [95% CI, 1.02–1.43]; NNT=8.2). There was no significant difference in tolerability of the regimens.

Terbinafine is well-tolerated by most patients. A telephone survey after treatment with daily terbinafine or pulse-dose itraconazole reported greater ease and convenience, and higher overall satisfaction with continuous terbinafine vs pulse-dose itraconazole.⁶

A multicenter trial of diabetic patients with onychomycosis (mean±SD age, 55.7±11.7 years) revealed that terbinafine had comparable efficacy and caused no hypoglycemic reactions in this group, who were being treated with insulin or oral hypoglycemics.⁷ The terbinafine prescribing information suggests not using the drug for patients with chronic or active liver disease and recommends checking a pretreatment AST and ALT.⁸

TABLE
Efficacy and cost of treating toenail onychomycosis^1,4

Recommendations from others

Guidelines from the British Association of Dermatologists point out that terbinafine is superior to itraconazole, and consider it a first-line treatment because it has a better cure rate and lower relapse rate.⁹ UpToDate suggests oral terbinafine as initial treatment for onychomycosis at a dose of 250 mg daily for 12 weeks.¹⁰

Evidence summary

Fungal infections of the nail (onychomycosis) are often treated for relief of local symptoms and cosmetic reasons. Griseofulvin, fluconazole, itraconazole, and terbinafine have all been used orally.

A meta-analysis comparing the efficacy of terbinafine (Lamisil), pulse-dosed and continuous-dosed itraconazole (Sporanox), fluconazole (Diflucan), and griseofulvin showed mycological cure rates of varying degrees for each treatment (TABLE).¹ Another meta-analysis of 6 studies comparing terbinafine with itraconazole reported odds ratios ranging from 1.8 (95% confidence interval [CI], 1.1–2.8) to 2.9 (95% CI, 1.9–4.1), indicating an 80% to 190% increased likelihood of clinical cure with terbinafine compared with itraconazole.²

Lower relapse rates with terbinafine

Longer-term mycologic cure and clinical relapse rates have also been reported. A 5-year blinded prospective study found long-term mycologic cures of 46% for terbinafine vs 13% for itraconazole (number needed to treat [NNT]=4.3). This study also showed a lower clinical relapse for terbinafine (21% vs 48%; NNT=3.7).³ A cost-efficacy analysis of terbinafine, itraconazole, and griseofulvin found terbinafine to be the most cost-effective (TABLE).⁴

A randomized, double-blind, controlled trial compared daily terbinafine with pulse-dose terbinafine.⁵ Daily terbinafine (250 mg for 3 months) had a 70.9% mycologic cure, while pulse-dose terbinafine (500 mg daily for 1 week per month for 3 months) had only a 58.7% mycologic cure (relative risk [RR]=1.21 [95% CI, 1.02–1.43]; NNT=8.2). There was no significant difference in tolerability of the regimens.

Terbinafine is well-tolerated by most patients. A telephone survey after treatment with daily terbinafine or pulse-dose itraconazole reported greater ease and convenience, and higher overall satisfaction with continuous terbinafine vs pulse-dose itraconazole.⁶

A multicenter trial of diabetic patients with onychomycosis (mean±SD age, 55.7±11.7 years) revealed that terbinafine had comparable efficacy and caused no hypoglycemic reactions in this group, who were being treated with insulin or oral hypoglycemics.⁷ The terbinafine prescribing information suggests not using the drug for patients with chronic or active liver disease and recommends checking a pretreatment AST and ALT.⁸

TABLE
Efficacy and cost of treating toenail onychomycosis^1,4

Recommendations from others

Guidelines from the British Association of Dermatologists point out that terbinafine is superior to itraconazole, and consider it a first-line treatment because it has a better cure rate and lower relapse rate.⁹ UpToDate suggests oral terbinafine as initial treatment for onychomycosis at a dose of 250 mg daily for 12 weeks.¹⁰

Evidence summary

Fungal infections of the nail (onychomycosis) are often treated for relief of local symptoms and cosmetic reasons. Griseofulvin, fluconazole, itraconazole, and terbinafine have all been used orally.

