Barbara Jamieson, MLS

Evidence summary

AA is a common inflammatory condition that causes hair loss and subsequent social consequences. Spontaneous remission occurs in 34% to 50% of patients within 1 year.¹ Many trials of commonly used AA treatments have identified no significant patient benefits. A 2008 Cochrane review that examined 17 studies (14 RCTs and 3 within-patient studies) of AA interventions in 540 participants found no clinically significant hair regrowth (>50%) when patients were treated with topical corticosteroids, cyclosporine, minoxidil, photodynamic therapy, or oral corticosteroids.²

Documenting patient outcomes is problematic because of spontaneous resolution and frequent relapses.² Moreover, few quality-controlled trials have studied children, and no long-term, randomized outcome trials of AA treatments exist.

Intralesional steroids and SADBE show results
In a moderately sized retrospective cohort study in Singapore (392 patients <16 years), 57% of patients experienced more than 50% improvement after 12 weeks of intralesional steroids for limited AA, and 75% showed similar improvement after 24 weeks. Of 43 children treated with anthralin, only 10 with limited AA showed more than 50% clinical improvement within 6 months.³ Fifty-four patients with extensive AA received SADBE; 74% experienced greater than 50% hair regrowth at 6 months.³

SADBE effects aren’t long-lived
A 1996 individual cohort study of 33 children (6*#8211;14 years of age) with extensive AA who were treated with SADBE once a week for a year showed a complete regrowth rate of 30.3%. Only 9% of the children maintained total or partial regrowth during long-term follow-up (mean 6 years), however.⁴

In another individual cohort study, 28 pediatric patients with extensive AA had mixed results with 2% SADBE used once a week for a year.⁵ Nine patients (32.1%) showed total or acceptable hair growth; 6 (21.4%) had diffuse regrowth but thinner than normal hair. Eighty-seven percent of patients relapsed within 6 months of discontinuing therapy.⁵

Studies of DPCP are too small
A 1996 small individual cohort investigation recorded a 40% response rate (90%–100% regrowth) to DPCP in 10 pediatric patients with extensive AA who were treated for an average of 8.6 months. The same study found cosmetically acceptable growth in 27% of patients (4 of 15 patients 4–15 years of age) treated for an average of 9.6 months.⁶

A small individual study of DPCP reported complete regrowth in 4 of 12 (33%) children with extensive AA; growth persisted at 6 months in 3 of the 4 responders.⁷ Another cohort study reported a 50% response rate (>80% regrowth) using DPCP in 10 patients (11–14 years of age) with extensive disease.⁸

Use SADBE and DPCP with caution
SADBE and DPCP are unlicensed treatments that can cause occipital and cervical lymphadenopathy, severe dermatitis (minimized by careful titration), urticaria, and hypo- or hyperpigmentation disorders (especially in racially pigmented patients). These agents shouldn’t be used during pregnancy and should be applied using gloves and aprons to avoid allergic contact dermatitis.

In light of these cautions, and handling and storage limitations, SADBE and DPCP should be reserved for patients with extensive disease (after obtaining signed informed consent). Patients should avoid ultraviolet light for 24 to 48 hours after application to avoid degradation of the medication.

Recommendations

The National Alopecia Areata Foundation and the American Academy of Dermatology recommend corticosteroids, topical minoxidil, and anthralin to treat AA.^9,10

The British Association of Dermatologists’ guidelines for managing AA advise using intralesional corticosteroids for limited AA and contact immunotherapy for more extensive disease.¹ They also note that intralesional corticosteroids are poorly tolerated and clinicians are reluctant to use contact immunotherapy in children.

Acknowledgements

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

Evidence summary

AA is a common inflammatory condition that causes hair loss and subsequent social consequences. Spontaneous remission occurs in 34% to 50% of patients within 1 year.¹ Many trials of commonly used AA treatments have identified no significant patient benefits. A 2008 Cochrane review that examined 17 studies (14 RCTs and 3 within-patient studies) of AA interventions in 540 participants found no clinically significant hair regrowth (>50%) when patients were treated with topical corticosteroids, cyclosporine, minoxidil, photodynamic therapy, or oral corticosteroids.²

Documenting patient outcomes is problematic because of spontaneous resolution and frequent relapses.² Moreover, few quality-controlled trials have studied children, and no long-term, randomized outcome trials of AA treatments exist.

Intralesional steroids and SADBE show results
In a moderately sized retrospective cohort study in Singapore (392 patients <16 years), 57% of patients experienced more than 50% improvement after 12 weeks of intralesional steroids for limited AA, and 75% showed similar improvement after 24 weeks. Of 43 children treated with anthralin, only 10 with limited AA showed more than 50% clinical improvement within 6 months.³ Fifty-four patients with extensive AA received SADBE; 74% experienced greater than 50% hair regrowth at 6 months.³

SADBE effects aren’t long-lived
A 1996 individual cohort study of 33 children (6*#8211;14 years of age) with extensive AA who were treated with SADBE once a week for a year showed a complete regrowth rate of 30.3%. Only 9% of the children maintained total or partial regrowth during long-term follow-up (mean 6 years), however.⁴

In another individual cohort study, 28 pediatric patients with extensive AA had mixed results with 2% SADBE used once a week for a year.⁵ Nine patients (32.1%) showed total or acceptable hair growth; 6 (21.4%) had diffuse regrowth but thinner than normal hair. Eighty-seven percent of patients relapsed within 6 months of discontinuing therapy.⁵

Studies of DPCP are too small
A 1996 small individual cohort investigation recorded a 40% response rate (90%–100% regrowth) to DPCP in 10 pediatric patients with extensive AA who were treated for an average of 8.6 months. The same study found cosmetically acceptable growth in 27% of patients (4 of 15 patients 4–15 years of age) treated for an average of 9.6 months.⁶

A small individual study of DPCP reported complete regrowth in 4 of 12 (33%) children with extensive AA; growth persisted at 6 months in 3 of the 4 responders.⁷ Another cohort study reported a 50% response rate (>80% regrowth) using DPCP in 10 patients (11–14 years of age) with extensive disease.⁸

Use SADBE and DPCP with caution
SADBE and DPCP are unlicensed treatments that can cause occipital and cervical lymphadenopathy, severe dermatitis (minimized by careful titration), urticaria, and hypo- or hyperpigmentation disorders (especially in racially pigmented patients). These agents shouldn’t be used during pregnancy and should be applied using gloves and aprons to avoid allergic contact dermatitis.

In light of these cautions, and handling and storage limitations, SADBE and DPCP should be reserved for patients with extensive disease (after obtaining signed informed consent). Patients should avoid ultraviolet light for 24 to 48 hours after application to avoid degradation of the medication.

Recommendations

The National Alopecia Areata Foundation and the American Academy of Dermatology recommend corticosteroids, topical minoxidil, and anthralin to treat AA.^9,10

The British Association of Dermatologists’ guidelines for managing AA advise using intralesional corticosteroids for limited AA and contact immunotherapy for more extensive disease.¹ They also note that intralesional corticosteroids are poorly tolerated and clinicians are reluctant to use contact immunotherapy in children.

Acknowledgements

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

Evidence summary

AA is a common inflammatory condition that causes hair loss and subsequent social consequences. Spontaneous remission occurs in 34% to 50% of patients within 1 year.¹ Many trials of commonly used AA treatments have identified no significant patient benefits. A 2008 Cochrane review that examined 17 studies (14 RCTs and 3 within-patient studies) of AA interventions in 540 participants found no clinically significant hair regrowth (>50%) when patients were treated with topical corticosteroids, cyclosporine, minoxidil, photodynamic therapy, or oral corticosteroids.²

Documenting patient outcomes is problematic because of spontaneous resolution and frequent relapses.² Moreover, few quality-controlled trials have studied children, and no long-term, randomized outcome trials of AA treatments exist.

Intralesional steroids and SADBE show results
In a moderately sized retrospective cohort study in Singapore (392 patients <16 years), 57% of patients experienced more than 50% improvement after 12 weeks of intralesional steroids for limited AA, and 75% showed similar improvement after 24 weeks. Of 43 children treated with anthralin, only 10 with limited AA showed more than 50% clinical improvement within 6 months.³ Fifty-four patients with extensive AA received SADBE; 74% experienced greater than 50% hair regrowth at 6 months.³

SADBE effects aren’t long-lived
A 1996 individual cohort study of 33 children (6*#8211;14 years of age) with extensive AA who were treated with SADBE once a week for a year showed a complete regrowth rate of 30.3%. Only 9% of the children maintained total or partial regrowth during long-term follow-up (mean 6 years), however.⁴

In another individual cohort study, 28 pediatric patients with extensive AA had mixed results with 2% SADBE used once a week for a year.⁵ Nine patients (32.1%) showed total or acceptable hair growth; 6 (21.4%) had diffuse regrowth but thinner than normal hair. Eighty-seven percent of patients relapsed within 6 months of discontinuing therapy.⁵

Studies of DPCP are too small
A 1996 small individual cohort investigation recorded a 40% response rate (90%–100% regrowth) to DPCP in 10 pediatric patients with extensive AA who were treated for an average of 8.6 months. The same study found cosmetically acceptable growth in 27% of patients (4 of 15 patients 4–15 years of age) treated for an average of 9.6 months.⁶

A small individual study of DPCP reported complete regrowth in 4 of 12 (33%) children with extensive AA; growth persisted at 6 months in 3 of the 4 responders.⁷ Another cohort study reported a 50% response rate (>80% regrowth) using DPCP in 10 patients (11–14 years of age) with extensive disease.⁸

Use SADBE and DPCP with caution
SADBE and DPCP are unlicensed treatments that can cause occipital and cervical lymphadenopathy, severe dermatitis (minimized by careful titration), urticaria, and hypo- or hyperpigmentation disorders (especially in racially pigmented patients). These agents shouldn’t be used during pregnancy and should be applied using gloves and aprons to avoid allergic contact dermatitis.

In light of these cautions, and handling and storage limitations, SADBE and DPCP should be reserved for patients with extensive disease (after obtaining signed informed consent). Patients should avoid ultraviolet light for 24 to 48 hours after application to avoid degradation of the medication.

Recommendations

The National Alopecia Areata Foundation and the American Academy of Dermatology recommend corticosteroids, topical minoxidil, and anthralin to treat AA.^9,10

The British Association of Dermatologists’ guidelines for managing AA advise using intralesional corticosteroids for limited AA and contact immunotherapy for more extensive disease.¹ They also note that intralesional corticosteroids are poorly tolerated and clinicians are reluctant to use contact immunotherapy in children.

Acknowledgements

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

Evidence summary

Continuous EFM is designed to detect early fetal hypoxia and thereby decrease neonatal morbidity and mortality compared with IA. IA is defined as auscultation of the fetal heart rate for at least 60 seconds every 15 minutes during the first stage of labor and every 5 minutes during the second stage of labor.

A decrease in seizures, but not deaths or cerebral palsy
A 2006 Cochrane systematic review examined 12 RCTs (with >37,000 women) that compared continuous EFM with IA.¹ Continuous EFM reduced the risk of neonatal seizure by 50% (relative risk [RR]=0.50; 95% confidence interval [CI], 0.31-0.80), but had no effect on the rate of neonatal death (RR=0.85; 95% CI, 0.59-1.23) or development of cerebral palsy (RR=1.74; 95% CI, 0.97-3.11).

Reduction of seizures was consistent across all trials. However, a subgroup analysis of high-risk pregnancies (advanced maternal age, diabetes mellitus, chronic hypertension, renal disease, preeclampsia, cardiac disease, renal disease, previous delivery of a low-birth-weight infant) didn’t find a statistically significant decrease in seizures.

Cesarean deliveries rise, regardless of patient risk status
Continuous EFM raised the rates of cesarean delivery (RR=1.66; 95% CI, 1.30-2.13) and instrumental vaginal deliveries (RR=1.16; 95% CI, 1.01-1.32). The increased rate of cesarean section in the EFM group was consistent regardless of clinical risk status (low- vs high-risk women). One additional cesarean section was performed for every 58 women monitored continuously. For “high-risk” women, 1 additional cesarean section was performed for every 12 women monitored continuously.¹

Cesarean section rates varied widely among the individual trials (2.3%-35%). Analysis suggested that studies with higher baseline rates showed the greatest increases with continuous EFM. The rate for all studies combined was just 4.3%; 69% of patients included in the meta-analysis were contributed by the Dublin trial, which had an average cesarean rate of 2.3%.¹ By comparison, the US Division of Vital Statistics reported a cesarean rate of 32.3% in 2008.²

EFM reduces death from fetal hypoxia
A 1995 meta-analysis, including 9 of the Cochrane review studies with a total of 18,561 women, evaluated the additional outcome of death resulting from fetal hypoxia.³ Compared with IA, EFM was associated with a 59% reduction in death from fetal hypoxia (RR=0.41; 95% CI, 0.17-0.98). Continuous EFM prevented 1 perinatal death per 1000 births. The reduction in perinatal mortality was offset by a 53% increase in cesarean deliveries and a 23% increase in operative vaginal deliveries.³

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) doesn’t recommend for or against continuous fetal heart rate monitoring in uncomplicated labor, recognizing either EFM or IA as acceptable in uncomplicated patients.⁴ ACOG does recommend continuous EFM for women with high-risk conditions (suspected fetal growth restriction, preeclampsia, and type 1 diabetes mellitus).

The US Preventive Services Task Force doesn’t support routine intrapartum EFM for low-risk woman. The Task Force found insufficient evidence for using EFM in high-risk pregnancies.⁵

The Royal College of Obstetricians and Gynaecologists and the Royal Australian and New Zealand College of Obstetricians and Gynecologists both recommend continuous EFM for high-risk women and IA for low-risk patients.^6,7

Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army Medical Department or the US Army at large.

Evidence summary

Continuous EFM is designed to detect early fetal hypoxia and thereby decrease neonatal morbidity and mortality compared with IA. IA is defined as auscultation of the fetal heart rate for at least 60 seconds every 15 minutes during the first stage of labor and every 5 minutes during the second stage of labor.

A decrease in seizures, but not deaths or cerebral palsy
A 2006 Cochrane systematic review examined 12 RCTs (with >37,000 women) that compared continuous EFM with IA.¹ Continuous EFM reduced the risk of neonatal seizure by 50% (relative risk [RR]=0.50; 95% confidence interval [CI], 0.31-0.80), but had no effect on the rate of neonatal death (RR=0.85; 95% CI, 0.59-1.23) or development of cerebral palsy (RR=1.74; 95% CI, 0.97-3.11).

