Terry L. Seaton, PharmD

Evidence summary

Statins are the most effective at reducing LDL-C and the associated cardiovascular risk. The 5-year West of Scotland study (WOSCOPS) showed that a 26% reduction in LDL-C (from a mean of 192 to 142 mg/dL) using pravastatin 40 mg per day reduced the risk of either nonfatal myocardial infarction (MI) or coronary heart disease (CHD) death (number needed to treat [NNT] = 42; relative risk [RR] = 31; 95% confidence interval [CI],17 - 43).¹ This trial enrolled middle-aged men with an LDL-C level > 155 mg/dL without a history of prior MI, although subjects with stable angina (5% of the participants) were still eligible. Similar reductions were seen in cardiovascular death and in all-cause death (RR = 22; 95% CI = 0 - 40). Lovastatin reduced the risk of a first major acute coronary event (NNT = 24) in the 5-year AFCAPS/TexCAPS trial that enrolled 5608 men and 997 women with below-average high-density lipoprotein cholesterol (HDL-C) (men, 36 mg/dL; women, 40 mg/dL) without signs or symptoms of CHD.² LDL-C was lowered 25% (from a mean of 156 to 115 mg/dL). Unpublished results suggest that simvastatin may have a similar effect. Primary prevention data are still lacking for atorvastatin and fluvastatin.

The 7-year Lipid Research Clinics Coronary Prevention Trial (LRC-CPPT) documented a reduction in CHD death and/or nonfatal MI (NNT = 59) with a 12.6% reduction in LDL-C with the use of cholestyramine, a bile acid resin, 24 g per day.³

Results of studies of the fibric acid derivatives are mixed. Subjects taking gemfibrozil 1200 mg per day in the 5-year Helsinki Heart Study had fewer coronary events compared with those taking a placebo (NNT = 71).⁴ Subsequent analysis suggests that patients with a high LDL-C/HDL-C ratio (> 5) plus hypertriglyceridemia ( 205 mg/dL) benefited the most.⁵ Clofibrate is no longer used because of an unexplained increase in deaths in the WHO Cooperative Trial.⁶ To date, outcomes in fenofibrate trials have only focused on surrogate markers and not long-term clinical outcomes.

Recommendations from others

The recommendations of the Third Report of the National Cholesterol Education Program⁷ (NCEP, Adult Treatment Panel III) are in the table. This report is an excellent source of additional information (http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf).

Read a clinical commentary by David Switzer, MD, at www.fpin.org.

Evidence summary

Statins are the most effective at reducing LDL-C and the associated cardiovascular risk. The 5-year West of Scotland study (WOSCOPS) showed that a 26% reduction in LDL-C (from a mean of 192 to 142 mg/dL) using pravastatin 40 mg per day reduced the risk of either nonfatal myocardial infarction (MI) or coronary heart disease (CHD) death (number needed to treat [NNT] = 42; relative risk [RR] = 31; 95% confidence interval [CI],17 - 43).¹ This trial enrolled middle-aged men with an LDL-C level > 155 mg/dL without a history of prior MI, although subjects with stable angina (5% of the participants) were still eligible. Similar reductions were seen in cardiovascular death and in all-cause death (RR = 22; 95% CI = 0 - 40). Lovastatin reduced the risk of a first major acute coronary event (NNT = 24) in the 5-year AFCAPS/TexCAPS trial that enrolled 5608 men and 997 women with below-average high-density lipoprotein cholesterol (HDL-C) (men, 36 mg/dL; women, 40 mg/dL) without signs or symptoms of CHD.² LDL-C was lowered 25% (from a mean of 156 to 115 mg/dL). Unpublished results suggest that simvastatin may have a similar effect. Primary prevention data are still lacking for atorvastatin and fluvastatin.

The 7-year Lipid Research Clinics Coronary Prevention Trial (LRC-CPPT) documented a reduction in CHD death and/or nonfatal MI (NNT = 59) with a 12.6% reduction in LDL-C with the use of cholestyramine, a bile acid resin, 24 g per day.³

Results of studies of the fibric acid derivatives are mixed. Subjects taking gemfibrozil 1200 mg per day in the 5-year Helsinki Heart Study had fewer coronary events compared with those taking a placebo (NNT = 71).⁴ Subsequent analysis suggests that patients with a high LDL-C/HDL-C ratio (> 5) plus hypertriglyceridemia ( 205 mg/dL) benefited the most.⁵ Clofibrate is no longer used because of an unexplained increase in deaths in the WHO Cooperative Trial.⁶ To date, outcomes in fenofibrate trials have only focused on surrogate markers and not long-term clinical outcomes.

Recommendations from others

The recommendations of the Third Report of the National Cholesterol Education Program⁷ (NCEP, Adult Treatment Panel III) are in the table. This report is an excellent source of additional information (http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf).

Read a clinical commentary by David Switzer, MD, at www.fpin.org.

Evidence summary

Statins are the most effective at reducing LDL-C and the associated cardiovascular risk. The 5-year West of Scotland study (WOSCOPS) showed that a 26% reduction in LDL-C (from a mean of 192 to 142 mg/dL) using pravastatin 40 mg per day reduced the risk of either nonfatal myocardial infarction (MI) or coronary heart disease (CHD) death (number needed to treat [NNT] = 42; relative risk [RR] = 31; 95% confidence interval [CI],17 - 43).¹ This trial enrolled middle-aged men with an LDL-C level > 155 mg/dL without a history of prior MI, although subjects with stable angina (5% of the participants) were still eligible. Similar reductions were seen in cardiovascular death and in all-cause death (RR = 22; 95% CI = 0 - 40). Lovastatin reduced the risk of a first major acute coronary event (NNT = 24) in the 5-year AFCAPS/TexCAPS trial that enrolled 5608 men and 997 women with below-average high-density lipoprotein cholesterol (HDL-C) (men, 36 mg/dL; women, 40 mg/dL) without signs or symptoms of CHD.² LDL-C was lowered 25% (from a mean of 156 to 115 mg/dL). Unpublished results suggest that simvastatin may have a similar effect. Primary prevention data are still lacking for atorvastatin and fluvastatin.

The 7-year Lipid Research Clinics Coronary Prevention Trial (LRC-CPPT) documented a reduction in CHD death and/or nonfatal MI (NNT = 59) with a 12.6% reduction in LDL-C with the use of cholestyramine, a bile acid resin, 24 g per day.³

Results of studies of the fibric acid derivatives are mixed. Subjects taking gemfibrozil 1200 mg per day in the 5-year Helsinki Heart Study had fewer coronary events compared with those taking a placebo (NNT = 71).⁴ Subsequent analysis suggests that patients with a high LDL-C/HDL-C ratio (> 5) plus hypertriglyceridemia ( 205 mg/dL) benefited the most.⁵ Clofibrate is no longer used because of an unexplained increase in deaths in the WHO Cooperative Trial.⁶ To date, outcomes in fenofibrate trials have only focused on surrogate markers and not long-term clinical outcomes.