A meta-analysis comparing the efficacy of terbinafine (Lamisil), pulse-dosed and continuous-dosed itraconazole (Sporanox), fluconazole (Diflucan), and griseofulvin showed mycological cure rates of varying degrees for each treatment (TABLE).¹ Another meta-analysis of 6 studies comparing terbinafine with itraconazole reported odds ratios ranging from 1.8 (95% confidence interval [CI], 1.1–2.8) to 2.9 (95% CI, 1.9–4.1), indicating an 80% to 190% increased likelihood of clinical cure with terbinafine compared with itraconazole.²

Lower relapse rates with terbinafine

Longer-term mycologic cure and clinical relapse rates have also been reported. A 5-year blinded prospective study found long-term mycologic cures of 46% for terbinafine vs 13% for itraconazole (number needed to treat [NNT]=4.3). This study also showed a lower clinical relapse for terbinafine (21% vs 48%; NNT=3.7).³ A cost-efficacy analysis of terbinafine, itraconazole, and griseofulvin found terbinafine to be the most cost-effective (TABLE).⁴

A randomized, double-blind, controlled trial compared daily terbinafine with pulse-dose terbinafine.⁵ Daily terbinafine (250 mg for 3 months) had a 70.9% mycologic cure, while pulse-dose terbinafine (500 mg daily for 1 week per month for 3 months) had only a 58.7% mycologic cure (relative risk [RR]=1.21 [95% CI, 1.02–1.43]; NNT=8.2). There was no significant difference in tolerability of the regimens.

Terbinafine is well-tolerated by most patients. A telephone survey after treatment with daily terbinafine or pulse-dose itraconazole reported greater ease and convenience, and higher overall satisfaction with continuous terbinafine vs pulse-dose itraconazole.⁶

A multicenter trial of diabetic patients with onychomycosis (mean±SD age, 55.7±11.7 years) revealed that terbinafine had comparable efficacy and caused no hypoglycemic reactions in this group, who were being treated with insulin or oral hypoglycemics.⁷ The terbinafine prescribing information suggests not using the drug for patients with chronic or active liver disease and recommends checking a pretreatment AST and ALT.⁸

TABLE
Efficacy and cost of treating toenail onychomycosis^1,4

Recommendations from others

Guidelines from the British Association of Dermatologists point out that terbinafine is superior to itraconazole, and consider it a first-line treatment because it has a better cure rate and lower relapse rate.⁹ UpToDate suggests oral terbinafine as initial treatment for onychomycosis at a dose of 250 mg daily for 12 weeks.¹⁰

Evidence summary

Night sweats are a common complaint in the ambulatory primary care setting: Of 2267 patients in 1 cross-sectional study, 41% reported night sweats, defined as “sweating at night even when it isn’t excessively hot in your bedroom” within the previous month.¹ Because the peak prevalence in both men and women occurred in the group ages 41 to 55 years, there was concern that menopausal hot flashes were a confounding factor, at least for women. In a subsequent study of 795 patients older than 64 years, 10% still reported being bothered by night sweats.²

The more common causes are not widely studied

Few studies look at the causes of night sweats. Although they have been associated with tuberculosis, lymphoma, and HIV infection, these are not common causes of night sweats in outpatient care.

In the only study that specifically addressed the causes of night sweats in an ambulatory population, Reynolds³ interviewed 200 consecutive patients, 70% from a primary care practice and 30% from a gastroenterology practice. Of the 81 patients who reported having an episode of night sweats at least once a week, esophageal reflux and menopause were the most frequent causes.