Reduction of seizures was consistent across all trials. However, a subgroup analysis of high-risk pregnancies (advanced maternal age, diabetes mellitus, chronic hypertension, renal disease, preeclampsia, cardiac disease, renal disease, previous delivery of a low-birth-weight infant) didn’t find a statistically significant decrease in seizures.

Cesarean deliveries rise, regardless of patient risk status
Continuous EFM raised the rates of cesarean delivery (RR=1.66; 95% CI, 1.30-2.13) and instrumental vaginal deliveries (RR=1.16; 95% CI, 1.01-1.32). The increased rate of cesarean section in the EFM group was consistent regardless of clinical risk status (low- vs high-risk women). One additional cesarean section was performed for every 58 women monitored continuously. For “high-risk” women, 1 additional cesarean section was performed for every 12 women monitored continuously.¹

Cesarean section rates varied widely among the individual trials (2.3%-35%). Analysis suggested that studies with higher baseline rates showed the greatest increases with continuous EFM. The rate for all studies combined was just 4.3%; 69% of patients included in the meta-analysis were contributed by the Dublin trial, which had an average cesarean rate of 2.3%.¹ By comparison, the US Division of Vital Statistics reported a cesarean rate of 32.3% in 2008.²

EFM reduces death from fetal hypoxia
A 1995 meta-analysis, including 9 of the Cochrane review studies with a total of 18,561 women, evaluated the additional outcome of death resulting from fetal hypoxia.³ Compared with IA, EFM was associated with a 59% reduction in death from fetal hypoxia (RR=0.41; 95% CI, 0.17-0.98). Continuous EFM prevented 1 perinatal death per 1000 births. The reduction in perinatal mortality was offset by a 53% increase in cesarean deliveries and a 23% increase in operative vaginal deliveries.³

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) doesn’t recommend for or against continuous fetal heart rate monitoring in uncomplicated labor, recognizing either EFM or IA as acceptable in uncomplicated patients.⁴ ACOG does recommend continuous EFM for women with high-risk conditions (suspected fetal growth restriction, preeclampsia, and type 1 diabetes mellitus).

The US Preventive Services Task Force doesn’t support routine intrapartum EFM for low-risk woman. The Task Force found insufficient evidence for using EFM in high-risk pregnancies.⁵

The Royal College of Obstetricians and Gynaecologists and the Royal Australian and New Zealand College of Obstetricians and Gynecologists both recommend continuous EFM for high-risk women and IA for low-risk patients.^6,7

Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army Medical Department or the US Army at large.

Evidence summary

Continuous EFM is designed to detect early fetal hypoxia and thereby decrease neonatal morbidity and mortality compared with IA. IA is defined as auscultation of the fetal heart rate for at least 60 seconds every 15 minutes during the first stage of labor and every 5 minutes during the second stage of labor.

A decrease in seizures, but not deaths or cerebral palsy
A 2006 Cochrane systematic review examined 12 RCTs (with >37,000 women) that compared continuous EFM with IA.¹ Continuous EFM reduced the risk of neonatal seizure by 50% (relative risk [RR]=0.50; 95% confidence interval [CI], 0.31-0.80), but had no effect on the rate of neonatal death (RR=0.85; 95% CI, 0.59-1.23) or development of cerebral palsy (RR=1.74; 95% CI, 0.97-3.11).

Reduction of seizures was consistent across all trials. However, a subgroup analysis of high-risk pregnancies (advanced maternal age, diabetes mellitus, chronic hypertension, renal disease, preeclampsia, cardiac disease, renal disease, previous delivery of a low-birth-weight infant) didn’t find a statistically significant decrease in seizures.

Cesarean deliveries rise, regardless of patient risk status
Continuous EFM raised the rates of cesarean delivery (RR=1.66; 95% CI, 1.30-2.13) and instrumental vaginal deliveries (RR=1.16; 95% CI, 1.01-1.32). The increased rate of cesarean section in the EFM group was consistent regardless of clinical risk status (low- vs high-risk women). One additional cesarean section was performed for every 58 women monitored continuously. For “high-risk” women, 1 additional cesarean section was performed for every 12 women monitored continuously.¹

Cesarean section rates varied widely among the individual trials (2.3%-35%). Analysis suggested that studies with higher baseline rates showed the greatest increases with continuous EFM. The rate for all studies combined was just 4.3%; 69% of patients included in the meta-analysis were contributed by the Dublin trial, which had an average cesarean rate of 2.3%.¹ By comparison, the US Division of Vital Statistics reported a cesarean rate of 32.3% in 2008.²

EFM reduces death from fetal hypoxia
A 1995 meta-analysis, including 9 of the Cochrane review studies with a total of 18,561 women, evaluated the additional outcome of death resulting from fetal hypoxia.³ Compared with IA, EFM was associated with a 59% reduction in death from fetal hypoxia (RR=0.41; 95% CI, 0.17-0.98). Continuous EFM prevented 1 perinatal death per 1000 births. The reduction in perinatal mortality was offset by a 53% increase in cesarean deliveries and a 23% increase in operative vaginal deliveries.³

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) doesn’t recommend for or against continuous fetal heart rate monitoring in uncomplicated labor, recognizing either EFM or IA as acceptable in uncomplicated patients.⁴ ACOG does recommend continuous EFM for women with high-risk conditions (suspected fetal growth restriction, preeclampsia, and type 1 diabetes mellitus).

The US Preventive Services Task Force doesn’t support routine intrapartum EFM for low-risk woman. The Task Force found insufficient evidence for using EFM in high-risk pregnancies.⁵

The Royal College of Obstetricians and Gynaecologists and the Royal Australian and New Zealand College of Obstetricians and Gynecologists both recommend continuous EFM for high-risk women and IA for low-risk patients.^6,7

Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army Medical Department or the US Army at large.

Evidence summary

A systematic review of 9 RCTs demonstrated that aspirin (75-325 mg) started soon after the onset of acute MI significantly reduced mortality, reinfarction, and stroke at 1 month compared with placebo (absolute risk reduction [ARR]=3.8%; number needed to treat [NNT]=26; 95% confidence interval [CI], 23-30).¹

One large RCT involving 17,187 patients with suspected acute MI showed that 162 mg aspirin given on the day of the MI resulted in a 2.6% ARR (NNT=38; 95% CI, 29-63) in vascular deaths at 35 days compared with placebo.² The survival benefit persisted for as long as 10 years. The RCT also found no significant difference between aspirin and placebo in rates of cerebral hemorrhage or bleeding requiring transfusions.

Patients who have had an MI without ST segment elevation should take clopidogrel (75 mg/d) and aspirin (81 mg/d) for 12 months. The combination has been shown to result in a 2.1% ARR (NNT=48) in deaths, recurrent MI, and stroke compared with aspirin alone.³ Patients who have had an ST segment elevation MI should take clopidogrel in combination with aspirin for at least 2 weeks.⁴

TABLE
Recommended drugs for post-MI patients

Intensive atorvastatin therapy lowers risk of death

The PROVE IT-TIMI 22 trial showed the benefit of early intensive therapy with the hydroxymethyl glutaryl coenzyme A reductase inhibitor atorvastatin to lower low-density lipoprotein <70 mg/dL post-MI.⁵ At 30 days after the event, atorvastatin 80 mg daily resulted in a 1.2% ARR in death and recurrent acute coronary syndrome (NNT=83; hazard ratio [HR]=0.72; 95% CI, 0.52-0.99). From 6 months to 24 months after the event, the ARR was 2.6% (NNT=38; HR=0.82; 95% CI, 0.69-0.99).

Beta-blockers significantly decrease late mortality
One systematic review of 63 RCTs showed that, in long-term trials, use of a beta-blocker significantly reduced the late mortality rate (NNT=48; odds ratio [OR]=0.77; 95% CI, 0.70-0.85).⁶ In another review of 82 RCTs, the mortality rate between 6 months and 4 years after MI decreased markedly in patients receiving a beta-blocker (OR=0.77; 95% CI, 0.69-0.85).⁷

ACE inhibitors decrease overall mortality, sudden cardiac death
An ACE inhibitor should be started regardless of the ejection fraction or the presence or absence of left ventricular systolic dysfunction. One systematic review that compared long-term mortality rates of patients started on an ACE inhibitor within 14 days of acute MI versus placebo found that ACE inhibitors significantly decreased overall mortality and sudden cardiac deaths between 2 and 42 months after the MI (NNT=42; OR=0.83; 95% CI, 0.71-0.97).⁸

Eplerenone + ACE inhibitor benefit patients with post-MI heart failure
The selective aldosterone blocker eplerenone appears to benefit patients with a decreased ejection fraction post-MI. The EPHESUS study demonstrated that eplerenone, when added to an ACE inhibitor, reduced all-cause mortality (ARR=1.4%; NNT=71; 95% CI, 47-200; RR=0.69; 95% CI, 0.54-0.89) and sudden cardiac death (ARR=0.5%; NNT=200; 95% CI, 125-∞; RR=0.63; 95% CI, 0.40-1.00) up to 30 days in patients with post-MI heart failure. Benefits were also seen after 16 months of treatment.⁹

Recommendations

The American College of Cardiology (ACC) and American Heart Association (AHA) provide the following recommendations in their joint 2006 Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease:¹⁰

• Low-dose aspirin should be used, as well as clopidogrel in combination with aspirin for up to 12 months after a non-ST elevation MI
• ACE inhibitors or angiotensin receptor blockers should be considered in all patients, and an aldosterone antagonist should be prescribed for patients with a diminished ejection fraction post-MI
• Beta-blockers should be used in all post-MI patients without contraindications.

The ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non–ST-Elevation Myocardial Infarction recommend the same medication combinations.¹¹ So does the 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, with the exception that clopidogrel in combination with aspirin is recommended for at least 14 days.¹²

Similarly, the British National Institute for Clinical Excellence Clinical Guideline 48 recommends that all post-MI patients be offered a combination of an ACE inhibitor, aspirin with clopidogrel, a beta-blocker, and a statin.¹³

Acknowledgement
The opinions and assertions contained herein are the private views of the authors and should not be construed as official or as reflecting the views of the US Department of the Navy or the Department of Defense.

Evidence summary

A systematic review of 9 RCTs demonstrated that aspirin (75-325 mg) started soon after the onset of acute MI significantly reduced mortality, reinfarction, and stroke at 1 month compared with placebo (absolute risk reduction [ARR]=3.8%; number needed to treat [NNT]=26; 95% confidence interval [CI], 23-30).¹

One large RCT involving 17,187 patients with suspected acute MI showed that 162 mg aspirin given on the day of the MI resulted in a 2.6% ARR (NNT=38; 95% CI, 29-63) in vascular deaths at 35 days compared with placebo.² The survival benefit persisted for as long as 10 years. The RCT also found no significant difference between aspirin and placebo in rates of cerebral hemorrhage or bleeding requiring transfusions.

Patients who have had an MI without ST segment elevation should take clopidogrel (75 mg/d) and aspirin (81 mg/d) for 12 months. The combination has been shown to result in a 2.1% ARR (NNT=48) in deaths, recurrent MI, and stroke compared with aspirin alone.³ Patients who have had an ST segment elevation MI should take clopidogrel in combination with aspirin for at least 2 weeks.⁴

TABLE
Recommended drugs for post-MI patients

Intensive atorvastatin therapy lowers risk of death

The PROVE IT-TIMI 22 trial showed the benefit of early intensive therapy with the hydroxymethyl glutaryl coenzyme A reductase inhibitor atorvastatin to lower low-density lipoprotein <70 mg/dL post-MI.⁵ At 30 days after the event, atorvastatin 80 mg daily resulted in a 1.2% ARR in death and recurrent acute coronary syndrome (NNT=83; hazard ratio [HR]=0.72; 95% CI, 0.52-0.99). From 6 months to 24 months after the event, the ARR was 2.6% (NNT=38; HR=0.82; 95% CI, 0.69-0.99).

Beta-blockers significantly decrease late mortality
One systematic review of 63 RCTs showed that, in long-term trials, use of a beta-blocker significantly reduced the late mortality rate (NNT=48; odds ratio [OR]=0.77; 95% CI, 0.70-0.85).⁶ In another review of 82 RCTs, the mortality rate between 6 months and 4 years after MI decreased markedly in patients receiving a beta-blocker (OR=0.77; 95% CI, 0.69-0.85).⁷

ACE inhibitors decrease overall mortality, sudden cardiac death
An ACE inhibitor should be started regardless of the ejection fraction or the presence or absence of left ventricular systolic dysfunction. One systematic review that compared long-term mortality rates of patients started on an ACE inhibitor within 14 days of acute MI versus placebo found that ACE inhibitors significantly decreased overall mortality and sudden cardiac deaths between 2 and 42 months after the MI (NNT=42; OR=0.83; 95% CI, 0.71-0.97).⁸

Eplerenone + ACE inhibitor benefit patients with post-MI heart failure
The selective aldosterone blocker eplerenone appears to benefit patients with a decreased ejection fraction post-MI. The EPHESUS study demonstrated that eplerenone, when added to an ACE inhibitor, reduced all-cause mortality (ARR=1.4%; NNT=71; 95% CI, 47-200; RR=0.69; 95% CI, 0.54-0.89) and sudden cardiac death (ARR=0.5%; NNT=200; 95% CI, 125-∞; RR=0.63; 95% CI, 0.40-1.00) up to 30 days in patients with post-MI heart failure. Benefits were also seen after 16 months of treatment.⁹

Recommendations

The American College of Cardiology (ACC) and American Heart Association (AHA) provide the following recommendations in their joint 2006 Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease:¹⁰

• Low-dose aspirin should be used, as well as clopidogrel in combination with aspirin for up to 12 months after a non-ST elevation MI
• ACE inhibitors or angiotensin receptor blockers should be considered in all patients, and an aldosterone antagonist should be prescribed for patients with a diminished ejection fraction post-MI
• Beta-blockers should be used in all post-MI patients without contraindications.

The ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non–ST-Elevation Myocardial Infarction recommend the same medication combinations.¹¹ So does the 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, with the exception that clopidogrel in combination with aspirin is recommended for at least 14 days.¹²

Similarly, the British National Institute for Clinical Excellence Clinical Guideline 48 recommends that all post-MI patients be offered a combination of an ACE inhibitor, aspirin with clopidogrel, a beta-blocker, and a statin.¹³

Acknowledgement
The opinions and assertions contained herein are the private views of the authors and should not be construed as official or as reflecting the views of the US Department of the Navy or the Department of Defense.