Recommendations from others

The recommendations of the Third Report of the National Cholesterol Education Program⁷ (NCEP, Adult Treatment Panel III) are in the table. This report is an excellent source of additional information (http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf).

Read a clinical commentary by David Switzer, MD, at www.fpin.org.

ABSTRACT

BACKGROUND: Significant morbidity and mortality may result after influenza infection in the elderly. Influenza vaccination is recommended for all persons older than 65 years but does not confer universal protection against disease or complications. Chemoprophylaxis against influenza with oseltamivir is effective in a younger unvaccinated population but has not been studied in an elderly vaccinated population.

POPULATION STUDIED: The study population included residents of long-term care facilities located throughout the United States and Europe. Of the 548 subjects enrolled (272 placebo, 276 oseltamivir), 493 completed the study. Study groups were similar at baseline. Residents 65 years and older were included; the mean age was approximately 81 years. Participants had a mean of 6.1 concurrent diseases and were taking an average of 7.7 medications. Approximately 80% of participants received the influenza vaccination.

STUDY DESIGN AND VALIDITY: This was a randomized double-blind placebo-controlled study. Participants were recruited during the 1998-1999 influenza season and performed a stratified randomization according to vaccination status and coexistence of chronic obstructive airways disease. Subjects took either oseltamivir 75 mg or placebo once daily for 6 weeks. Treatment was started when influenza infection was detected in either one resident of the center or in two individuals in the immediate community. Participants were examined at 3, 6, and 8 weeks and when influenza-like symptoms were documented on daily diary cards.

OUTCOMES MEASURED: The primary outcome was incidence of laboratory-confirmed clinical influenza A or B, defined as fever, one respiratory symptom, and one constitutional symptom plus a greater than 4-fold increase in influenza antibody titer or viral replication from nasal or throat swabs. Secondary outcomes included symptomatic laboratory-confirmed influenza not meeting clinical criteria, asymptomatic laboratory-confirmed influenza, influenza-like illness, and secondary influenza complications (otitis media, sinusitis, bronchitis, or pneumonia).

RESULTS: Thirteen cases of laboratory-confirmed clinical influenza were identified; 12 of the 13 infected patients previously had been vaccinated. No influenza occurred in 22 of the 31 participating study sites. Compared with placebo, treatment with oseltamivir significantly protected against laboratory-confirmed influenza (4.4% vs. 0.4%; P=.002; number needed to treat [NNT]=25) and reduced secondary influenza complications (2.6% vs 0.4%; P=.037; NNT=45). The difference in rates of pneumonia (1.1% vs 0.0%) is not clinically significant. Adverse events were not more likely in oseltamivir-treated patients and withdrawals due to adverse events was similar among the patients in the 2 groups. One patient died in each study group (unrelated to influenza or study medication).

ABSTRACT

BACKGROUND: Significant morbidity and mortality may result after influenza infection in the elderly. Influenza vaccination is recommended for all persons older than 65 years but does not confer universal protection against disease or complications. Chemoprophylaxis against influenza with oseltamivir is effective in a younger unvaccinated population but has not been studied in an elderly vaccinated population.

POPULATION STUDIED: The study population included residents of long-term care facilities located throughout the United States and Europe. Of the 548 subjects enrolled (272 placebo, 276 oseltamivir), 493 completed the study. Study groups were similar at baseline. Residents 65 years and older were included; the mean age was approximately 81 years. Participants had a mean of 6.1 concurrent diseases and were taking an average of 7.7 medications. Approximately 80% of participants received the influenza vaccination.

STUDY DESIGN AND VALIDITY: This was a randomized double-blind placebo-controlled study. Participants were recruited during the 1998-1999 influenza season and performed a stratified randomization according to vaccination status and coexistence of chronic obstructive airways disease. Subjects took either oseltamivir 75 mg or placebo once daily for 6 weeks. Treatment was started when influenza infection was detected in either one resident of the center or in two individuals in the immediate community. Participants were examined at 3, 6, and 8 weeks and when influenza-like symptoms were documented on daily diary cards.

OUTCOMES MEASURED: The primary outcome was incidence of laboratory-confirmed clinical influenza A or B, defined as fever, one respiratory symptom, and one constitutional symptom plus a greater than 4-fold increase in influenza antibody titer or viral replication from nasal or throat swabs. Secondary outcomes included symptomatic laboratory-confirmed influenza not meeting clinical criteria, asymptomatic laboratory-confirmed influenza, influenza-like illness, and secondary influenza complications (otitis media, sinusitis, bronchitis, or pneumonia).

RESULTS: Thirteen cases of laboratory-confirmed clinical influenza were identified; 12 of the 13 infected patients previously had been vaccinated. No influenza occurred in 22 of the 31 participating study sites. Compared with placebo, treatment with oseltamivir significantly protected against laboratory-confirmed influenza (4.4% vs. 0.4%; P=.002; number needed to treat [NNT]=25) and reduced secondary influenza complications (2.6% vs 0.4%; P=.037; NNT=45). The difference in rates of pneumonia (1.1% vs 0.0%) is not clinically significant. Adverse events were not more likely in oseltamivir-treated patients and withdrawals due to adverse events was similar among the patients in the 2 groups. One patient died in each study group (unrelated to influenza or study medication).

ABSTRACT

BACKGROUND: Significant morbidity and mortality may result after influenza infection in the elderly. Influenza vaccination is recommended for all persons older than 65 years but does not confer universal protection against disease or complications. Chemoprophylaxis against influenza with oseltamivir is effective in a younger unvaccinated population but has not been studied in an elderly vaccinated population.

POPULATION STUDIED: The study population included residents of long-term care facilities located throughout the United States and Europe. Of the 548 subjects enrolled (272 placebo, 276 oseltamivir), 493 completed the study. Study groups were similar at baseline. Residents 65 years and older were included; the mean age was approximately 81 years. Participants had a mean of 6.1 concurrent diseases and were taking an average of 7.7 medications. Approximately 80% of participants received the influenza vaccination.