Several authors agree that certain medications are frequently associated with night sweats, although the exact incidence is unknown due to a lack of published epidemiologic data.^4-6 Antidepressants and antipyretics are among the more commonly cited offenders (TABLE 1).⁴

TABLE 1
Medications that may cause sweating or flushing

Finding the right diagnosis requires thorough history & exam

With such a long differential diagnosis (TABLE 2),^4-6 night sweats should initially be evaluated with a thorough history and physical examination (according to a consensus opinion of various authors). If these don’t elicit possible causes, the appropriate next step in the work-up can vary. Some authors recommend multiple laboratory and imaging studies, while others advise against any routine tests. None of these approaches is evidence-based.

One reasonable algorithm recommends an initial work-up including a complete blood count, thyroid-stimulating hormone (TSH) and erythrocyte sedimentation rate (ESR) level, a purified protein derivative (PPD) and HIV test, and a chest x-ray.⁵ If the results are unrevealing, a trial of antireflux medication is recommended. If the patient does not improve, consider a diary of nocturnal temperatures to help discern the presence or absence of febrile pulses and further evaluate for suspected endocarditis or lymphoma.

TABLE 2
Differential diagnosis for night sweats

Evidence is scant for symptom relief

Very few clinical trials have directly studied symptomatic relief of night sweats. A large Cochrane meta-analysis found that oral hormone therapy—estrogens alone or estrogens with progesterone—reduced the frequency of night sweats associated with hot flashes among menopausal women by 75% when compared with placebo alone.⁷ Neither primrose oil nor foot reflexology proved effective.⁸

A cohort study found that 80% of the patients with frequent night sweats responded to antireflux therapy.³ One author suggests using therapies aimed at relieving hyperhydrosis.⁶ These include local treatment with aluminum chloride hexahydrate (Drysol), antiperspirants, scopolamine, or phenoxybenzamine hydrochloride (Dibenzyline).

Recommendations from others

A thorough literature search through Cochrane Database Systematic Reviews, AHRQ, National Guideline Clearing-house, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on the evaluation or treatment of night sweats.

Evidence summary

Night sweats are a common complaint in the ambulatory primary care setting: Of 2267 patients in 1 cross-sectional study, 41% reported night sweats, defined as “sweating at night even when it isn’t excessively hot in your bedroom” within the previous month.¹ Because the peak prevalence in both men and women occurred in the group ages 41 to 55 years, there was concern that menopausal hot flashes were a confounding factor, at least for women. In a subsequent study of 795 patients older than 64 years, 10% still reported being bothered by night sweats.²

The more common causes are not widely studied

Few studies look at the causes of night sweats. Although they have been associated with tuberculosis, lymphoma, and HIV infection, these are not common causes of night sweats in outpatient care.

In the only study that specifically addressed the causes of night sweats in an ambulatory population, Reynolds³ interviewed 200 consecutive patients, 70% from a primary care practice and 30% from a gastroenterology practice. Of the 81 patients who reported having an episode of night sweats at least once a week, esophageal reflux and menopause were the most frequent causes.

Several authors agree that certain medications are frequently associated with night sweats, although the exact incidence is unknown due to a lack of published epidemiologic data.^4-6 Antidepressants and antipyretics are among the more commonly cited offenders (TABLE 1).⁴

TABLE 1
Medications that may cause sweating or flushing

Finding the right diagnosis requires thorough history & exam

With such a long differential diagnosis (TABLE 2),^4-6 night sweats should initially be evaluated with a thorough history and physical examination (according to a consensus opinion of various authors). If these don’t elicit possible causes, the appropriate next step in the work-up can vary. Some authors recommend multiple laboratory and imaging studies, while others advise against any routine tests. None of these approaches is evidence-based.

One reasonable algorithm recommends an initial work-up including a complete blood count, thyroid-stimulating hormone (TSH) and erythrocyte sedimentation rate (ESR) level, a purified protein derivative (PPD) and HIV test, and a chest x-ray.⁵ If the results are unrevealing, a trial of antireflux medication is recommended. If the patient does not improve, consider a diary of nocturnal temperatures to help discern the presence or absence of febrile pulses and further evaluate for suspected endocarditis or lymphoma.