Evidence summary

A systematic review of 9 RCTs demonstrated that aspirin (75-325 mg) started soon after the onset of acute MI significantly reduced mortality, reinfarction, and stroke at 1 month compared with placebo (absolute risk reduction [ARR]=3.8%; number needed to treat [NNT]=26; 95% confidence interval [CI], 23-30).¹

One large RCT involving 17,187 patients with suspected acute MI showed that 162 mg aspirin given on the day of the MI resulted in a 2.6% ARR (NNT=38; 95% CI, 29-63) in vascular deaths at 35 days compared with placebo.² The survival benefit persisted for as long as 10 years. The RCT also found no significant difference between aspirin and placebo in rates of cerebral hemorrhage or bleeding requiring transfusions.

Patients who have had an MI without ST segment elevation should take clopidogrel (75 mg/d) and aspirin (81 mg/d) for 12 months. The combination has been shown to result in a 2.1% ARR (NNT=48) in deaths, recurrent MI, and stroke compared with aspirin alone.³ Patients who have had an ST segment elevation MI should take clopidogrel in combination with aspirin for at least 2 weeks.⁴

TABLE
Recommended drugs for post-MI patients

Intensive atorvastatin therapy lowers risk of death

The PROVE IT-TIMI 22 trial showed the benefit of early intensive therapy with the hydroxymethyl glutaryl coenzyme A reductase inhibitor atorvastatin to lower low-density lipoprotein <70 mg/dL post-MI.⁵ At 30 days after the event, atorvastatin 80 mg daily resulted in a 1.2% ARR in death and recurrent acute coronary syndrome (NNT=83; hazard ratio [HR]=0.72; 95% CI, 0.52-0.99). From 6 months to 24 months after the event, the ARR was 2.6% (NNT=38; HR=0.82; 95% CI, 0.69-0.99).

Beta-blockers significantly decrease late mortality
One systematic review of 63 RCTs showed that, in long-term trials, use of a beta-blocker significantly reduced the late mortality rate (NNT=48; odds ratio [OR]=0.77; 95% CI, 0.70-0.85).⁶ In another review of 82 RCTs, the mortality rate between 6 months and 4 years after MI decreased markedly in patients receiving a beta-blocker (OR=0.77; 95% CI, 0.69-0.85).⁷

ACE inhibitors decrease overall mortality, sudden cardiac death
An ACE inhibitor should be started regardless of the ejection fraction or the presence or absence of left ventricular systolic dysfunction. One systematic review that compared long-term mortality rates of patients started on an ACE inhibitor within 14 days of acute MI versus placebo found that ACE inhibitors significantly decreased overall mortality and sudden cardiac deaths between 2 and 42 months after the MI (NNT=42; OR=0.83; 95% CI, 0.71-0.97).⁸

Eplerenone + ACE inhibitor benefit patients with post-MI heart failure
The selective aldosterone blocker eplerenone appears to benefit patients with a decreased ejection fraction post-MI. The EPHESUS study demonstrated that eplerenone, when added to an ACE inhibitor, reduced all-cause mortality (ARR=1.4%; NNT=71; 95% CI, 47-200; RR=0.69; 95% CI, 0.54-0.89) and sudden cardiac death (ARR=0.5%; NNT=200; 95% CI, 125-∞; RR=0.63; 95% CI, 0.40-1.00) up to 30 days in patients with post-MI heart failure. Benefits were also seen after 16 months of treatment.⁹

Recommendations

The American College of Cardiology (ACC) and American Heart Association (AHA) provide the following recommendations in their joint 2006 Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease:¹⁰

• Low-dose aspirin should be used, as well as clopidogrel in combination with aspirin for up to 12 months after a non-ST elevation MI
• ACE inhibitors or angiotensin receptor blockers should be considered in all patients, and an aldosterone antagonist should be prescribed for patients with a diminished ejection fraction post-MI
• Beta-blockers should be used in all post-MI patients without contraindications.

The ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non–ST-Elevation Myocardial Infarction recommend the same medication combinations.¹¹ So does the 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, with the exception that clopidogrel in combination with aspirin is recommended for at least 14 days.¹²

Similarly, the British National Institute for Clinical Excellence Clinical Guideline 48 recommends that all post-MI patients be offered a combination of an ACE inhibitor, aspirin with clopidogrel, a beta-blocker, and a statin.¹³

Acknowledgement
The opinions and assertions contained herein are the private views of the authors and should not be construed as official or as reflecting the views of the US Department of the Navy or the Department of Defense.

Evidence summary

Upper extremity venous thrombosis (UEVT)—which typically refers to thrombosis of the brachial, axillary, or subclavian veins—accounts for approximately 10% of all cases of venous thromboembolism.¹ UEVT can occur spontaneously (Paget-Schroetter syndrome) or develop as a complication of cancer or in-dwelling medical devices (such as long-term central venous catheters).

Although significant evidence-based data exist on treatment of lower extremity venous thrombosis, no good-quality studies specifically address management of UEVT. Review of the current literature revealed several small studies that compared various treatment strategies.

Thrombolytics may work better than anticoagulants in some patients
A small retrospective study randomized 20 patients with UEVT to either treatment with anticoagulant therapy with heparin and warfarin (n=11) or thrombolytic therapy (n=9).² After a mean follow-up period of 81.7 months for the anticoagulation group and 52.1 months for the thrombolytic group, 4 more patients in the thrombolytic group achieved complete clinical recovery and vein patency than in the anticoagulant group (P=.04). When patients who recovered completely were added to those who showed some clinical improvement, 89% of the thrombolytic therapy group had satisfactory outcomes, compared with 36% of the anticoagulant group (P=.028).

Another small retrospective study looked at 10 consecutive patients with UEVT who were treated with either anticoagulant therapy (n=6) or thrombolytics (n=4).³ Fifty percent of patients treated with anticoagulants experienced partial or complete improvement in symptoms, whereas 100% of patients treated with thrombolytics had partial or complete resolution of both symptoms and thrombi.

Overall, both studies raise the possibility that thrombolytic therapy is more effective than anticoagulation therapy in certain patients. The studies evaluated only active patients, 23 to 58 years of age, who had no contraindications to thrombolytic therapy. Neither study reported data on long-term outcomes such as recurrences, bleeding, or post-thrombotic sequelae.

Surgery may avoid long-term anticoagulation
Two case studies evaluated treatment of UEVT with thrombolytic therapy followed by various surgical interventions (angioplasty, thrombectomy, decompression via first rib resection or anterior scalenectomy, and venous bypass).^4,5 The first study reported that 8 of 9 patients who underwent first-rib resection and 1 of 2 who underwent scalenectomy were free of residual symptoms at follow-up (mean 2 years, range 6 months to 5 years).⁴ All patients were treated with thrombolytics before surgery.

The second study demonstrated that 50% of the patients treated with a surgical intervention without thrombolysis had complete symptom relief, while the remaining 50% reported relief from pain but still had occasional swelling.⁵ Although more invasive, surgery may eliminate the need for long-term anticoagulation therapy and enable a more rapid return to normal activities.

Data on vena cava filters are limited
Data supporting superior vena cava Green-field filters to treat UEVT are extremely limited. Of 6 patients with contraindications to anticoagulation therapy who were treated with a Greenfield filter, none had clinical evidence of pulmonary embolism at 14 months.⁶ The study reported no data regarding long-term sequelae or effects of the UEVT on the patients’ upper extremity.⁶

When in doubt, don’t (necessarily) take it out
For patients with central venous catheter-related deep vein thrombosis, taking out the catheter as part of treatment is controversial and should depend on clinical symptoms, the reason for the catheter, and duration of use, as well as physician judgment.⁷ No RCTs have studied the effects of catheter removal as part of initial treatment. Current guidelines recommend removing the catheter from patients with persistent symptoms who have failed anticoagulant or thrombolytic treatment.¹

Recommendations

The American College of Chest Physicians recommends therapeutic doses of intravenous unfractionated heparin, low-molecular-weight heparin, or fondaparinux for initial treatment of UEVT, followed by at least 3 months of treatment with a vitamin K antagonist.¹ The organization also suggests that surgical thrombectomy, superior vena caval filters, thrombolytic therapy, or catheter extraction may benefit selected patients.

Acknowledgement
The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Upper extremity venous thrombosis (UEVT)—which typically refers to thrombosis of the brachial, axillary, or subclavian veins—accounts for approximately 10% of all cases of venous thromboembolism.¹ UEVT can occur spontaneously (Paget-Schroetter syndrome) or develop as a complication of cancer or in-dwelling medical devices (such as long-term central venous catheters).

Although significant evidence-based data exist on treatment of lower extremity venous thrombosis, no good-quality studies specifically address management of UEVT. Review of the current literature revealed several small studies that compared various treatment strategies.

Thrombolytics may work better than anticoagulants in some patients
A small retrospective study randomized 20 patients with UEVT to either treatment with anticoagulant therapy with heparin and warfarin (n=11) or thrombolytic therapy (n=9).² After a mean follow-up period of 81.7 months for the anticoagulation group and 52.1 months for the thrombolytic group, 4 more patients in the thrombolytic group achieved complete clinical recovery and vein patency than in the anticoagulant group (P=.04). When patients who recovered completely were added to those who showed some clinical improvement, 89% of the thrombolytic therapy group had satisfactory outcomes, compared with 36% of the anticoagulant group (P=.028).

Another small retrospective study looked at 10 consecutive patients with UEVT who were treated with either anticoagulant therapy (n=6) or thrombolytics (n=4).³ Fifty percent of patients treated with anticoagulants experienced partial or complete improvement in symptoms, whereas 100% of patients treated with thrombolytics had partial or complete resolution of both symptoms and thrombi.

Overall, both studies raise the possibility that thrombolytic therapy is more effective than anticoagulation therapy in certain patients. The studies evaluated only active patients, 23 to 58 years of age, who had no contraindications to thrombolytic therapy. Neither study reported data on long-term outcomes such as recurrences, bleeding, or post-thrombotic sequelae.

Surgery may avoid long-term anticoagulation
Two case studies evaluated treatment of UEVT with thrombolytic therapy followed by various surgical interventions (angioplasty, thrombectomy, decompression via first rib resection or anterior scalenectomy, and venous bypass).^4,5 The first study reported that 8 of 9 patients who underwent first-rib resection and 1 of 2 who underwent scalenectomy were free of residual symptoms at follow-up (mean 2 years, range 6 months to 5 years).⁴ All patients were treated with thrombolytics before surgery.

The second study demonstrated that 50% of the patients treated with a surgical intervention without thrombolysis had complete symptom relief, while the remaining 50% reported relief from pain but still had occasional swelling.⁵ Although more invasive, surgery may eliminate the need for long-term anticoagulation therapy and enable a more rapid return to normal activities.

Data on vena cava filters are limited
Data supporting superior vena cava Green-field filters to treat UEVT are extremely limited. Of 6 patients with contraindications to anticoagulation therapy who were treated with a Greenfield filter, none had clinical evidence of pulmonary embolism at 14 months.⁶ The study reported no data regarding long-term sequelae or effects of the UEVT on the patients’ upper extremity.⁶

When in doubt, don’t (necessarily) take it out
For patients with central venous catheter-related deep vein thrombosis, taking out the catheter as part of treatment is controversial and should depend on clinical symptoms, the reason for the catheter, and duration of use, as well as physician judgment.⁷ No RCTs have studied the effects of catheter removal as part of initial treatment. Current guidelines recommend removing the catheter from patients with persistent symptoms who have failed anticoagulant or thrombolytic treatment.¹

Recommendations

The American College of Chest Physicians recommends therapeutic doses of intravenous unfractionated heparin, low-molecular-weight heparin, or fondaparinux for initial treatment of UEVT, followed by at least 3 months of treatment with a vitamin K antagonist.¹ The organization also suggests that surgical thrombectomy, superior vena caval filters, thrombolytic therapy, or catheter extraction may benefit selected patients.

Acknowledgement
The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Upper extremity venous thrombosis (UEVT)—which typically refers to thrombosis of the brachial, axillary, or subclavian veins—accounts for approximately 10% of all cases of venous thromboembolism.¹ UEVT can occur spontaneously (Paget-Schroetter syndrome) or develop as a complication of cancer or in-dwelling medical devices (such as long-term central venous catheters).

Although significant evidence-based data exist on treatment of lower extremity venous thrombosis, no good-quality studies specifically address management of UEVT. Review of the current literature revealed several small studies that compared various treatment strategies.

Thrombolytics may work better than anticoagulants in some patients
A small retrospective study randomized 20 patients with UEVT to either treatment with anticoagulant therapy with heparin and warfarin (n=11) or thrombolytic therapy (n=9).² After a mean follow-up period of 81.7 months for the anticoagulation group and 52.1 months for the thrombolytic group, 4 more patients in the thrombolytic group achieved complete clinical recovery and vein patency than in the anticoagulant group (P=.04). When patients who recovered completely were added to those who showed some clinical improvement, 89% of the thrombolytic therapy group had satisfactory outcomes, compared with 36% of the anticoagulant group (P=.028).

Another small retrospective study looked at 10 consecutive patients with UEVT who were treated with either anticoagulant therapy (n=6) or thrombolytics (n=4).³ Fifty percent of patients treated with anticoagulants experienced partial or complete improvement in symptoms, whereas 100% of patients treated with thrombolytics had partial or complete resolution of both symptoms and thrombi.

Overall, both studies raise the possibility that thrombolytic therapy is more effective than anticoagulation therapy in certain patients. The studies evaluated only active patients, 23 to 58 years of age, who had no contraindications to thrombolytic therapy. Neither study reported data on long-term outcomes such as recurrences, bleeding, or post-thrombotic sequelae.

Surgery may avoid long-term anticoagulation
Two case studies evaluated treatment of UEVT with thrombolytic therapy followed by various surgical interventions (angioplasty, thrombectomy, decompression via first rib resection or anterior scalenectomy, and venous bypass).^4,5 The first study reported that 8 of 9 patients who underwent first-rib resection and 1 of 2 who underwent scalenectomy were free of residual symptoms at follow-up (mean 2 years, range 6 months to 5 years).⁴ All patients were treated with thrombolytics before surgery.

The second study demonstrated that 50% of the patients treated with a surgical intervention without thrombolysis had complete symptom relief, while the remaining 50% reported relief from pain but still had occasional swelling.⁵ Although more invasive, surgery may eliminate the need for long-term anticoagulation therapy and enable a more rapid return to normal activities.