STUDY DESIGN AND VALIDITY: This was a randomized double-blind placebo-controlled study. Participants were recruited during the 1998-1999 influenza season and performed a stratified randomization according to vaccination status and coexistence of chronic obstructive airways disease. Subjects took either oseltamivir 75 mg or placebo once daily for 6 weeks. Treatment was started when influenza infection was detected in either one resident of the center or in two individuals in the immediate community. Participants were examined at 3, 6, and 8 weeks and when influenza-like symptoms were documented on daily diary cards.

OUTCOMES MEASURED: The primary outcome was incidence of laboratory-confirmed clinical influenza A or B, defined as fever, one respiratory symptom, and one constitutional symptom plus a greater than 4-fold increase in influenza antibody titer or viral replication from nasal or throat swabs. Secondary outcomes included symptomatic laboratory-confirmed influenza not meeting clinical criteria, asymptomatic laboratory-confirmed influenza, influenza-like illness, and secondary influenza complications (otitis media, sinusitis, bronchitis, or pneumonia).

RESULTS: Thirteen cases of laboratory-confirmed clinical influenza were identified; 12 of the 13 infected patients previously had been vaccinated. No influenza occurred in 22 of the 31 participating study sites. Compared with placebo, treatment with oseltamivir significantly protected against laboratory-confirmed influenza (4.4% vs. 0.4%; P=.002; number needed to treat [NNT]=25) and reduced secondary influenza complications (2.6% vs 0.4%; P=.037; NNT=45). The difference in rates of pneumonia (1.1% vs 0.0%) is not clinically significant. Adverse events were not more likely in oseltamivir-treated patients and withdrawals due to adverse events was similar among the patients in the 2 groups. One patient died in each study group (unrelated to influenza or study medication).

BACKGROUND: Recent public and legislative focus on pain management practices has led to scrutiny of guidelines for the role of opioids in pain therapy. A survey by the World Health Organization in 1998 revealed that 22% of patients seeing primary care physicians reported persistent pain. Better, more acceptable methods of pain control are needed. This study compared 2 methods of administering potent opioids to patients to determine which method produced better results.

POPULATION STUDIED: A panel of 256 adult patients (age range = 26-82 years) was drawn from specialist pain clinics in Europe, Canada, and South Africa. Many of these patients (70%) had previous therapy with opioids for chronic non-cancer pain. Patients (N=24) were excluded who had previous exposure to morphine and had rated it “bad” or “very bad.” Sixty patients withdrew, leaving 196 patients to complete the study. Duration of pain ranged from less than 1 year to 50 years, with a mean duration of 9 years.

STUDY DESIGN AND VALIDITY: The researchers of this randomized multicenter open label crossover trial enrolled patients with nociceptive and/or neuropathic pain. As the method of administration of the 2 drugs is different, patients were aware of the change in therapy. Patients received doses of opioid equivalent to their pre-study requirements. The study compared fentanyl patch (25, 50, 75, or 100 μg/hr) and sustained-release oral morphine (10-, 30-, 60-, 100-, or 200-mg tablets). One group received 4 weeks of fentanyl followed by 4 weeks of morphine; the other received the drugs in reverse sequence. Medication dosage was fixed and not titrated to achieve pain control. This is perhaps the most important study limitation, because empiric dosage conversions are based on opioid equivalents determined in populations and often do not predict individual response.

OUTCOMES MEASURED: Overall, patient preference was assessed, as well as feelings regarding convenience, adverse events, and pain relief. Pain control was evaluated through intensity of pain (scale of 0-100) and need for a rescue drug. Quality of life was evaluated using the Medical Outcomes Study 36-item short form quality-of-life instrument. Safety-related outcomes included the rate of nausea, constipation (using a bowel function questionnaire), and hypoventilation.

RESULTS: A preference for one product over another could not be assessed in 39 patients (15%). The 212 remaining patients (65%) either “preferred” or “very much preferred” transdermal fentanyl, compared with 28% preferring sustained-release oral morphine (P <.001.) Seven percent expressed no preference. Patients in the fentanyl group had lower pain intensity with a mean rating of 57.8 mm (range=33.1-82.5 mm), compared with a mean rating of 62.9 mm (range = 41.2-84.6 mm; P <.001). Pain control was rated “good” or “very good” by 35% of the patients while receiving fentanyl, but only by 23% of the patients while taking morphine (P=.002.) They also reported higher quality-of-life scores during fentanyl therapy than during sustained-release oral morphine use, with scores in the categories of bodily pain, vitality, social functioning, and mental health being significantly different. The incidence and proportion of adverse events was similar; fentanyl, however, produced higher rates of nausea (26% vs 18%) but less constipation (16% vs 22%).

BACKGROUND: Recent public and legislative focus on pain management practices has led to scrutiny of guidelines for the role of opioids in pain therapy. A survey by the World Health Organization in 1998 revealed that 22% of patients seeing primary care physicians reported persistent pain. Better, more acceptable methods of pain control are needed. This study compared 2 methods of administering potent opioids to patients to determine which method produced better results.

POPULATION STUDIED: A panel of 256 adult patients (age range = 26-82 years) was drawn from specialist pain clinics in Europe, Canada, and South Africa. Many of these patients (70%) had previous therapy with opioids for chronic non-cancer pain. Patients (N=24) were excluded who had previous exposure to morphine and had rated it “bad” or “very bad.” Sixty patients withdrew, leaving 196 patients to complete the study. Duration of pain ranged from less than 1 year to 50 years, with a mean duration of 9 years.

STUDY DESIGN AND VALIDITY: The researchers of this randomized multicenter open label crossover trial enrolled patients with nociceptive and/or neuropathic pain. As the method of administration of the 2 drugs is different, patients were aware of the change in therapy. Patients received doses of opioid equivalent to their pre-study requirements. The study compared fentanyl patch (25, 50, 75, or 100 μg/hr) and sustained-release oral morphine (10-, 30-, 60-, 100-, or 200-mg tablets). One group received 4 weeks of fentanyl followed by 4 weeks of morphine; the other received the drugs in reverse sequence. Medication dosage was fixed and not titrated to achieve pain control. This is perhaps the most important study limitation, because empiric dosage conversions are based on opioid equivalents determined in populations and often do not predict individual response.

OUTCOMES MEASURED: Overall, patient preference was assessed, as well as feelings regarding convenience, adverse events, and pain relief. Pain control was evaluated through intensity of pain (scale of 0-100) and need for a rescue drug. Quality of life was evaluated using the Medical Outcomes Study 36-item short form quality-of-life instrument. Safety-related outcomes included the rate of nausea, constipation (using a bowel function questionnaire), and hypoventilation.