TABLE 2
Differential diagnosis for night sweats

Evidence is scant for symptom relief

Very few clinical trials have directly studied symptomatic relief of night sweats. A large Cochrane meta-analysis found that oral hormone therapy—estrogens alone or estrogens with progesterone—reduced the frequency of night sweats associated with hot flashes among menopausal women by 75% when compared with placebo alone.⁷ Neither primrose oil nor foot reflexology proved effective.⁸

A cohort study found that 80% of the patients with frequent night sweats responded to antireflux therapy.³ One author suggests using therapies aimed at relieving hyperhydrosis.⁶ These include local treatment with aluminum chloride hexahydrate (Drysol), antiperspirants, scopolamine, or phenoxybenzamine hydrochloride (Dibenzyline).

Recommendations from others

A thorough literature search through Cochrane Database Systematic Reviews, AHRQ, National Guideline Clearing-house, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on the evaluation or treatment of night sweats.

Evidence summary

Night sweats are a common complaint in the ambulatory primary care setting: Of 2267 patients in 1 cross-sectional study, 41% reported night sweats, defined as “sweating at night even when it isn’t excessively hot in your bedroom” within the previous month.¹ Because the peak prevalence in both men and women occurred in the group ages 41 to 55 years, there was concern that menopausal hot flashes were a confounding factor, at least for women. In a subsequent study of 795 patients older than 64 years, 10% still reported being bothered by night sweats.²

The more common causes are not widely studied

Few studies look at the causes of night sweats. Although they have been associated with tuberculosis, lymphoma, and HIV infection, these are not common causes of night sweats in outpatient care.

In the only study that specifically addressed the causes of night sweats in an ambulatory population, Reynolds³ interviewed 200 consecutive patients, 70% from a primary care practice and 30% from a gastroenterology practice. Of the 81 patients who reported having an episode of night sweats at least once a week, esophageal reflux and menopause were the most frequent causes.

Several authors agree that certain medications are frequently associated with night sweats, although the exact incidence is unknown due to a lack of published epidemiologic data.^4-6 Antidepressants and antipyretics are among the more commonly cited offenders (TABLE 1).⁴

TABLE 1
Medications that may cause sweating or flushing

Finding the right diagnosis requires thorough history & exam

With such a long differential diagnosis (TABLE 2),^4-6 night sweats should initially be evaluated with a thorough history and physical examination (according to a consensus opinion of various authors). If these don’t elicit possible causes, the appropriate next step in the work-up can vary. Some authors recommend multiple laboratory and imaging studies, while others advise against any routine tests. None of these approaches is evidence-based.

One reasonable algorithm recommends an initial work-up including a complete blood count, thyroid-stimulating hormone (TSH) and erythrocyte sedimentation rate (ESR) level, a purified protein derivative (PPD) and HIV test, and a chest x-ray.⁵ If the results are unrevealing, a trial of antireflux medication is recommended. If the patient does not improve, consider a diary of nocturnal temperatures to help discern the presence or absence of febrile pulses and further evaluate for suspected endocarditis or lymphoma.

TABLE 2
Differential diagnosis for night sweats

Evidence is scant for symptom relief

Very few clinical trials have directly studied symptomatic relief of night sweats. A large Cochrane meta-analysis found that oral hormone therapy—estrogens alone or estrogens with progesterone—reduced the frequency of night sweats associated with hot flashes among menopausal women by 75% when compared with placebo alone.⁷ Neither primrose oil nor foot reflexology proved effective.⁸

A cohort study found that 80% of the patients with frequent night sweats responded to antireflux therapy.³ One author suggests using therapies aimed at relieving hyperhydrosis.⁶ These include local treatment with aluminum chloride hexahydrate (Drysol), antiperspirants, scopolamine, or phenoxybenzamine hydrochloride (Dibenzyline).

Recommendations from others

A thorough literature search through Cochrane Database Systematic Reviews, AHRQ, National Guideline Clearing-house, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on the evaluation or treatment of night sweats.