Data on vena cava filters are limited
Data supporting superior vena cava Green-field filters to treat UEVT are extremely limited. Of 6 patients with contraindications to anticoagulation therapy who were treated with a Greenfield filter, none had clinical evidence of pulmonary embolism at 14 months.⁶ The study reported no data regarding long-term sequelae or effects of the UEVT on the patients’ upper extremity.⁶

When in doubt, don’t (necessarily) take it out
For patients with central venous catheter-related deep vein thrombosis, taking out the catheter as part of treatment is controversial and should depend on clinical symptoms, the reason for the catheter, and duration of use, as well as physician judgment.⁷ No RCTs have studied the effects of catheter removal as part of initial treatment. Current guidelines recommend removing the catheter from patients with persistent symptoms who have failed anticoagulant or thrombolytic treatment.¹

Recommendations

The American College of Chest Physicians recommends therapeutic doses of intravenous unfractionated heparin, low-molecular-weight heparin, or fondaparinux for initial treatment of UEVT, followed by at least 3 months of treatment with a vitamin K antagonist.¹ The organization also suggests that surgical thrombectomy, superior vena caval filters, thrombolytic therapy, or catheter extraction may benefit selected patients.

Acknowledgement
The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

EVIDENCE-BASED ANSWER

A high-fiber diet may help; available evidence doesn’t support other interventions. A high-fiber diet is often prescribed after recovery from acute diverticulitis, based on extrapolation from epidemiologic data showing an association between low-fiber diets and diverticulosis (strength of recommendation [SOR]: C, expert opinion). No direct evidence establishes a role for fiber in preventing recurrent diverticulitis, however.

No evidence supports the common advice to avoid nuts and seeds to prevent diverticulitis. Eating nuts, corn, and popcorn doesn’t increase the risk; in fact, nuts and popcorn may have a protective effect (SOR: B, large cohort study).

There isn’t enough evidence to recommend the anti-inflammatory drug mesalamine or a polybacterial lysate for immunostimulation. Retrospective data don’t support routine prophylactic colectomy after 1 or 2 episodes of acute diverticulitis (SOR: B, observational studies).

Evidence summary

A 2006 Family Physicians Inquiries Network Clinical Inquiry on diverticulosis found inconsistent evidence that fiber decreases the risk of symptomatic diverticular disease (SOR: C, case control studies and a large prospective cohort study).¹

A 2007 literature review found no systematic reviews or randomized controlled trials (RCTs) of fiber for preventing complications of diverticular disease. The reviewers noted that observational studies have found less diverticulosis in populations with higher fiber consumption.²

Nuts, popcorn may be protective

A trial conducted as part of a large prospective cohort study—the Health Professionals Follow-up Study—followed 47,228 male health professionals in the United States, ages 40 to 75 years, from 1986 to 2004.³ The subjects, all of whom returned a food-frequency questionnaire, were at baseline free of diverticulosis and related complications, cancer, and inflammatory bowel disease. During the follow-up period, 801 cases of diverticulitis and 383 cases of diverticular bleeding (the main outcome measures) occurred.

The investigators found an inverse association between consumption of nuts and popcorn and risk of diverticulitis. Men with the highest intake of each food (at least twice per week) compared with men with the lowest intake (less than once per month) had a hazard ratio of 0.80 (95% confidence interval [CI], 0.63-1.01; P for trend=.04) for nuts and 0.72 (95% CI, 0.56-0.92; P for trend=.007) for popcorn. No association was noted between corn consumption and diverticulitis or between nut, corn, or popcorn consumption and diverticular bleeding or uncomplicated diverticulosis.

Mesalamine’s efficacy is unknown

A 2007 systematic review found 1 RCT of the anti-inflammatory drug mesalamine (mesalazine, 5-aminosalicylic acid) for preventing diverticulitis. Mesalamine reduced the recurrence rate of diverticulitis from 46% to 15% among 166 subjects.

The reviewers judged the study to be flawed by unreported diagnostic criteria and a high withdrawal rate. They concluded that the effectiveness of mesalamine remains unknown.²

1 small study of oral enterovaccine

An oral polybacterial lysate suspension designed to stimulate gut secretion of immunoglobulin A was investigated in a study of 83 patients with recurrent diverticulitis. In the treated group, 4.6% (2/43) of patients had recurrent diverticulitis during the 3 months of the study, compared with 12.5% (5/40) of the untreated group (P<.05).⁴

Prophylactic surgery rarely helps

No randomized trials have compared surgical with medical therapy to prevent recurrent diverticulitis. Extensive retrospective literature fails to support elective surgery after a second episode. Sixty-eight percent to 96% of patients requiring surgery for diverticulitis-associated perforation or abscess had no previous symptoms and couldn’t be helped by prophylactic surgery,⁵ and diverticulitis symptoms persisted after bowel resection in 27% to 33% of patients.⁵

One large retrospective study followed 3165 patients for 6 to 12 years after hospitalization for diverticulitis. Of the patients treated nonoperatively, 13% had a single recurrence and 4% had multiple recurrences; the annual recurrence rate was approximately 2%. The authors concluded that routine elective colectomy is rarely indicated after a first episode of uncomplicated acute diverticulitis.⁶

A decision analysis using a Markov model found that performing a colectomy after a fourth, rather than a second, episode of diverticulitis would result in somewhat fewer deaths and colostomies, equivalent quality-adjusted years of life, and cost savings per patient of $1035 to $5429. The results held for both older and younger patients.⁷

Recommendations

The American Society of Colon and Rectal Surgeons (ASCRS) concludes that recommendations for elective sigmoid colectomy after recovery from acute diverticulitis should be made on a case-by-case basis.⁸ Computed tomography to grade the severity of a first attack may help determine the need for surgery. The ASCRS guidelines mention that long-term fiber supplementation may prevent recurrences of diverticulitis in most patients.

The American College of Gastroenterology Practice Parameters Committee states that prophylactic surgery may be recommended for recurrent attacks of diverticulitis, but generally isn’t indicated after a single uncomplicated episode.⁹ The group also notes that high-fiber diets may decrease the development of colonic diverticulosis, but no consistent data exist regarding fiber to prevent recurrent diverticulitis.

EVIDENCE-BASED ANSWER

A high-fiber diet may help; available evidence doesn’t support other interventions. A high-fiber diet is often prescribed after recovery from acute diverticulitis, based on extrapolation from epidemiologic data showing an association between low-fiber diets and diverticulosis (strength of recommendation [SOR]: C, expert opinion). No direct evidence establishes a role for fiber in preventing recurrent diverticulitis, however.

No evidence supports the common advice to avoid nuts and seeds to prevent diverticulitis. Eating nuts, corn, and popcorn doesn’t increase the risk; in fact, nuts and popcorn may have a protective effect (SOR: B, large cohort study).

There isn’t enough evidence to recommend the anti-inflammatory drug mesalamine or a polybacterial lysate for immunostimulation. Retrospective data don’t support routine prophylactic colectomy after 1 or 2 episodes of acute diverticulitis (SOR: B, observational studies).

Evidence summary

A 2006 Family Physicians Inquiries Network Clinical Inquiry on diverticulosis found inconsistent evidence that fiber decreases the risk of symptomatic diverticular disease (SOR: C, case control studies and a large prospective cohort study).¹

A 2007 literature review found no systematic reviews or randomized controlled trials (RCTs) of fiber for preventing complications of diverticular disease. The reviewers noted that observational studies have found less diverticulosis in populations with higher fiber consumption.²

Nuts, popcorn may be protective

A trial conducted as part of a large prospective cohort study—the Health Professionals Follow-up Study—followed 47,228 male health professionals in the United States, ages 40 to 75 years, from 1986 to 2004.³ The subjects, all of whom returned a food-frequency questionnaire, were at baseline free of diverticulosis and related complications, cancer, and inflammatory bowel disease. During the follow-up period, 801 cases of diverticulitis and 383 cases of diverticular bleeding (the main outcome measures) occurred.

The investigators found an inverse association between consumption of nuts and popcorn and risk of diverticulitis. Men with the highest intake of each food (at least twice per week) compared with men with the lowest intake (less than once per month) had a hazard ratio of 0.80 (95% confidence interval [CI], 0.63-1.01; P for trend=.04) for nuts and 0.72 (95% CI, 0.56-0.92; P for trend=.007) for popcorn. No association was noted between corn consumption and diverticulitis or between nut, corn, or popcorn consumption and diverticular bleeding or uncomplicated diverticulosis.

Mesalamine’s efficacy is unknown

A 2007 systematic review found 1 RCT of the anti-inflammatory drug mesalamine (mesalazine, 5-aminosalicylic acid) for preventing diverticulitis. Mesalamine reduced the recurrence rate of diverticulitis from 46% to 15% among 166 subjects.

The reviewers judged the study to be flawed by unreported diagnostic criteria and a high withdrawal rate. They concluded that the effectiveness of mesalamine remains unknown.²

1 small study of oral enterovaccine

An oral polybacterial lysate suspension designed to stimulate gut secretion of immunoglobulin A was investigated in a study of 83 patients with recurrent diverticulitis. In the treated group, 4.6% (2/43) of patients had recurrent diverticulitis during the 3 months of the study, compared with 12.5% (5/40) of the untreated group (P<.05).⁴

Prophylactic surgery rarely helps

No randomized trials have compared surgical with medical therapy to prevent recurrent diverticulitis. Extensive retrospective literature fails to support elective surgery after a second episode. Sixty-eight percent to 96% of patients requiring surgery for diverticulitis-associated perforation or abscess had no previous symptoms and couldn’t be helped by prophylactic surgery,⁵ and diverticulitis symptoms persisted after bowel resection in 27% to 33% of patients.⁵

One large retrospective study followed 3165 patients for 6 to 12 years after hospitalization for diverticulitis. Of the patients treated nonoperatively, 13% had a single recurrence and 4% had multiple recurrences; the annual recurrence rate was approximately 2%. The authors concluded that routine elective colectomy is rarely indicated after a first episode of uncomplicated acute diverticulitis.⁶

A decision analysis using a Markov model found that performing a colectomy after a fourth, rather than a second, episode of diverticulitis would result in somewhat fewer deaths and colostomies, equivalent quality-adjusted years of life, and cost savings per patient of $1035 to $5429. The results held for both older and younger patients.⁷

Recommendations

The American Society of Colon and Rectal Surgeons (ASCRS) concludes that recommendations for elective sigmoid colectomy after recovery from acute diverticulitis should be made on a case-by-case basis.⁸ Computed tomography to grade the severity of a first attack may help determine the need for surgery. The ASCRS guidelines mention that long-term fiber supplementation may prevent recurrences of diverticulitis in most patients.

The American College of Gastroenterology Practice Parameters Committee states that prophylactic surgery may be recommended for recurrent attacks of diverticulitis, but generally isn’t indicated after a single uncomplicated episode.⁹ The group also notes that high-fiber diets may decrease the development of colonic diverticulosis, but no consistent data exist regarding fiber to prevent recurrent diverticulitis.

EVIDENCE-BASED ANSWER

A high-fiber diet may help; available evidence doesn’t support other interventions. A high-fiber diet is often prescribed after recovery from acute diverticulitis, based on extrapolation from epidemiologic data showing an association between low-fiber diets and diverticulosis (strength of recommendation [SOR]: C, expert opinion). No direct evidence establishes a role for fiber in preventing recurrent diverticulitis, however.

No evidence supports the common advice to avoid nuts and seeds to prevent diverticulitis. Eating nuts, corn, and popcorn doesn’t increase the risk; in fact, nuts and popcorn may have a protective effect (SOR: B, large cohort study).

There isn’t enough evidence to recommend the anti-inflammatory drug mesalamine or a polybacterial lysate for immunostimulation. Retrospective data don’t support routine prophylactic colectomy after 1 or 2 episodes of acute diverticulitis (SOR: B, observational studies).

Evidence summary

A 2006 Family Physicians Inquiries Network Clinical Inquiry on diverticulosis found inconsistent evidence that fiber decreases the risk of symptomatic diverticular disease (SOR: C, case control studies and a large prospective cohort study).¹

A 2007 literature review found no systematic reviews or randomized controlled trials (RCTs) of fiber for preventing complications of diverticular disease. The reviewers noted that observational studies have found less diverticulosis in populations with higher fiber consumption.²

Nuts, popcorn may be protective

A trial conducted as part of a large prospective cohort study—the Health Professionals Follow-up Study—followed 47,228 male health professionals in the United States, ages 40 to 75 years, from 1986 to 2004.³ The subjects, all of whom returned a food-frequency questionnaire, were at baseline free of diverticulosis and related complications, cancer, and inflammatory bowel disease. During the follow-up period, 801 cases of diverticulitis and 383 cases of diverticular bleeding (the main outcome measures) occurred.

The investigators found an inverse association between consumption of nuts and popcorn and risk of diverticulitis. Men with the highest intake of each food (at least twice per week) compared with men with the lowest intake (less than once per month) had a hazard ratio of 0.80 (95% confidence interval [CI], 0.63-1.01; P for trend=.04) for nuts and 0.72 (95% CI, 0.56-0.92; P for trend=.007) for popcorn. No association was noted between corn consumption and diverticulitis or between nut, corn, or popcorn consumption and diverticular bleeding or uncomplicated diverticulosis.

Mesalamine’s efficacy is unknown

A 2007 systematic review found 1 RCT of the anti-inflammatory drug mesalamine (mesalazine, 5-aminosalicylic acid) for preventing diverticulitis. Mesalamine reduced the recurrence rate of diverticulitis from 46% to 15% among 166 subjects.

The reviewers judged the study to be flawed by unreported diagnostic criteria and a high withdrawal rate. They concluded that the effectiveness of mesalamine remains unknown.²

1 small study of oral enterovaccine

An oral polybacterial lysate suspension designed to stimulate gut secretion of immunoglobulin A was investigated in a study of 83 patients with recurrent diverticulitis. In the treated group, 4.6% (2/43) of patients had recurrent diverticulitis during the 3 months of the study, compared with 12.5% (5/40) of the untreated group (P<.05).⁴

Prophylactic surgery rarely helps

No randomized trials have compared surgical with medical therapy to prevent recurrent diverticulitis. Extensive retrospective literature fails to support elective surgery after a second episode. Sixty-eight percent to 96% of patients requiring surgery for diverticulitis-associated perforation or abscess had no previous symptoms and couldn’t be helped by prophylactic surgery,⁵ and diverticulitis symptoms persisted after bowel resection in 27% to 33% of patients.⁵

One large retrospective study followed 3165 patients for 6 to 12 years after hospitalization for diverticulitis. Of the patients treated nonoperatively, 13% had a single recurrence and 4% had multiple recurrences; the annual recurrence rate was approximately 2%. The authors concluded that routine elective colectomy is rarely indicated after a first episode of uncomplicated acute diverticulitis.⁶

A decision analysis using a Markov model found that performing a colectomy after a fourth, rather than a second, episode of diverticulitis would result in somewhat fewer deaths and colostomies, equivalent quality-adjusted years of life, and cost savings per patient of $1035 to $5429. The results held for both older and younger patients.⁷

Recommendations

The American Society of Colon and Rectal Surgeons (ASCRS) concludes that recommendations for elective sigmoid colectomy after recovery from acute diverticulitis should be made on a case-by-case basis.⁸ Computed tomography to grade the severity of a first attack may help determine the need for surgery. The ASCRS guidelines mention that long-term fiber supplementation may prevent recurrences of diverticulitis in most patients.