RESULTS: A preference for one product over another could not be assessed in 39 patients (15%). The 212 remaining patients (65%) either “preferred” or “very much preferred” transdermal fentanyl, compared with 28% preferring sustained-release oral morphine (P <.001.) Seven percent expressed no preference. Patients in the fentanyl group had lower pain intensity with a mean rating of 57.8 mm (range=33.1-82.5 mm), compared with a mean rating of 62.9 mm (range = 41.2-84.6 mm; P <.001). Pain control was rated “good” or “very good” by 35% of the patients while receiving fentanyl, but only by 23% of the patients while taking morphine (P=.002.) They also reported higher quality-of-life scores during fentanyl therapy than during sustained-release oral morphine use, with scores in the categories of bodily pain, vitality, social functioning, and mental health being significantly different. The incidence and proportion of adverse events was similar; fentanyl, however, produced higher rates of nausea (26% vs 18%) but less constipation (16% vs 22%).

BACKGROUND: Recent public and legislative focus on pain management practices has led to scrutiny of guidelines for the role of opioids in pain therapy. A survey by the World Health Organization in 1998 revealed that 22% of patients seeing primary care physicians reported persistent pain. Better, more acceptable methods of pain control are needed. This study compared 2 methods of administering potent opioids to patients to determine which method produced better results.

POPULATION STUDIED: A panel of 256 adult patients (age range = 26-82 years) was drawn from specialist pain clinics in Europe, Canada, and South Africa. Many of these patients (70%) had previous therapy with opioids for chronic non-cancer pain. Patients (N=24) were excluded who had previous exposure to morphine and had rated it “bad” or “very bad.” Sixty patients withdrew, leaving 196 patients to complete the study. Duration of pain ranged from less than 1 year to 50 years, with a mean duration of 9 years.

STUDY DESIGN AND VALIDITY: The researchers of this randomized multicenter open label crossover trial enrolled patients with nociceptive and/or neuropathic pain. As the method of administration of the 2 drugs is different, patients were aware of the change in therapy. Patients received doses of opioid equivalent to their pre-study requirements. The study compared fentanyl patch (25, 50, 75, or 100 μg/hr) and sustained-release oral morphine (10-, 30-, 60-, 100-, or 200-mg tablets). One group received 4 weeks of fentanyl followed by 4 weeks of morphine; the other received the drugs in reverse sequence. Medication dosage was fixed and not titrated to achieve pain control. This is perhaps the most important study limitation, because empiric dosage conversions are based on opioid equivalents determined in populations and often do not predict individual response.

OUTCOMES MEASURED: Overall, patient preference was assessed, as well as feelings regarding convenience, adverse events, and pain relief. Pain control was evaluated through intensity of pain (scale of 0-100) and need for a rescue drug. Quality of life was evaluated using the Medical Outcomes Study 36-item short form quality-of-life instrument. Safety-related outcomes included the rate of nausea, constipation (using a bowel function questionnaire), and hypoventilation.

RESULTS: A preference for one product over another could not be assessed in 39 patients (15%). The 212 remaining patients (65%) either “preferred” or “very much preferred” transdermal fentanyl, compared with 28% preferring sustained-release oral morphine (P <.001.) Seven percent expressed no preference. Patients in the fentanyl group had lower pain intensity with a mean rating of 57.8 mm (range=33.1-82.5 mm), compared with a mean rating of 62.9 mm (range = 41.2-84.6 mm; P <.001). Pain control was rated “good” or “very good” by 35% of the patients while receiving fentanyl, but only by 23% of the patients while taking morphine (P=.002.) They also reported higher quality-of-life scores during fentanyl therapy than during sustained-release oral morphine use, with scores in the categories of bodily pain, vitality, social functioning, and mental health being significantly different. The incidence and proportion of adverse events was similar; fentanyl, however, produced higher rates of nausea (26% vs 18%) but less constipation (16% vs 22%).

BACKGROUND: One of the more contentious clinical issues in the use of postmenopausal hormone replacement is the association between HRT, cognitive function, and dementia. The authors of this study examined published literature that assesses the relationship between estrogens and cognition by pooling the results of individual trials.

POPULATION STUDIED: The effects of HRT were examined in postmenopausal women. The individual studies varied significantly in the types of women they included. The women ranged in age from 29 to 80 years and had both surgical and natural menopause. The degree of menopausal symptoms they experienced also differed greatly.

STUDY DESIGN AND VALIDITY: English language research articles were identified using MEDLINE, HealthSTAR, PsychINFO, and The Cochrane Library databases. Twenty-nine studies that met inclusion criteria were rated for scientific rigor by 2 independent researchers. For the outcome of dementia, only retrospective cohort and case-control studies were available. Randomized controlled trials (RCTs) and cohort studies focusing on HRT and cognitive decline were included. Three of the RCTs used a crossover design. Ultimately, only 9 RCTs and 8 cohort studies were reviewed in the final analysis. The greatest limitations of this meta-analysis stem from the relatively poor and variable study design of the original articles. As a result, the conclusions of this meta-analysis, although based on the best available evidence, should be viewed with suspicion. Of the 17 included trials, the quality of 2 of the RCTs was rated as 2 out of 5 points. Two of the cohort studies were rated poor, and 1 was rated good. Although the duration of estrogen use in the RCTs was very short (21 days to 6 months), the retrospective trials ranged from 1.5 to 15 years. Only 7 of the 40 different cognitive tests were used in more than 2 studies. There were insufficient data to make conclusions regarding differences in outcomes between estrogen type, method of administration, dose, or use with or without progestins.

OUTCOMES MEASURED: Each study measured different outcomes. Most focused on aspects of memory, attention, concept formation and reasoning, motor speed, mental status, and verbal functions and language. Patient-oriented outcomes were not assessed, such as the ability to perform activities of daily living or the ability to live independently. The development of clinically diagnosed Alzheimer disease was the main outcome of the dementia trials. Only 1 study assessed the risk of vascular dementia.

RESULTS: Overall, women with preexisting menopausal symptoms appeared to receive more cognitive benefit than those without symptoms. Estrogen exposure was associated with slightly improved verbal memory, vigilance, reasoning, and motor speed, but not with other cognitive functions. The retrospective data suggests HRT use reduces the risk of dementia by approximately one third (summary odds ratio [OR]= 0.66; 95% confidence interval [CI], 0.53-0.82). HRT did not reduce the risk of vascular dementia (OR=0.50; 95% CI, 0.20-1.2).

BACKGROUND: One of the more contentious clinical issues in the use of postmenopausal hormone replacement is the association between HRT, cognitive function, and dementia. The authors of this study examined published literature that assesses the relationship between estrogens and cognition by pooling the results of individual trials.

POPULATION STUDIED: The effects of HRT were examined in postmenopausal women. The individual studies varied significantly in the types of women they included. The women ranged in age from 29 to 80 years and had both surgical and natural menopause. The degree of menopausal symptoms they experienced also differed greatly.

STUDY DESIGN AND VALIDITY: English language research articles were identified using MEDLINE, HealthSTAR, PsychINFO, and The Cochrane Library databases. Twenty-nine studies that met inclusion criteria were rated for scientific rigor by 2 independent researchers. For the outcome of dementia, only retrospective cohort and case-control studies were available. Randomized controlled trials (RCTs) and cohort studies focusing on HRT and cognitive decline were included. Three of the RCTs used a crossover design. Ultimately, only 9 RCTs and 8 cohort studies were reviewed in the final analysis. The greatest limitations of this meta-analysis stem from the relatively poor and variable study design of the original articles. As a result, the conclusions of this meta-analysis, although based on the best available evidence, should be viewed with suspicion. Of the 17 included trials, the quality of 2 of the RCTs was rated as 2 out of 5 points. Two of the cohort studies were rated poor, and 1 was rated good. Although the duration of estrogen use in the RCTs was very short (21 days to 6 months), the retrospective trials ranged from 1.5 to 15 years. Only 7 of the 40 different cognitive tests were used in more than 2 studies. There were insufficient data to make conclusions regarding differences in outcomes between estrogen type, method of administration, dose, or use with or without progestins.

OUTCOMES MEASURED: Each study measured different outcomes. Most focused on aspects of memory, attention, concept formation and reasoning, motor speed, mental status, and verbal functions and language. Patient-oriented outcomes were not assessed, such as the ability to perform activities of daily living or the ability to live independently. The development of clinically diagnosed Alzheimer disease was the main outcome of the dementia trials. Only 1 study assessed the risk of vascular dementia.

RESULTS: Overall, women with preexisting menopausal symptoms appeared to receive more cognitive benefit than those without symptoms. Estrogen exposure was associated with slightly improved verbal memory, vigilance, reasoning, and motor speed, but not with other cognitive functions. The retrospective data suggests HRT use reduces the risk of dementia by approximately one third (summary odds ratio [OR]= 0.66; 95% confidence interval [CI], 0.53-0.82). HRT did not reduce the risk of vascular dementia (OR=0.50; 95% CI, 0.20-1.2).

BACKGROUND: One of the more contentious clinical issues in the use of postmenopausal hormone replacement is the association between HRT, cognitive function, and dementia. The authors of this study examined published literature that assesses the relationship between estrogens and cognition by pooling the results of individual trials.

POPULATION STUDIED: The effects of HRT were examined in postmenopausal women. The individual studies varied significantly in the types of women they included. The women ranged in age from 29 to 80 years and had both surgical and natural menopause. The degree of menopausal symptoms they experienced also differed greatly.

STUDY DESIGN AND VALIDITY: English language research articles were identified using MEDLINE, HealthSTAR, PsychINFO, and The Cochrane Library databases. Twenty-nine studies that met inclusion criteria were rated for scientific rigor by 2 independent researchers. For the outcome of dementia, only retrospective cohort and case-control studies were available. Randomized controlled trials (RCTs) and cohort studies focusing on HRT and cognitive decline were included. Three of the RCTs used a crossover design. Ultimately, only 9 RCTs and 8 cohort studies were reviewed in the final analysis. The greatest limitations of this meta-analysis stem from the relatively poor and variable study design of the original articles. As a result, the conclusions of this meta-analysis, although based on the best available evidence, should be viewed with suspicion. Of the 17 included trials, the quality of 2 of the RCTs was rated as 2 out of 5 points. Two of the cohort studies were rated poor, and 1 was rated good. Although the duration of estrogen use in the RCTs was very short (21 days to 6 months), the retrospective trials ranged from 1.5 to 15 years. Only 7 of the 40 different cognitive tests were used in more than 2 studies. There were insufficient data to make conclusions regarding differences in outcomes between estrogen type, method of administration, dose, or use with or without progestins.

OUTCOMES MEASURED: Each study measured different outcomes. Most focused on aspects of memory, attention, concept formation and reasoning, motor speed, mental status, and verbal functions and language. Patient-oriented outcomes were not assessed, such as the ability to perform activities of daily living or the ability to live independently. The development of clinically diagnosed Alzheimer disease was the main outcome of the dementia trials. Only 1 study assessed the risk of vascular dementia.

RESULTS: Overall, women with preexisting menopausal symptoms appeared to receive more cognitive benefit than those without symptoms. Estrogen exposure was associated with slightly improved verbal memory, vigilance, reasoning, and motor speed, but not with other cognitive functions. The retrospective data suggests HRT use reduces the risk of dementia by approximately one third (summary odds ratio [OR]= 0.66; 95% confidence interval [CI], 0.53-0.82). HRT did not reduce the risk of vascular dementia (OR=0.50; 95% CI, 0.20-1.2).

BACKGROUND: Acute migraine headache treatment may be approached in 3 ways. Stratified care implies treatment selection based on headache severity and associated disability. Step care either across a number of attacks or within an attack suggests choosing a common initial remedy that collectively optimizes efficacy, tolerability, and cost. Alternative regimens that may be higher in toxicity or cost are then progressively picked as necessary for treatment failure. Although commonly advocated for migraine management, these strategies have not yet been systematically compared to determine the best approach.

POPULATION STUDIED: Patients were eligible if they were aged 18 to 65 years and diagnosed with a migraine headache according to International Headache Society criteria. Subjects were recruited from 88 sites in 13 countries, but only those with a Migraine Disability Assessment Scale (MIDAS) of grade II, III, or IV were studied. Additional criteria included age at onset younger than 50 years, 1 to 8 attacks per month for the preceding 3 months, fewer than 10 nonmigraine headache days per month, and no change in preventive therapy during the trial. Participants were mostly women (83.2%), young (mean=37 years), and described their baseline disability as grade III or IV (mean=55%).