The American College of Gastroenterology Practice Parameters Committee states that prophylactic surgery may be recommended for recurrent attacks of diverticulitis, but generally isn’t indicated after a single uncomplicated episode.⁹ The group also notes that high-fiber diets may decrease the development of colonic diverticulosis, but no consistent data exist regarding fiber to prevent recurrent diverticulitis.

Evidence summary

Nearly 50% of late-pregnancy IUFDs have no associated risk factors. Fetal demise, however, may be heralded by decreased fetal movement followed by cessation of movement at least 12 hours before death.¹ Maternal monitoring of fetal movement by kick counts has been proposed as a method to verify fetal well-being and decrease the rate of IUFD in the general obstetric population.

Counting doesn’t reduce antenatal death, large study shows

A well-done RCT randomized 68,654 women to either usual care or structured, daily monitoring of fetal movement using the count-to-10 method—daily maternal documentation of the amount of time it takes to perceive 10 fetal movements. Usual care was comprised of a query about fetal movement at antenatal visits and instruction to perform fetal movement monitoring at the provider’s discretion. Mothers were told to visit their health-care provider for evaluation if they felt no movement in 24 hours or fewer than 10 movements in 10 hours during a 48-hour period. The trial showed no benefit from monitoring in reducing the rate of antenatal death from all causes.

The rate of all fetal deaths in the counting group was 2.9 per 1000 normally formed, live, singleton births; the rate in the control group was 2.67 (absolute risk reduction=0.24; 95% confidence interval [CI], –0.5 to 0.98). Women in the counting group spent an average of 160 hours counting during pregnancy and had a statistically significant increase in fetal non-stress-test (NST) monitoring (odds ratio [OR]=1.39; 95% CI, 1.31-1.49; number needed to harm [NNH]=50 to cause 1 additional NST). A statistically insignificant trend toward increased antepartum admissions was also noted in the counting group.²

Maternal perception of less movement not linked to fetal outcome

A retrospective cohort study of 6793 patients compared pregnancy outcomes of 463 women who presented for evaluation of decreased fetal movement with outcomes among the general obstetric population. The study excluded women who reported complete cessation of fetal movement.

Pregnancies evaluated for decreased fetal movement were less likely to have an Apgar score <7 at 5 minutes (relative risk [RR]=0.56; 95% CI, 0.29-0.96; P=.05) and less likely to be preterm (RR=0.68; 95% CI, 0.48-0.94; P=.02). No significant difference in cesarean section for fetal distress or admission to the neonatal intensive care unit was noted between the study and control groups. The study suggests that maternal perception of decreased fetal movement is not associated with poor fetal outcome.³

A recent rigorous systematic review yielded no significant outcome effect related to fetal kick counts.⁴ A prospective cohort study of 4383 births in California, using historical controls, found a drop in fetal mortality from 8.7 to 2.1 deaths/1000. The historical control rate was higher than statewide data from the same time period, however. The overall weaker design of the study and probable effect of regression to the mean significantly limit the interpretation of outcomes.⁵

Recommendations

The American College of Obstetrics and Gynecology (ACOG) makes no recommendation for or against assessing daily fetal movement in routine pregnancies. ACOG notes that no consistent evidence suggests that formal assessment of fetal movement decreases IUFD.⁶

The Institute for Clinical Systems Improvement recommends instructing patients on “daily identification of fetal movement at the 28-week visit.” The institute doesn’t recommend specific criteria for evaluating fetal movements or offer recommendations for follow-up of a maternal report of decreased fetal movement.¹ The National Institute for Clinical Excellence in Great Britain recommends against routine formal fetal-movement counting.⁷

Evidence summary

Nearly 50% of late-pregnancy IUFDs have no associated risk factors. Fetal demise, however, may be heralded by decreased fetal movement followed by cessation of movement at least 12 hours before death.¹ Maternal monitoring of fetal movement by kick counts has been proposed as a method to verify fetal well-being and decrease the rate of IUFD in the general obstetric population.

Counting doesn’t reduce antenatal death, large study shows

A well-done RCT randomized 68,654 women to either usual care or structured, daily monitoring of fetal movement using the count-to-10 method—daily maternal documentation of the amount of time it takes to perceive 10 fetal movements. Usual care was comprised of a query about fetal movement at antenatal visits and instruction to perform fetal movement monitoring at the provider’s discretion. Mothers were told to visit their health-care provider for evaluation if they felt no movement in 24 hours or fewer than 10 movements in 10 hours during a 48-hour period. The trial showed no benefit from monitoring in reducing the rate of antenatal death from all causes.

The rate of all fetal deaths in the counting group was 2.9 per 1000 normally formed, live, singleton births; the rate in the control group was 2.67 (absolute risk reduction=0.24; 95% confidence interval [CI], –0.5 to 0.98). Women in the counting group spent an average of 160 hours counting during pregnancy and had a statistically significant increase in fetal non-stress-test (NST) monitoring (odds ratio [OR]=1.39; 95% CI, 1.31-1.49; number needed to harm [NNH]=50 to cause 1 additional NST). A statistically insignificant trend toward increased antepartum admissions was also noted in the counting group.²

Maternal perception of less movement not linked to fetal outcome

A retrospective cohort study of 6793 patients compared pregnancy outcomes of 463 women who presented for evaluation of decreased fetal movement with outcomes among the general obstetric population. The study excluded women who reported complete cessation of fetal movement.

Pregnancies evaluated for decreased fetal movement were less likely to have an Apgar score <7 at 5 minutes (relative risk [RR]=0.56; 95% CI, 0.29-0.96; P=.05) and less likely to be preterm (RR=0.68; 95% CI, 0.48-0.94; P=.02). No significant difference in cesarean section for fetal distress or admission to the neonatal intensive care unit was noted between the study and control groups. The study suggests that maternal perception of decreased fetal movement is not associated with poor fetal outcome.³

A recent rigorous systematic review yielded no significant outcome effect related to fetal kick counts.⁴ A prospective cohort study of 4383 births in California, using historical controls, found a drop in fetal mortality from 8.7 to 2.1 deaths/1000. The historical control rate was higher than statewide data from the same time period, however. The overall weaker design of the study and probable effect of regression to the mean significantly limit the interpretation of outcomes.⁵

Recommendations

The American College of Obstetrics and Gynecology (ACOG) makes no recommendation for or against assessing daily fetal movement in routine pregnancies. ACOG notes that no consistent evidence suggests that formal assessment of fetal movement decreases IUFD.⁶

The Institute for Clinical Systems Improvement recommends instructing patients on “daily identification of fetal movement at the 28-week visit.” The institute doesn’t recommend specific criteria for evaluating fetal movements or offer recommendations for follow-up of a maternal report of decreased fetal movement.¹ The National Institute for Clinical Excellence in Great Britain recommends against routine formal fetal-movement counting.⁷

Evidence summary

Nearly 50% of late-pregnancy IUFDs have no associated risk factors. Fetal demise, however, may be heralded by decreased fetal movement followed by cessation of movement at least 12 hours before death.¹ Maternal monitoring of fetal movement by kick counts has been proposed as a method to verify fetal well-being and decrease the rate of IUFD in the general obstetric population.

Counting doesn’t reduce antenatal death, large study shows

A well-done RCT randomized 68,654 women to either usual care or structured, daily monitoring of fetal movement using the count-to-10 method—daily maternal documentation of the amount of time it takes to perceive 10 fetal movements. Usual care was comprised of a query about fetal movement at antenatal visits and instruction to perform fetal movement monitoring at the provider’s discretion. Mothers were told to visit their health-care provider for evaluation if they felt no movement in 24 hours or fewer than 10 movements in 10 hours during a 48-hour period. The trial showed no benefit from monitoring in reducing the rate of antenatal death from all causes.

The rate of all fetal deaths in the counting group was 2.9 per 1000 normally formed, live, singleton births; the rate in the control group was 2.67 (absolute risk reduction=0.24; 95% confidence interval [CI], –0.5 to 0.98). Women in the counting group spent an average of 160 hours counting during pregnancy and had a statistically significant increase in fetal non-stress-test (NST) monitoring (odds ratio [OR]=1.39; 95% CI, 1.31-1.49; number needed to harm [NNH]=50 to cause 1 additional NST). A statistically insignificant trend toward increased antepartum admissions was also noted in the counting group.²

Maternal perception of less movement not linked to fetal outcome

A retrospective cohort study of 6793 patients compared pregnancy outcomes of 463 women who presented for evaluation of decreased fetal movement with outcomes among the general obstetric population. The study excluded women who reported complete cessation of fetal movement.

Pregnancies evaluated for decreased fetal movement were less likely to have an Apgar score <7 at 5 minutes (relative risk [RR]=0.56; 95% CI, 0.29-0.96; P=.05) and less likely to be preterm (RR=0.68; 95% CI, 0.48-0.94; P=.02). No significant difference in cesarean section for fetal distress or admission to the neonatal intensive care unit was noted between the study and control groups. The study suggests that maternal perception of decreased fetal movement is not associated with poor fetal outcome.³

A recent rigorous systematic review yielded no significant outcome effect related to fetal kick counts.⁴ A prospective cohort study of 4383 births in California, using historical controls, found a drop in fetal mortality from 8.7 to 2.1 deaths/1000. The historical control rate was higher than statewide data from the same time period, however. The overall weaker design of the study and probable effect of regression to the mean significantly limit the interpretation of outcomes.⁵

Recommendations

The American College of Obstetrics and Gynecology (ACOG) makes no recommendation for or against assessing daily fetal movement in routine pregnancies. ACOG notes that no consistent evidence suggests that formal assessment of fetal movement decreases IUFD.⁶

The Institute for Clinical Systems Improvement recommends instructing patients on “daily identification of fetal movement at the 28-week visit.” The institute doesn’t recommend specific criteria for evaluating fetal movements or offer recommendations for follow-up of a maternal report of decreased fetal movement.¹ The National Institute for Clinical Excellence in Great Britain recommends against routine formal fetal-movement counting.⁷

Evidence summary

An estimated 1.7 million people in the United States are living with limb loss. The number is expected to increase because of ongoing military conflicts.¹ The incidence of PLP is 60% to 80% among amputees.¹

A multidisciplinary approach

A lack of comparative clinical trials of therapies for PLP has led health-care providers to adopt a multidisciplinary approach that combines evaluative management, desensitization, psychotherapy, and pharmacotherapy (FIGURE).

Evaluative management, based largely on expert opinion, includes assessing the fit of the prosthesis, treating referred pain, and assessing aggravating factors. Because residual limb pain can exacerbate PLP, adjusting a poorly fitting prosthesis or providing the patient with NSAIDs when there is evidence of stump inflammation may adequately control pain.^2,3 Anatomically distant pain syndromes, such as hip or lower back pain, can also aggravate PLP and should be managed to provide optimal pain relief.²

Desensitization, using TENS, has reduced PLP in multiple placebo-controlled trials and epidemiologic surveys.^2-5 TENS is an easy-to-use, low-cost, noninvasive, first-line therapy.⁵ Its long-term effectiveness in alleviating PLP remains unknown.² Some experts suggest that pain reductions after 1 year of treatment are comparable to placebo.² Other forms of desensitization (percussion and massage) are supported only by anecdotal reports.

Psychotherapy, including biofeedback, has been found in several case studies to effectively treat chronic PLP.^2,5 Psychotherapy can reportedly reveal the underlying mechanisms (muscle spasm, vascular insufficiency) and therefore direct therapeutic interventions by biofeedback or other focus techniques.²

FIGURE Management of phantom limb pain^1-10

Pharmacotherapy is best used as an adjunct to other treatments.² Although PLP is typically treated as neuropathic pain, only a few medications have been critically evaluated for treating it.⁶ Morphine (number needed to treat [NNT]=2.5; 95% confidence interval [CI], 1.9-3.4) and other opioids, including tramadol (NNT=3.9; 95% CI, 2.7-6.7 in neuropathic pain) help some patients.^6,7 Despite the proven benefit of tricyclic antidepressants (TCAs) in other neuropathic pain conditions, a recent RCT demonstrated no benefit of TCAs over placebo in PLP.⁸ Anticonvulsants, including gabapentin, have documented benefit in neuropathic pain modalities and are often used for PLP.⁶ However, their value in reducing PLP is still under investigation.⁶ One 2002 RCT showed benefit regarding an improvement of the visual analog scale by an average of 3 points (on a 10-point scale) after 6 weeks of gabapentin therapy.⁹ A similarly designed 2006 RCT of gabapentin, however did not identify significant pain reductions.¹⁰

Promising adjuvant therapies use mirroring techniques

Of the adjuvant treatments mentioned previously, only mirror box therapy has shown promise. This technique allows the amputee to perceive the missing limb by focusing on the reflection of the remaining limb during specific movements and activities. Theoretically, this perception allows reconfiguration of the amputee’s sensory cortex.

Virtual reality therapy employs similar techniques based on the idea that the brain can be deceived. Initial case studies are promising and have prompted further research.¹¹

Recommendations

The US Department of Veterans Affairs and Department of Defense recently issued clinical guidelines for rehabilitating lower-limb amputees that include a segment on pain management.¹² The guidelines stress the importance of an interdisciplinary team approach that addresses each pathology plaguing the amputee.

They recommend narcotics during the immediate postoperative period, followed by transition to a non-narcotic medical regimen during the rehabilitation process. The guidelines don’t support a single, specific pain control method over others; they recommend the following approaches to PLP:

• pharmacologic treatment, which may include antiseizure medications, tricyclic antidepressants, selective serotonin reuptake inhibitors, NSAIDs, dextromethorathane, or long-acting narcotics
• epidural analgesia, patient-controlled analgesia, or regional analgesia
• nonpharmacologic therapies, including TENS, desensitization, scar mobilization, relaxation, and biofeedback.