STUDY DESIGN AND VALIDITY: The study was conducted in an unblinded randomized parallel group design. During the 15-month period patients treated up to 6 moderate to severe migraines. The stratified group received care based on headache severity: Grade II was treated with aspirin 800 to 1000 mg plus metoclopramide 10 mg and grades III and IV with zolmitriptan 2.5 mg. The step care across attacks group all administered aspirin plus metoclopramide 10 mg as initial treatment. Therapy was escalated to zolmitriptan 2.5 mg in those that failed to respond in 2 of the first 3 attacks. Lack of response was defined as failure to reduce headache severity from moderate-severe to none-mild. All subjects in the step care within attacks group received the aspirin/metoclopramide combination as initial therapy but could add zolmitriptan if a response was not achieved within 2 hours. Efficacy and adverse effect data were self-reported on diary cards. Overall, the study was well conducted. Although the lack of treatment blinding is a potentially significant limitation, it may more closely approximate clinical practice. More importantly, the results may be different if other study drugs were chosen, and other agents are more commonly used in the United States. Finally, the results were not analyzed according to intention to treat and the dropout rate for the efficacy analysis was approximately 20%.

OUTCOMES MEASURED: The 2 primary outcomes were headache response at 2 hours and disability time per treated attack at 4 hours. Secondary end points included 1- and 4-hour responses, 2-hour pain-free response, and the occurrence of adverse events.

RESULTS: Headache response at 2 hours was significantly greater for stratified care than for either step care across attacks (odds ratio [OR]=1.67; 95% confidence interval [CI], 1.31-2.12) or within attacks (OR=2.14; 95% CI, 1.66-2.77). These differences were mostly accounted for by the lack of response during the first 3 headaches (OR=2.91; 95% CI, 2.18-3.87) or within the first 2 hours of an attack, respectively. Disability time (from 0-4 hours) was also lower in the stratified care group than the step care across attacks group or the step care within attacks group. Again, there were no differences following treatment escalation in the step care groups. Adverse events were reported in approximately 14% of the attacks. They were more common in patients randomized to the stratified care group (19.5% vs 9.7% vs 13.1%). Those occurring less than 2% (asthenia, nausea, dizziness, paresthesias, and somnolence) were mild to moderate in severity and likely associated with zolmitriptan use. There was no difference in study withdrawal between treatment groups.

BACKGROUND: Acute migraine headache treatment may be approached in 3 ways. Stratified care implies treatment selection based on headache severity and associated disability. Step care either across a number of attacks or within an attack suggests choosing a common initial remedy that collectively optimizes efficacy, tolerability, and cost. Alternative regimens that may be higher in toxicity or cost are then progressively picked as necessary for treatment failure. Although commonly advocated for migraine management, these strategies have not yet been systematically compared to determine the best approach.

POPULATION STUDIED: Patients were eligible if they were aged 18 to 65 years and diagnosed with a migraine headache according to International Headache Society criteria. Subjects were recruited from 88 sites in 13 countries, but only those with a Migraine Disability Assessment Scale (MIDAS) of grade II, III, or IV were studied. Additional criteria included age at onset younger than 50 years, 1 to 8 attacks per month for the preceding 3 months, fewer than 10 nonmigraine headache days per month, and no change in preventive therapy during the trial. Participants were mostly women (83.2%), young (mean=37 years), and described their baseline disability as grade III or IV (mean=55%).

STUDY DESIGN AND VALIDITY: The study was conducted in an unblinded randomized parallel group design. During the 15-month period patients treated up to 6 moderate to severe migraines. The stratified group received care based on headache severity: Grade II was treated with aspirin 800 to 1000 mg plus metoclopramide 10 mg and grades III and IV with zolmitriptan 2.5 mg. The step care across attacks group all administered aspirin plus metoclopramide 10 mg as initial treatment. Therapy was escalated to zolmitriptan 2.5 mg in those that failed to respond in 2 of the first 3 attacks. Lack of response was defined as failure to reduce headache severity from moderate-severe to none-mild. All subjects in the step care within attacks group received the aspirin/metoclopramide combination as initial therapy but could add zolmitriptan if a response was not achieved within 2 hours. Efficacy and adverse effect data were self-reported on diary cards. Overall, the study was well conducted. Although the lack of treatment blinding is a potentially significant limitation, it may more closely approximate clinical practice. More importantly, the results may be different if other study drugs were chosen, and other agents are more commonly used in the United States. Finally, the results were not analyzed according to intention to treat and the dropout rate for the efficacy analysis was approximately 20%.

OUTCOMES MEASURED: The 2 primary outcomes were headache response at 2 hours and disability time per treated attack at 4 hours. Secondary end points included 1- and 4-hour responses, 2-hour pain-free response, and the occurrence of adverse events.

RESULTS: Headache response at 2 hours was significantly greater for stratified care than for either step care across attacks (odds ratio [OR]=1.67; 95% confidence interval [CI], 1.31-2.12) or within attacks (OR=2.14; 95% CI, 1.66-2.77). These differences were mostly accounted for by the lack of response during the first 3 headaches (OR=2.91; 95% CI, 2.18-3.87) or within the first 2 hours of an attack, respectively. Disability time (from 0-4 hours) was also lower in the stratified care group than the step care across attacks group or the step care within attacks group. Again, there were no differences following treatment escalation in the step care groups. Adverse events were reported in approximately 14% of the attacks. They were more common in patients randomized to the stratified care group (19.5% vs 9.7% vs 13.1%). Those occurring less than 2% (asthenia, nausea, dizziness, paresthesias, and somnolence) were mild to moderate in severity and likely associated with zolmitriptan use. There was no difference in study withdrawal between treatment groups.

BACKGROUND: Acute migraine headache treatment may be approached in 3 ways. Stratified care implies treatment selection based on headache severity and associated disability. Step care either across a number of attacks or within an attack suggests choosing a common initial remedy that collectively optimizes efficacy, tolerability, and cost. Alternative regimens that may be higher in toxicity or cost are then progressively picked as necessary for treatment failure. Although commonly advocated for migraine management, these strategies have not yet been systematically compared to determine the best approach.

POPULATION STUDIED: Patients were eligible if they were aged 18 to 65 years and diagnosed with a migraine headache according to International Headache Society criteria. Subjects were recruited from 88 sites in 13 countries, but only those with a Migraine Disability Assessment Scale (MIDAS) of grade II, III, or IV were studied. Additional criteria included age at onset younger than 50 years, 1 to 8 attacks per month for the preceding 3 months, fewer than 10 nonmigraine headache days per month, and no change in preventive therapy during the trial. Participants were mostly women (83.2%), young (mean=37 years), and described their baseline disability as grade III or IV (mean=55%).