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

An estimated 1.7 million people in the United States are living with limb loss. The number is expected to increase because of ongoing military conflicts.¹ The incidence of PLP is 60% to 80% among amputees.¹

A multidisciplinary approach

A lack of comparative clinical trials of therapies for PLP has led health-care providers to adopt a multidisciplinary approach that combines evaluative management, desensitization, psychotherapy, and pharmacotherapy (FIGURE).

Evaluative management, based largely on expert opinion, includes assessing the fit of the prosthesis, treating referred pain, and assessing aggravating factors. Because residual limb pain can exacerbate PLP, adjusting a poorly fitting prosthesis or providing the patient with NSAIDs when there is evidence of stump inflammation may adequately control pain.^2,3 Anatomically distant pain syndromes, such as hip or lower back pain, can also aggravate PLP and should be managed to provide optimal pain relief.²

Desensitization, using TENS, has reduced PLP in multiple placebo-controlled trials and epidemiologic surveys.^2-5 TENS is an easy-to-use, low-cost, noninvasive, first-line therapy.⁵ Its long-term effectiveness in alleviating PLP remains unknown.² Some experts suggest that pain reductions after 1 year of treatment are comparable to placebo.² Other forms of desensitization (percussion and massage) are supported only by anecdotal reports.

Psychotherapy, including biofeedback, has been found in several case studies to effectively treat chronic PLP.^2,5 Psychotherapy can reportedly reveal the underlying mechanisms (muscle spasm, vascular insufficiency) and therefore direct therapeutic interventions by biofeedback or other focus techniques.²

FIGURE Management of phantom limb pain^1-10

Pharmacotherapy is best used as an adjunct to other treatments.² Although PLP is typically treated as neuropathic pain, only a few medications have been critically evaluated for treating it.⁶ Morphine (number needed to treat [NNT]=2.5; 95% confidence interval [CI], 1.9-3.4) and other opioids, including tramadol (NNT=3.9; 95% CI, 2.7-6.7 in neuropathic pain) help some patients.^6,7 Despite the proven benefit of tricyclic antidepressants (TCAs) in other neuropathic pain conditions, a recent RCT demonstrated no benefit of TCAs over placebo in PLP.⁸ Anticonvulsants, including gabapentin, have documented benefit in neuropathic pain modalities and are often used for PLP.⁶ However, their value in reducing PLP is still under investigation.⁶ One 2002 RCT showed benefit regarding an improvement of the visual analog scale by an average of 3 points (on a 10-point scale) after 6 weeks of gabapentin therapy.⁹ A similarly designed 2006 RCT of gabapentin, however did not identify significant pain reductions.¹⁰

Promising adjuvant therapies use mirroring techniques

Of the adjuvant treatments mentioned previously, only mirror box therapy has shown promise. This technique allows the amputee to perceive the missing limb by focusing on the reflection of the remaining limb during specific movements and activities. Theoretically, this perception allows reconfiguration of the amputee’s sensory cortex.

Virtual reality therapy employs similar techniques based on the idea that the brain can be deceived. Initial case studies are promising and have prompted further research.¹¹

Recommendations

The US Department of Veterans Affairs and Department of Defense recently issued clinical guidelines for rehabilitating lower-limb amputees that include a segment on pain management.¹² The guidelines stress the importance of an interdisciplinary team approach that addresses each pathology plaguing the amputee.

They recommend narcotics during the immediate postoperative period, followed by transition to a non-narcotic medical regimen during the rehabilitation process. The guidelines don’t support a single, specific pain control method over others; they recommend the following approaches to PLP:

• pharmacologic treatment, which may include antiseizure medications, tricyclic antidepressants, selective serotonin reuptake inhibitors, NSAIDs, dextromethorathane, or long-acting narcotics
• epidural analgesia, patient-controlled analgesia, or regional analgesia
• nonpharmacologic therapies, including TENS, desensitization, scar mobilization, relaxation, and biofeedback.

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

An estimated 1.7 million people in the United States are living with limb loss. The number is expected to increase because of ongoing military conflicts.¹ The incidence of PLP is 60% to 80% among amputees.¹

A multidisciplinary approach

A lack of comparative clinical trials of therapies for PLP has led health-care providers to adopt a multidisciplinary approach that combines evaluative management, desensitization, psychotherapy, and pharmacotherapy (FIGURE).

Evaluative management, based largely on expert opinion, includes assessing the fit of the prosthesis, treating referred pain, and assessing aggravating factors. Because residual limb pain can exacerbate PLP, adjusting a poorly fitting prosthesis or providing the patient with NSAIDs when there is evidence of stump inflammation may adequately control pain.^2,3 Anatomically distant pain syndromes, such as hip or lower back pain, can also aggravate PLP and should be managed to provide optimal pain relief.²

Desensitization, using TENS, has reduced PLP in multiple placebo-controlled trials and epidemiologic surveys.^2-5 TENS is an easy-to-use, low-cost, noninvasive, first-line therapy.⁵ Its long-term effectiveness in alleviating PLP remains unknown.² Some experts suggest that pain reductions after 1 year of treatment are comparable to placebo.² Other forms of desensitization (percussion and massage) are supported only by anecdotal reports.

Psychotherapy, including biofeedback, has been found in several case studies to effectively treat chronic PLP.^2,5 Psychotherapy can reportedly reveal the underlying mechanisms (muscle spasm, vascular insufficiency) and therefore direct therapeutic interventions by biofeedback or other focus techniques.²

FIGURE Management of phantom limb pain^1-10

Pharmacotherapy is best used as an adjunct to other treatments.² Although PLP is typically treated as neuropathic pain, only a few medications have been critically evaluated for treating it.⁶ Morphine (number needed to treat [NNT]=2.5; 95% confidence interval [CI], 1.9-3.4) and other opioids, including tramadol (NNT=3.9; 95% CI, 2.7-6.7 in neuropathic pain) help some patients.^6,7 Despite the proven benefit of tricyclic antidepressants (TCAs) in other neuropathic pain conditions, a recent RCT demonstrated no benefit of TCAs over placebo in PLP.⁸ Anticonvulsants, including gabapentin, have documented benefit in neuropathic pain modalities and are often used for PLP.⁶ However, their value in reducing PLP is still under investigation.⁶ One 2002 RCT showed benefit regarding an improvement of the visual analog scale by an average of 3 points (on a 10-point scale) after 6 weeks of gabapentin therapy.⁹ A similarly designed 2006 RCT of gabapentin, however did not identify significant pain reductions.¹⁰

Promising adjuvant therapies use mirroring techniques

Of the adjuvant treatments mentioned previously, only mirror box therapy has shown promise. This technique allows the amputee to perceive the missing limb by focusing on the reflection of the remaining limb during specific movements and activities. Theoretically, this perception allows reconfiguration of the amputee’s sensory cortex.

Virtual reality therapy employs similar techniques based on the idea that the brain can be deceived. Initial case studies are promising and have prompted further research.¹¹

Recommendations

The US Department of Veterans Affairs and Department of Defense recently issued clinical guidelines for rehabilitating lower-limb amputees that include a segment on pain management.¹² The guidelines stress the importance of an interdisciplinary team approach that addresses each pathology plaguing the amputee.

They recommend narcotics during the immediate postoperative period, followed by transition to a non-narcotic medical regimen during the rehabilitation process. The guidelines don’t support a single, specific pain control method over others; they recommend the following approaches to PLP:

• pharmacologic treatment, which may include antiseizure medications, tricyclic antidepressants, selective serotonin reuptake inhibitors, NSAIDs, dextromethorathane, or long-acting narcotics
• epidural analgesia, patient-controlled analgesia, or regional analgesia
• nonpharmacologic therapies, including TENS, desensitization, scar mobilization, relaxation, and biofeedback.

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Few studies have compared treatment options for oropharyngeal candidiasis in immunocompetent infants. In a survey of 312 health care providers, approximately 75% of the respondents reported treating thrush with oral nystatin, citing fewer side effects and lower cost.¹ However, nystatin has proved less effective than either miconazole gel or oral fluconazole.

Nystatin is safe and available, but other options work better

Miconazole vs nystatin. An unblinded RCT assigned 83 immunocompetent infants with culture-positive oral thrush to receive either 25 mg miconazole oral gel (not commercially available in the United States) or nystatin suspension (1 mL of 100,000 IU/mL) qid after meals. The clinical cure rate, defined as absence of plaques by day 12, was significantly higher in the miconazole group (99% for miconazole, 54% for nystatin; P<.0001, number needed to treat [NNT]=2). The eradication rate, confirmed by cultures collected in a blinded manner on the day of clinical cure, was also higher in the miconazole group (55.7% for miconazole, 15.2% for nystatin; P<.0001, NNT=3). In successfully treated patients, infection recurred with similar frequency in both treatment groups within 4 weeks (miconazole, 12.4%; nystatin, 13.0%). Side effects—mostly vomiting and, infrequently, diarrhea—were rare in both groups (miconazole, 4.5%; nystatin 3.5%).²

An earlier, unblinded RCT of 95 infants compared miconazole gel to 2 nystatin oral gels (gel A: 250,000 IU/g with 250,000 IU administered as single dose; gel B: 100,000 IU/g with 50,000 IU administered as single dose). Each medication was given qid over the course of 8 to 14 days. The study confirmed higher clinical cure rates with miconazole gel (85.1% for miconazole vs 42.8% for nystatin gel A [P<.0007, NNT=2] and 48.5% for nystatin gel B [P<.004, NNT=3]).³

Fluconazole vs nystatin. In the only prospective RCT (unblinded) to compare oral suspensions of fluconazole and nystatin, 34 infants were randomized to receive either nystatin (1 mL of 100,000 IU/mL) qid for 10 days or fluconazole (3 mg/kg) once a day for 7 days. Mothers of breastfed infants applied nystatin cream to their nipples twice a day for the duration of the infant’s treatment. The clinical cure rate—defined as absence of oral plaques at the end of therapy (day 10 for the nystatin group, day 7 for the fluconazole group)—was significantly higher in the group treated with fluconazole (100% for fluconazole, 32% for nystatin; P<.0001, NNT=2). The eradication rate was also higher with fluconazole (73.3% for fluconazole, 5.6% for nystatin; P<.0001, NNT=2). The patients treated with fluconazole experienced no side effects.⁴ Fluconazole has been shown to be effective, safe, and easy to use to treat thrush in immunocompromised children,⁵ but has not been approved by the FDA for use in healthy infants.

Gentian violet is effective, but messy and irritating

A retrospective cohort study that reviewed 69 cases of oral thrush showed that gentian violet achieved a 75% cure rate in an average of 11 days (compared to 55% in 10 days for nystatin). Both treatments shortened the duration of illness compared with the average of 34 days for untreated children.⁶ However, gentian violet can stain skin and clothes, and case studies have shown an association with ulceration of the buccal mucosa.⁷

Recommendations

A thorough literature search through the Cochrane Database Systematic Reviews, Agency for Healthcare Research and Quality, National Guideline Clearinghouse, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on treating oropharyngeal candidiasis in infants. Neither the American Academy of Pediatrics nor the Infectious Diseases Society of America has issued applicable practice guidelines.

Evidence summary

Few studies have compared treatment options for oropharyngeal candidiasis in immunocompetent infants. In a survey of 312 health care providers, approximately 75% of the respondents reported treating thrush with oral nystatin, citing fewer side effects and lower cost.¹ However, nystatin has proved less effective than either miconazole gel or oral fluconazole.

Nystatin is safe and available, but other options work better

Miconazole vs nystatin. An unblinded RCT assigned 83 immunocompetent infants with culture-positive oral thrush to receive either 25 mg miconazole oral gel (not commercially available in the United States) or nystatin suspension (1 mL of 100,000 IU/mL) qid after meals. The clinical cure rate, defined as absence of plaques by day 12, was significantly higher in the miconazole group (99% for miconazole, 54% for nystatin; P<.0001, number needed to treat [NNT]=2). The eradication rate, confirmed by cultures collected in a blinded manner on the day of clinical cure, was also higher in the miconazole group (55.7% for miconazole, 15.2% for nystatin; P<.0001, NNT=3). In successfully treated patients, infection recurred with similar frequency in both treatment groups within 4 weeks (miconazole, 12.4%; nystatin, 13.0%). Side effects—mostly vomiting and, infrequently, diarrhea—were rare in both groups (miconazole, 4.5%; nystatin 3.5%).²

An earlier, unblinded RCT of 95 infants compared miconazole gel to 2 nystatin oral gels (gel A: 250,000 IU/g with 250,000 IU administered as single dose; gel B: 100,000 IU/g with 50,000 IU administered as single dose). Each medication was given qid over the course of 8 to 14 days. The study confirmed higher clinical cure rates with miconazole gel (85.1% for miconazole vs 42.8% for nystatin gel A [P<.0007, NNT=2] and 48.5% for nystatin gel B [P<.004, NNT=3]).³

Fluconazole vs nystatin. In the only prospective RCT (unblinded) to compare oral suspensions of fluconazole and nystatin, 34 infants were randomized to receive either nystatin (1 mL of 100,000 IU/mL) qid for 10 days or fluconazole (3 mg/kg) once a day for 7 days. Mothers of breastfed infants applied nystatin cream to their nipples twice a day for the duration of the infant’s treatment. The clinical cure rate—defined as absence of oral plaques at the end of therapy (day 10 for the nystatin group, day 7 for the fluconazole group)—was significantly higher in the group treated with fluconazole (100% for fluconazole, 32% for nystatin; P<.0001, NNT=2). The eradication rate was also higher with fluconazole (73.3% for fluconazole, 5.6% for nystatin; P<.0001, NNT=2). The patients treated with fluconazole experienced no side effects.⁴ Fluconazole has been shown to be effective, safe, and easy to use to treat thrush in immunocompromised children,⁵ but has not been approved by the FDA for use in healthy infants.

Gentian violet is effective, but messy and irritating

A retrospective cohort study that reviewed 69 cases of oral thrush showed that gentian violet achieved a 75% cure rate in an average of 11 days (compared to 55% in 10 days for nystatin). Both treatments shortened the duration of illness compared with the average of 34 days for untreated children.⁶ However, gentian violet can stain skin and clothes, and case studies have shown an association with ulceration of the buccal mucosa.⁷

Recommendations

A thorough literature search through the Cochrane Database Systematic Reviews, Agency for Healthcare Research and Quality, National Guideline Clearinghouse, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on treating oropharyngeal candidiasis in infants. Neither the American Academy of Pediatrics nor the Infectious Diseases Society of America has issued applicable practice guidelines.