STUDY DESIGN AND VALIDITY: The study was conducted in an unblinded randomized parallel group design. During the 15-month period patients treated up to 6 moderate to severe migraines. The stratified group received care based on headache severity: Grade II was treated with aspirin 800 to 1000 mg plus metoclopramide 10 mg and grades III and IV with zolmitriptan 2.5 mg. The step care across attacks group all administered aspirin plus metoclopramide 10 mg as initial treatment. Therapy was escalated to zolmitriptan 2.5 mg in those that failed to respond in 2 of the first 3 attacks. Lack of response was defined as failure to reduce headache severity from moderate-severe to none-mild. All subjects in the step care within attacks group received the aspirin/metoclopramide combination as initial therapy but could add zolmitriptan if a response was not achieved within 2 hours. Efficacy and adverse effect data were self-reported on diary cards. Overall, the study was well conducted. Although the lack of treatment blinding is a potentially significant limitation, it may more closely approximate clinical practice. More importantly, the results may be different if other study drugs were chosen, and other agents are more commonly used in the United States. Finally, the results were not analyzed according to intention to treat and the dropout rate for the efficacy analysis was approximately 20%.

OUTCOMES MEASURED: The 2 primary outcomes were headache response at 2 hours and disability time per treated attack at 4 hours. Secondary end points included 1- and 4-hour responses, 2-hour pain-free response, and the occurrence of adverse events.

RESULTS: Headache response at 2 hours was significantly greater for stratified care than for either step care across attacks (odds ratio [OR]=1.67; 95% confidence interval [CI], 1.31-2.12) or within attacks (OR=2.14; 95% CI, 1.66-2.77). These differences were mostly accounted for by the lack of response during the first 3 headaches (OR=2.91; 95% CI, 2.18-3.87) or within the first 2 hours of an attack, respectively. Disability time (from 0-4 hours) was also lower in the stratified care group than the step care across attacks group or the step care within attacks group. Again, there were no differences following treatment escalation in the step care groups. Adverse events were reported in approximately 14% of the attacks. They were more common in patients randomized to the stratified care group (19.5% vs 9.7% vs 13.1%). Those occurring less than 2% (asthenia, nausea, dizziness, paresthesias, and somnolence) were mild to moderate in severity and likely associated with zolmitriptan use. There was no difference in study withdrawal between treatment groups.

BACKGROUND: Options for removing cerumen include the use of a ceruminolytic, a curette, irrigation, or a combination. Irrigation and mechanical extraction carry the risk of patient discomfort, ossicle disruption, trauma, and infection. Ceruminolytics used in practice include water, sodium bicarbonate, hydrogen or carbamide peroxide, mineral or olive oil, glycerin, triethanolamine oleate, and propylene glycol. Although docusate has been used empirically, only in vitro data are available to support its use. The authors of this study evaluated the comparative efficacy of docusate and triethanolamine polypeptide for acute earwax removal.

POPULATION STUDIED: Fifty adult and pediatric patients from a university-based emergency department were enrolled on a convenience basis. The participants were older than 1 year, had a medical condition requiring tympanic membrane visualization, and had partially or totally obscured tympanic membranes. The sample subjects were 35% female and 26% very young (<5 years). Patients were excluded for known or suspected perforation, overt ear infection, or lack of cooperation.

STUDY DESIGN AND VALIDITY: The study was a randomized double-blind trial. A physician determined tympanic membrane obstruction. The authors reported an interobserver reliability of 79%, but the method of determination was not discussed. A 1-mL dose of either triethanolamine or docusate was placed in the affected ear canal and allowed to remain for 10 to 15 minutes. In an attempt to mask the treatments, doses were placed in opaque syringes to obscure the color difference. If the wax was not removed, the ear was irrigated once or twice with 50 mL normal saline. Overall the study has few faults. One concern is that a convenience sample of patients was used, and allocation may not have been concealed. As a result, the researchers could have chosen either particularly difficult or minor cerumen obstructions when enrolling patients in the study. The wide age range probably would not affect study results, because age does not affect cerumen quantity or quality.

OUTCOMES MEASURED: The main outcome measure was the percentage of tympanic membranes totally visualized with or without saline irrigation. The adverse events subjectively reported by patients were also recorded.

RESULTS: Immediately after ceruminolytic instillation there was no difference between the 2 treatments. However, after 2 irrigations with normal saline, complete clearing was achieved in 82% of the docusate-treated patients and 35% of the triethanolamine-treated patients (difference=47%; 95% confidence interval [CI], 22%-71%). In other words, every other patient treated with docusate instead of triethanolamine would have benefited (number needed to treat=2.13). Although this difference was markedly greater in children younger than 5 years (difference=90; 95% CI, 51%-100%), there were only 4 very young children who received triethanolamine. No adverse events were reported.

BACKGROUND: Options for removing cerumen include the use of a ceruminolytic, a curette, irrigation, or a combination. Irrigation and mechanical extraction carry the risk of patient discomfort, ossicle disruption, trauma, and infection. Ceruminolytics used in practice include water, sodium bicarbonate, hydrogen or carbamide peroxide, mineral or olive oil, glycerin, triethanolamine oleate, and propylene glycol. Although docusate has been used empirically, only in vitro data are available to support its use. The authors of this study evaluated the comparative efficacy of docusate and triethanolamine polypeptide for acute earwax removal.

POPULATION STUDIED: Fifty adult and pediatric patients from a university-based emergency department were enrolled on a convenience basis. The participants were older than 1 year, had a medical condition requiring tympanic membrane visualization, and had partially or totally obscured tympanic membranes. The sample subjects were 35% female and 26% very young (<5 years). Patients were excluded for known or suspected perforation, overt ear infection, or lack of cooperation.

STUDY DESIGN AND VALIDITY: The study was a randomized double-blind trial. A physician determined tympanic membrane obstruction. The authors reported an interobserver reliability of 79%, but the method of determination was not discussed. A 1-mL dose of either triethanolamine or docusate was placed in the affected ear canal and allowed to remain for 10 to 15 minutes. In an attempt to mask the treatments, doses were placed in opaque syringes to obscure the color difference. If the wax was not removed, the ear was irrigated once or twice with 50 mL normal saline. Overall the study has few faults. One concern is that a convenience sample of patients was used, and allocation may not have been concealed. As a result, the researchers could have chosen either particularly difficult or minor cerumen obstructions when enrolling patients in the study. The wide age range probably would not affect study results, because age does not affect cerumen quantity or quality.

OUTCOMES MEASURED: The main outcome measure was the percentage of tympanic membranes totally visualized with or without saline irrigation. The adverse events subjectively reported by patients were also recorded.

RESULTS: Immediately after ceruminolytic instillation there was no difference between the 2 treatments. However, after 2 irrigations with normal saline, complete clearing was achieved in 82% of the docusate-treated patients and 35% of the triethanolamine-treated patients (difference=47%; 95% confidence interval [CI], 22%-71%). In other words, every other patient treated with docusate instead of triethanolamine would have benefited (number needed to treat=2.13). Although this difference was markedly greater in children younger than 5 years (difference=90; 95% CI, 51%-100%), there were only 4 very young children who received triethanolamine. No adverse events were reported.