Evidence summary

Few studies have compared treatment options for oropharyngeal candidiasis in immunocompetent infants. In a survey of 312 health care providers, approximately 75% of the respondents reported treating thrush with oral nystatin, citing fewer side effects and lower cost.¹ However, nystatin has proved less effective than either miconazole gel or oral fluconazole.

Nystatin is safe and available, but other options work better

Miconazole vs nystatin. An unblinded RCT assigned 83 immunocompetent infants with culture-positive oral thrush to receive either 25 mg miconazole oral gel (not commercially available in the United States) or nystatin suspension (1 mL of 100,000 IU/mL) qid after meals. The clinical cure rate, defined as absence of plaques by day 12, was significantly higher in the miconazole group (99% for miconazole, 54% for nystatin; P<.0001, number needed to treat [NNT]=2). The eradication rate, confirmed by cultures collected in a blinded manner on the day of clinical cure, was also higher in the miconazole group (55.7% for miconazole, 15.2% for nystatin; P<.0001, NNT=3). In successfully treated patients, infection recurred with similar frequency in both treatment groups within 4 weeks (miconazole, 12.4%; nystatin, 13.0%). Side effects—mostly vomiting and, infrequently, diarrhea—were rare in both groups (miconazole, 4.5%; nystatin 3.5%).²

An earlier, unblinded RCT of 95 infants compared miconazole gel to 2 nystatin oral gels (gel A: 250,000 IU/g with 250,000 IU administered as single dose; gel B: 100,000 IU/g with 50,000 IU administered as single dose). Each medication was given qid over the course of 8 to 14 days. The study confirmed higher clinical cure rates with miconazole gel (85.1% for miconazole vs 42.8% for nystatin gel A [P<.0007, NNT=2] and 48.5% for nystatin gel B [P<.004, NNT=3]).³

Fluconazole vs nystatin. In the only prospective RCT (unblinded) to compare oral suspensions of fluconazole and nystatin, 34 infants were randomized to receive either nystatin (1 mL of 100,000 IU/mL) qid for 10 days or fluconazole (3 mg/kg) once a day for 7 days. Mothers of breastfed infants applied nystatin cream to their nipples twice a day for the duration of the infant’s treatment. The clinical cure rate—defined as absence of oral plaques at the end of therapy (day 10 for the nystatin group, day 7 for the fluconazole group)—was significantly higher in the group treated with fluconazole (100% for fluconazole, 32% for nystatin; P<.0001, NNT=2). The eradication rate was also higher with fluconazole (73.3% for fluconazole, 5.6% for nystatin; P<.0001, NNT=2). The patients treated with fluconazole experienced no side effects.⁴ Fluconazole has been shown to be effective, safe, and easy to use to treat thrush in immunocompromised children,⁵ but has not been approved by the FDA for use in healthy infants.

Gentian violet is effective, but messy and irritating

A retrospective cohort study that reviewed 69 cases of oral thrush showed that gentian violet achieved a 75% cure rate in an average of 11 days (compared to 55% in 10 days for nystatin). Both treatments shortened the duration of illness compared with the average of 34 days for untreated children.⁶ However, gentian violet can stain skin and clothes, and case studies have shown an association with ulceration of the buccal mucosa.⁷

Recommendations

A thorough literature search through the Cochrane Database Systematic Reviews, Agency for Healthcare Research and Quality, National Guideline Clearinghouse, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on treating oropharyngeal candidiasis in infants. Neither the American Academy of Pediatrics nor the Infectious Diseases Society of America has issued applicable practice guidelines.

Evidence summary

A 2006 meta-analysis, including 114 trials and 116,094 patients randomized to either cyclooxygenase-2 (COX-2) inhibitor or control (placebo, nonsteroidal anti-inflammatory drug [NSAID], or mixed), indicated that the COX-2 inhibitors, as a class, had no effect on renal endpoints.³ Trials were reviewed for data on renal endpoints, including peripheral edema, hypertension, and renal dysfunction (defined as significant worsening of serum urea or creatinine, or clinical evidence of kidney disease and renal failure).

When viewed separately, rofecoxib (Vioxx) was associated with a composite relative risk (RR) of 1.53 (95% confidence interval [CI], 1.33–1.76) for all renal endpoints compared with controls. In contrast, the composite RR for the same endpoints among patients taking celecoxib (Celebrex) was 0.97 (95% CI, 0.84–1.12), indicating no effect on renal function. In fact, for the specific outcomes of hypertension and renal dysfunction, celecoxib was associated with a decreased risk compared with controls (TABLE).³

Stratified analysis by type of control (placebo, alternate NSAID, or mixed) yielded consistent results; rofecoxib was uniquely associated with adverse renal outcomes. No effect on renal function was noted for celecoxib compared with the same controls: the RR for adverse renal effects was 0.87 (95% CI, 0.55–1.38), 0.93 (95% CI, 0.70–1.23), and 1.26 (95% CI, 0.94–1.69) for celecoxib vs placebo, NSAID, and mixed controls, respectively. Statistical analysis for heterogeneity showed that the variation in effects on renal function among the COX-2 inhibitors was more likely due to actual differences than due to chance (heterogeneity [I²]=57%; P<.001).

Data were not available to assess the effect of COX-2 agents on patients with pre-existing renal disease, primarily because trials reporting abnormal renal function at baseline were excluded from this meta-analysis.

A recent randomized controlled trial compared standard dosing of diclofenac (75 mg twice daily) and ibuprofen (800 mg 3 times daily) with high-dose celecoxib (400 mg twice daily) for patients with normal kidney function being treated for osteoarthritis and rheumatoid arthritis.⁴ The mean increase in serum creatinine in the celecoxib arm was less than that noted in the diclofenac controls (0.009 mg/dL vs 0.027 mg/dL; P<.05; number needed to harm [NNH]=56). No difference in mean serum creatinine was seen among those patients using ibuprofen (800 mg 3 times daily) compared with those using high-dose celecoxib.

This evidence further supports the safety of celecoxib vs standard NSAIDs with respect to renal dysfunction.

Recommendations from others The American Pain Society 2002 guideline recommends acetaminophen for mild pain from osteoarthritis.⁵ For moderate to severe pain and inflammation, a COX-2 inhibitor was the first choice, unless there is significant risk of hypertension or kidney disorder. For active rheumatoid arthritis, the addition of a COX-2 agent to disease-modifying anti-rheumatic drugs (DMARDs) is advised unless there is uncontrolled hypertension or renal disease.⁶ However, these recommendations came out before the data on the cardiovascular effects of some COX-2 inhibitors.

The American College of rheumatology recommends the use of a COX-2 agent for osteoarthritis or pain unresponsive to acetaminophen. Their 2000 guidelines warn that due to potential renal toxicity, COX-2 inhibitors should not be used for patients with severe renal insufficiency, and used with caution in cases of mild to moderate renal insufficiency.

In 2005, these guidelines were amended to include the recommendation that patients with increased cardiovascular risk be cautioned about the risks associated with COX-2 inhibitor use.⁷

TABLE
Celecoxib is associated with a decreased risk of hypertension and renal dysfunction

Evidence summary

A 2006 meta-analysis, including 114 trials and 116,094 patients randomized to either cyclooxygenase-2 (COX-2) inhibitor or control (placebo, nonsteroidal anti-inflammatory drug [NSAID], or mixed), indicated that the COX-2 inhibitors, as a class, had no effect on renal endpoints.³ Trials were reviewed for data on renal endpoints, including peripheral edema, hypertension, and renal dysfunction (defined as significant worsening of serum urea or creatinine, or clinical evidence of kidney disease and renal failure).

When viewed separately, rofecoxib (Vioxx) was associated with a composite relative risk (RR) of 1.53 (95% confidence interval [CI], 1.33–1.76) for all renal endpoints compared with controls. In contrast, the composite RR for the same endpoints among patients taking celecoxib (Celebrex) was 0.97 (95% CI, 0.84–1.12), indicating no effect on renal function. In fact, for the specific outcomes of hypertension and renal dysfunction, celecoxib was associated with a decreased risk compared with controls (TABLE).³

Stratified analysis by type of control (placebo, alternate NSAID, or mixed) yielded consistent results; rofecoxib was uniquely associated with adverse renal outcomes. No effect on renal function was noted for celecoxib compared with the same controls: the RR for adverse renal effects was 0.87 (95% CI, 0.55–1.38), 0.93 (95% CI, 0.70–1.23), and 1.26 (95% CI, 0.94–1.69) for celecoxib vs placebo, NSAID, and mixed controls, respectively. Statistical analysis for heterogeneity showed that the variation in effects on renal function among the COX-2 inhibitors was more likely due to actual differences than due to chance (heterogeneity [I²]=57%; P<.001).

Data were not available to assess the effect of COX-2 agents on patients with pre-existing renal disease, primarily because trials reporting abnormal renal function at baseline were excluded from this meta-analysis.

A recent randomized controlled trial compared standard dosing of diclofenac (75 mg twice daily) and ibuprofen (800 mg 3 times daily) with high-dose celecoxib (400 mg twice daily) for patients with normal kidney function being treated for osteoarthritis and rheumatoid arthritis.⁴ The mean increase in serum creatinine in the celecoxib arm was less than that noted in the diclofenac controls (0.009 mg/dL vs 0.027 mg/dL; P<.05; number needed to harm [NNH]=56). No difference in mean serum creatinine was seen among those patients using ibuprofen (800 mg 3 times daily) compared with those using high-dose celecoxib.

This evidence further supports the safety of celecoxib vs standard NSAIDs with respect to renal dysfunction.

Recommendations from others The American Pain Society 2002 guideline recommends acetaminophen for mild pain from osteoarthritis.⁵ For moderate to severe pain and inflammation, a COX-2 inhibitor was the first choice, unless there is significant risk of hypertension or kidney disorder. For active rheumatoid arthritis, the addition of a COX-2 agent to disease-modifying anti-rheumatic drugs (DMARDs) is advised unless there is uncontrolled hypertension or renal disease.⁶ However, these recommendations came out before the data on the cardiovascular effects of some COX-2 inhibitors.

The American College of rheumatology recommends the use of a COX-2 agent for osteoarthritis or pain unresponsive to acetaminophen. Their 2000 guidelines warn that due to potential renal toxicity, COX-2 inhibitors should not be used for patients with severe renal insufficiency, and used with caution in cases of mild to moderate renal insufficiency.

In 2005, these guidelines were amended to include the recommendation that patients with increased cardiovascular risk be cautioned about the risks associated with COX-2 inhibitor use.⁷

TABLE
Celecoxib is associated with a decreased risk of hypertension and renal dysfunction

Evidence summary

A 2006 meta-analysis, including 114 trials and 116,094 patients randomized to either cyclooxygenase-2 (COX-2) inhibitor or control (placebo, nonsteroidal anti-inflammatory drug [NSAID], or mixed), indicated that the COX-2 inhibitors, as a class, had no effect on renal endpoints.³ Trials were reviewed for data on renal endpoints, including peripheral edema, hypertension, and renal dysfunction (defined as significant worsening of serum urea or creatinine, or clinical evidence of kidney disease and renal failure).

When viewed separately, rofecoxib (Vioxx) was associated with a composite relative risk (RR) of 1.53 (95% confidence interval [CI], 1.33–1.76) for all renal endpoints compared with controls. In contrast, the composite RR for the same endpoints among patients taking celecoxib (Celebrex) was 0.97 (95% CI, 0.84–1.12), indicating no effect on renal function. In fact, for the specific outcomes of hypertension and renal dysfunction, celecoxib was associated with a decreased risk compared with controls (TABLE).³

Stratified analysis by type of control (placebo, alternate NSAID, or mixed) yielded consistent results; rofecoxib was uniquely associated with adverse renal outcomes. No effect on renal function was noted for celecoxib compared with the same controls: the RR for adverse renal effects was 0.87 (95% CI, 0.55–1.38), 0.93 (95% CI, 0.70–1.23), and 1.26 (95% CI, 0.94–1.69) for celecoxib vs placebo, NSAID, and mixed controls, respectively. Statistical analysis for heterogeneity showed that the variation in effects on renal function among the COX-2 inhibitors was more likely due to actual differences than due to chance (heterogeneity [I²]=57%; P<.001).

Data were not available to assess the effect of COX-2 agents on patients with pre-existing renal disease, primarily because trials reporting abnormal renal function at baseline were excluded from this meta-analysis.

A recent randomized controlled trial compared standard dosing of diclofenac (75 mg twice daily) and ibuprofen (800 mg 3 times daily) with high-dose celecoxib (400 mg twice daily) for patients with normal kidney function being treated for osteoarthritis and rheumatoid arthritis.⁴ The mean increase in serum creatinine in the celecoxib arm was less than that noted in the diclofenac controls (0.009 mg/dL vs 0.027 mg/dL; P<.05; number needed to harm [NNH]=56). No difference in mean serum creatinine was seen among those patients using ibuprofen (800 mg 3 times daily) compared with those using high-dose celecoxib.

This evidence further supports the safety of celecoxib vs standard NSAIDs with respect to renal dysfunction.

Recommendations from others The American Pain Society 2002 guideline recommends acetaminophen for mild pain from osteoarthritis.⁵ For moderate to severe pain and inflammation, a COX-2 inhibitor was the first choice, unless there is significant risk of hypertension or kidney disorder. For active rheumatoid arthritis, the addition of a COX-2 agent to disease-modifying anti-rheumatic drugs (DMARDs) is advised unless there is uncontrolled hypertension or renal disease.⁶ However, these recommendations came out before the data on the cardiovascular effects of some COX-2 inhibitors.

The American College of rheumatology recommends the use of a COX-2 agent for osteoarthritis or pain unresponsive to acetaminophen. Their 2000 guidelines warn that due to potential renal toxicity, COX-2 inhibitors should not be used for patients with severe renal insufficiency, and used with caution in cases of mild to moderate renal insufficiency.

In 2005, these guidelines were amended to include the recommendation that patients with increased cardiovascular risk be cautioned about the risks associated with COX-2 inhibitor use.⁷

TABLE
Celecoxib is associated with a decreased risk of hypertension and renal dysfunction

Evidence summary

The use of DMARDs has become standard of care for rheumatoid arthritis, for both therapy and prevention of progression of this debilitating disease. However, the use of DMARDs in nonrheumatoid rheumatologic disease is still under investigation, and at this point, the use of DMARDs as first-line therapy is not recommended; however, second-line therapy with DMARDs is common.

For psoriatic arthritis, DMARDs are beneficial as a second-line therapy

A Cochrane systematic review identified 13 randomized controlled trials enrolling a combined 1022 patients with psoriatic arthritis randomly assigned to receive a DMARD—methotrexate, sulfasalazine (Azulfidine), azathioprine (Imuran/ Azasan), or etretinate (Tegison; no longer available in the US)—compared with placebo.² All agents were better than placebo; however, only 2 agents (parenteral high-dose methotrexate and sulfasalazine) had clinically important benefits for more than half the patients. The studies were too small to establish toxicity or to evaluate the other agents.

NSAIDs are still the preferred first-line therapy, concluded a recent publication on the treatment of psoriatic arthritis, which looked at 54 different studies; however, second-line therapy could include methotrexate, sulfasalazine, etanercept (Enbrel), infliximab (Remicade), cyclosporine, or combination therapy.³ Sulfasalazine appeared to be clinically beneficial for peripheral psoriatic arthritis.

Etanercept vs placebo. An initial study (60 patients) of etanercept vs placebo among patients who were permitted to stay on methotrexate or prednisone showed a response rate of 87% vs 23% (P<.0001; number needed to treat [NNT]=1.56).⁴

Infliximab vs placebo. A study of infliximab vs placebo involving 104 patients had similar results, with good response in 65% vs 10% (NNT=1.81) at 16 weeks; infliximab also inhibited radiographic progression by 22%.⁵

Cyclosporine. Although it is effective, reserve cyclosporine for patients who do not improve on other regimens, because of its nephrotoxicity.³

DMARDs show some benefit in treating ankylosing spondylitis

Two recent Cochrane systematic reviews on ankylosing spondylitis examined the use of sulfasalazine and methotrexate as second-line agents.^6,7 Eleven trials were included in the sulfasalazine analysis, with a total of 895 patients. Sulfasalazine demonstrated some benefit in reducing erythrocyte sedimentation rates (ESRs) and morning stiffness, but there was no evidence that the drug reduced pain or improved physical function, spinal mobility, or rate of enthesitis. Sulfasalazine was well tolerated and may be useful in early mild disease for patients with peripheral arthritis and high ESRs. On the other hand, evidence was insufficient to determine whether methotrexate benefited patients with ankylosing spondylitis.

In other trials, infliximab and etanercept showed good potential for benefit in treating ankylosing spondylitis.

One study of infliximab vs placebo showed 61.2% vs 19.2% patients with good clinical benefit at 24 weeks and only mild or moderate adverse events (P<.001; NNT=2.38).⁸

Similarly, a smaller study (84 patients) showed that 60% of patients on etanercept vs 20% on placebo had good clinical benefit at only 12 weeks (P<.001, NNT=2.5).⁹

For other rheumatic diseases, studies are mixed

Due to cyclosporine’s toxicity, less toxic DMARDs are being evaluated to replace it for treatment of other rheumatic diseases. A recent randomized controlled trial of 100 patients with antineutrophil cytoplasmic antibody–associated systemic vasculitis showed methotrexate may be able to replace cyclosporine for both induction of remission (methotrexate=89.8% vs cyclosporine=93.5%; P=.041) and maintenance of remission (69.5% vs 46.5% at 18 months; P=.023).¹⁰

Initial trials on other rheumatic diseases have been small and have had varied results. There are mixed studies on the effectiveness of adding methotrexate to corticosteroids for giant cell arteritis.^11,12

There has been no evidence of efficacy for the new TNF antagonists in either a small study on Sjögren’s syndrome (n=14)¹³ or a larger study on Wegener’s granulomatosis (n=180).¹⁴

The studies for use of DMARDs in lupus or scleroderma are of limited quality.

Recommendations from others

The Italian Society for Rheumatology consensus guidelines recommends TNF antagonists be considered in active psoriatic arthritis resistant to (a) NSAIDs, (b) at least 2 local steroid injections, and (c) at least 2 conventional DMARDs for patients with peripheral arthritis or enthesitis. They also recommend TNF antagonists be considered for psoriatic spondylitis resistant to NSAIDs.¹⁵

The Assessment in Ankylosing Spondylitis (ASAS) International Working Group and the European League Against Rheumatism (EULAR) recommendations for the treatment of ankylosing spondylitis, based on a systematic review of the literature and expert opinion, indicate that:

• There is good evidence for using NSAIDs and COX-2 inhibitors for symptomatic treatment.
• Conventional DMARDs are not well supported.
• TNF antagonists show a large benefit in both pain and function.

The ASAS/EULAR recommendation indicate that there is no evidence that any of these treatments actually modify the disease progression.¹⁶

Acknowledgments

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force medical service or the US Air Force at large.

Evidence summary

The use of DMARDs has become standard of care for rheumatoid arthritis, for both therapy and prevention of progression of this debilitating disease. However, the use of DMARDs in nonrheumatoid rheumatologic disease is still under investigation, and at this point, the use of DMARDs as first-line therapy is not recommended; however, second-line therapy with DMARDs is common.

For psoriatic arthritis, DMARDs are beneficial as a second-line therapy

A Cochrane systematic review identified 13 randomized controlled trials enrolling a combined 1022 patients with psoriatic arthritis randomly assigned to receive a DMARD—methotrexate, sulfasalazine (Azulfidine), azathioprine (Imuran/ Azasan), or etretinate (Tegison; no longer available in the US)—compared with placebo.² All agents were better than placebo; however, only 2 agents (parenteral high-dose methotrexate and sulfasalazine) had clinically important benefits for more than half the patients. The studies were too small to establish toxicity or to evaluate the other agents.

NSAIDs are still the preferred first-line therapy, concluded a recent publication on the treatment of psoriatic arthritis, which looked at 54 different studies; however, second-line therapy could include methotrexate, sulfasalazine, etanercept (Enbrel), infliximab (Remicade), cyclosporine, or combination therapy.³ Sulfasalazine appeared to be clinically beneficial for peripheral psoriatic arthritis.

Etanercept vs placebo. An initial study (60 patients) of etanercept vs placebo among patients who were permitted to stay on methotrexate or prednisone showed a response rate of 87% vs 23% (P<.0001; number needed to treat [NNT]=1.56).⁴

Infliximab vs placebo. A study of infliximab vs placebo involving 104 patients had similar results, with good response in 65% vs 10% (NNT=1.81) at 16 weeks; infliximab also inhibited radiographic progression by 22%.⁵

Cyclosporine. Although it is effective, reserve cyclosporine for patients who do not improve on other regimens, because of its nephrotoxicity.³

DMARDs show some benefit in treating ankylosing spondylitis

Two recent Cochrane systematic reviews on ankylosing spondylitis examined the use of sulfasalazine and methotrexate as second-line agents.^6,7 Eleven trials were included in the sulfasalazine analysis, with a total of 895 patients. Sulfasalazine demonstrated some benefit in reducing erythrocyte sedimentation rates (ESRs) and morning stiffness, but there was no evidence that the drug reduced pain or improved physical function, spinal mobility, or rate of enthesitis. Sulfasalazine was well tolerated and may be useful in early mild disease for patients with peripheral arthritis and high ESRs. On the other hand, evidence was insufficient to determine whether methotrexate benefited patients with ankylosing spondylitis.

In other trials, infliximab and etanercept showed good potential for benefit in treating ankylosing spondylitis.

One study of infliximab vs placebo showed 61.2% vs 19.2% patients with good clinical benefit at 24 weeks and only mild or moderate adverse events (P<.001; NNT=2.38).⁸

Similarly, a smaller study (84 patients) showed that 60% of patients on etanercept vs 20% on placebo had good clinical benefit at only 12 weeks (P<.001, NNT=2.5).⁹

For other rheumatic diseases, studies are mixed

Due to cyclosporine’s toxicity, less toxic DMARDs are being evaluated to replace it for treatment of other rheumatic diseases. A recent randomized controlled trial of 100 patients with antineutrophil cytoplasmic antibody–associated systemic vasculitis showed methotrexate may be able to replace cyclosporine for both induction of remission (methotrexate=89.8% vs cyclosporine=93.5%; P=.041) and maintenance of remission (69.5% vs 46.5% at 18 months; P=.023).¹⁰

Initial trials on other rheumatic diseases have been small and have had varied results. There are mixed studies on the effectiveness of adding methotrexate to corticosteroids for giant cell arteritis.^11,12

There has been no evidence of efficacy for the new TNF antagonists in either a small study on Sjögren’s syndrome (n=14)¹³ or a larger study on Wegener’s granulomatosis (n=180).¹⁴

The studies for use of DMARDs in lupus or scleroderma are of limited quality.

Recommendations from others

The Italian Society for Rheumatology consensus guidelines recommends TNF antagonists be considered in active psoriatic arthritis resistant to (a) NSAIDs, (b) at least 2 local steroid injections, and (c) at least 2 conventional DMARDs for patients with peripheral arthritis or enthesitis. They also recommend TNF antagonists be considered for psoriatic spondylitis resistant to NSAIDs.¹⁵

The Assessment in Ankylosing Spondylitis (ASAS) International Working Group and the European League Against Rheumatism (EULAR) recommendations for the treatment of ankylosing spondylitis, based on a systematic review of the literature and expert opinion, indicate that:

• There is good evidence for using NSAIDs and COX-2 inhibitors for symptomatic treatment.
• Conventional DMARDs are not well supported.
• TNF antagonists show a large benefit in both pain and function.

The ASAS/EULAR recommendation indicate that there is no evidence that any of these treatments actually modify the disease progression.¹⁶

Acknowledgments

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force medical service or the US Air Force at large.

Evidence summary

The use of DMARDs has become standard of care for rheumatoid arthritis, for both therapy and prevention of progression of this debilitating disease. However, the use of DMARDs in nonrheumatoid rheumatologic disease is still under investigation, and at this point, the use of DMARDs as first-line therapy is not recommended; however, second-line therapy with DMARDs is common.

For psoriatic arthritis, DMARDs are beneficial as a second-line therapy

A Cochrane systematic review identified 13 randomized controlled trials enrolling a combined 1022 patients with psoriatic arthritis randomly assigned to receive a DMARD—methotrexate, sulfasalazine (Azulfidine), azathioprine (Imuran/ Azasan), or etretinate (Tegison; no longer available in the US)—compared with placebo.² All agents were better than placebo; however, only 2 agents (parenteral high-dose methotrexate and sulfasalazine) had clinically important benefits for more than half the patients. The studies were too small to establish toxicity or to evaluate the other agents.

NSAIDs are still the preferred first-line therapy, concluded a recent publication on the treatment of psoriatic arthritis, which looked at 54 different studies; however, second-line therapy could include methotrexate, sulfasalazine, etanercept (Enbrel), infliximab (Remicade), cyclosporine, or combination therapy.³ Sulfasalazine appeared to be clinically beneficial for peripheral psoriatic arthritis.

Etanercept vs placebo. An initial study (60 patients) of etanercept vs placebo among patients who were permitted to stay on methotrexate or prednisone showed a response rate of 87% vs 23% (P<.0001; number needed to treat [NNT]=1.56).⁴

Infliximab vs placebo. A study of infliximab vs placebo involving 104 patients had similar results, with good response in 65% vs 10% (NNT=1.81) at 16 weeks; infliximab also inhibited radiographic progression by 22%.⁵

Cyclosporine. Although it is effective, reserve cyclosporine for patients who do not improve on other regimens, because of its nephrotoxicity.³

DMARDs show some benefit in treating ankylosing spondylitis

Two recent Cochrane systematic reviews on ankylosing spondylitis examined the use of sulfasalazine and methotrexate as second-line agents.^6,7 Eleven trials were included in the sulfasalazine analysis, with a total of 895 patients. Sulfasalazine demonstrated some benefit in reducing erythrocyte sedimentation rates (ESRs) and morning stiffness, but there was no evidence that the drug reduced pain or improved physical function, spinal mobility, or rate of enthesitis. Sulfasalazine was well tolerated and may be useful in early mild disease for patients with peripheral arthritis and high ESRs. On the other hand, evidence was insufficient to determine whether methotrexate benefited patients with ankylosing spondylitis.

In other trials, infliximab and etanercept showed good potential for benefit in treating ankylosing spondylitis.

One study of infliximab vs placebo showed 61.2% vs 19.2% patients with good clinical benefit at 24 weeks and only mild or moderate adverse events (P<.001; NNT=2.38).⁸

Similarly, a smaller study (84 patients) showed that 60% of patients on etanercept vs 20% on placebo had good clinical benefit at only 12 weeks (P<.001, NNT=2.5).⁹

For other rheumatic diseases, studies are mixed

Due to cyclosporine’s toxicity, less toxic DMARDs are being evaluated to replace it for treatment of other rheumatic diseases. A recent randomized controlled trial of 100 patients with antineutrophil cytoplasmic antibody–associated systemic vasculitis showed methotrexate may be able to replace cyclosporine for both induction of remission (methotrexate=89.8% vs cyclosporine=93.5%; P=.041) and maintenance of remission (69.5% vs 46.5% at 18 months; P=.023).¹⁰

Initial trials on other rheumatic diseases have been small and have had varied results. There are mixed studies on the effectiveness of adding methotrexate to corticosteroids for giant cell arteritis.^11,12

There has been no evidence of efficacy for the new TNF antagonists in either a small study on Sjögren’s syndrome (n=14)¹³ or a larger study on Wegener’s granulomatosis (n=180).¹⁴

The studies for use of DMARDs in lupus or scleroderma are of limited quality.

Recommendations from others

The Italian Society for Rheumatology consensus guidelines recommends TNF antagonists be considered in active psoriatic arthritis resistant to (a) NSAIDs, (b) at least 2 local steroid injections, and (c) at least 2 conventional DMARDs for patients with peripheral arthritis or enthesitis. They also recommend TNF antagonists be considered for psoriatic spondylitis resistant to NSAIDs.¹⁵

The Assessment in Ankylosing Spondylitis (ASAS) International Working Group and the European League Against Rheumatism (EULAR) recommendations for the treatment of ankylosing spondylitis, based on a systematic review of the literature and expert opinion, indicate that:

• There is good evidence for using NSAIDs and COX-2 inhibitors for symptomatic treatment.
• Conventional DMARDs are not well supported.
• TNF antagonists show a large benefit in both pain and function.

The ASAS/EULAR recommendation indicate that there is no evidence that any of these treatments actually modify the disease progression.¹⁶

Acknowledgments

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force medical service or the US Air Force at large.