BACKGROUND: Options for removing cerumen include the use of a ceruminolytic, a curette, irrigation, or a combination. Irrigation and mechanical extraction carry the risk of patient discomfort, ossicle disruption, trauma, and infection. Ceruminolytics used in practice include water, sodium bicarbonate, hydrogen or carbamide peroxide, mineral or olive oil, glycerin, triethanolamine oleate, and propylene glycol. Although docusate has been used empirically, only in vitro data are available to support its use. The authors of this study evaluated the comparative efficacy of docusate and triethanolamine polypeptide for acute earwax removal.

POPULATION STUDIED: Fifty adult and pediatric patients from a university-based emergency department were enrolled on a convenience basis. The participants were older than 1 year, had a medical condition requiring tympanic membrane visualization, and had partially or totally obscured tympanic membranes. The sample subjects were 35% female and 26% very young (<5 years). Patients were excluded for known or suspected perforation, overt ear infection, or lack of cooperation.

STUDY DESIGN AND VALIDITY: The study was a randomized double-blind trial. A physician determined tympanic membrane obstruction. The authors reported an interobserver reliability of 79%, but the method of determination was not discussed. A 1-mL dose of either triethanolamine or docusate was placed in the affected ear canal and allowed to remain for 10 to 15 minutes. In an attempt to mask the treatments, doses were placed in opaque syringes to obscure the color difference. If the wax was not removed, the ear was irrigated once or twice with 50 mL normal saline. Overall the study has few faults. One concern is that a convenience sample of patients was used, and allocation may not have been concealed. As a result, the researchers could have chosen either particularly difficult or minor cerumen obstructions when enrolling patients in the study. The wide age range probably would not affect study results, because age does not affect cerumen quantity or quality.

OUTCOMES MEASURED: The main outcome measure was the percentage of tympanic membranes totally visualized with or without saline irrigation. The adverse events subjectively reported by patients were also recorded.

RESULTS: Immediately after ceruminolytic instillation there was no difference between the 2 treatments. However, after 2 irrigations with normal saline, complete clearing was achieved in 82% of the docusate-treated patients and 35% of the triethanolamine-treated patients (difference=47%; 95% confidence interval [CI], 22%-71%). In other words, every other patient treated with docusate instead of triethanolamine would have benefited (number needed to treat=2.13). Although this difference was markedly greater in children younger than 5 years (difference=90; 95% CI, 51%-100%), there were only 4 very young children who received triethanolamine. No adverse events were reported.

BACKGROUND: The nearly 23,000 daily ankle injuries in the United States account for approximately 25% of all musculoskeletal injuries. The anterior talofibular ligament (a lateral supporting ligament) is most often involved. Current management options include casting, surgery, functional treatment, or minimal-to-no treatment. Despite recently published reviews suggesting that functional treatment and early mobilization provide the best results, other studies recommend operative treatment. This meta-analysis was designed to systematically determine the best treatment approach.

POPULATION STUDIED: More than 3300 patients with acute lateral ankle ligament ruptures enrolled in 27 randomized controlled trials were evaluated. Fifteen of the 42 trials initially identified were excluded because of poor follow-up (<40% dropout), republication of the same trial, or lack of relevant outcome variables. Diagnosis based on imaging by an arthrogram or stress radiograph was required. Study duration ranged from 6 to 46 months. Articles were included regardless of published language. Patients were largely recruited from the general population, so the results likely apply to those managed by family physicians.

STUDY DESIGN AND VALIDITY: The authors of this meta-analysis reviewed randomized controlled trials found by searching the MEDLINE, Cochrane, and EMBASE databases from 1966 to 1998. Three independent investigators blinded to author and institution reviewed each trial and assessed its quality. Quality was determined by randomization that included concealed allocation assignment, adequate follow-up, and blinded outcome assessment. Treatments included operative (using a similar surgical protocol), casting for 6 weeks, and different types of functional intervention (bracing, wrapping, orthoses such as air casts, special shoes, and cast immobilization for 3 weeks). Three methods employing minimal treatment (less than 3 weeks of socks, braces, wraps, or casts) were also included because no trials of nonintervention were identified. Data were analyzed for homogeneity by calculating the Q statistic.

OUTCOMES MEASURED: The authors evaluated 2 long-term outcomes (residual pain and giving way) and one short-term outcome (time lost from work).

RESULTS: The natural history of untreated lateral ankle ligament ruptures is unknown. Treatments of short duration or inadequate ankle joint support are associated with more frequent residual symptoms (pain and giving way). Operative treatment followed by functional treatment resulted in less giving way than functional treatment alone (relative risk [RR]=0.23; 95% confidence interval [CI], 0.17-0.31). Functional treatment alone led to less giving way than 6-week cast treatment (RR=0.69; 95% CI, 0.50-0.94). Functional treatment was also associated with less pain than 6-week cast treatment (RR=0.67; 95% CI, 0.50-0.90). No other differences between interventions were found with regard to pain. Time lost from work varied greatly. Approximately 10% of patients undergoing operative treatment developed surgical complications. Results of a subgroup analysis of the high-quality studies only were not different from the results of the corresponding analysis of all studies.

BACKGROUND: The nearly 23,000 daily ankle injuries in the United States account for approximately 25% of all musculoskeletal injuries. The anterior talofibular ligament (a lateral supporting ligament) is most often involved. Current management options include casting, surgery, functional treatment, or minimal-to-no treatment. Despite recently published reviews suggesting that functional treatment and early mobilization provide the best results, other studies recommend operative treatment. This meta-analysis was designed to systematically determine the best treatment approach.

POPULATION STUDIED: More than 3300 patients with acute lateral ankle ligament ruptures enrolled in 27 randomized controlled trials were evaluated. Fifteen of the 42 trials initially identified were excluded because of poor follow-up (<40% dropout), republication of the same trial, or lack of relevant outcome variables. Diagnosis based on imaging by an arthrogram or stress radiograph was required. Study duration ranged from 6 to 46 months. Articles were included regardless of published language. Patients were largely recruited from the general population, so the results likely apply to those managed by family physicians.

STUDY DESIGN AND VALIDITY: The authors of this meta-analysis reviewed randomized controlled trials found by searching the MEDLINE, Cochrane, and EMBASE databases from 1966 to 1998. Three independent investigators blinded to author and institution reviewed each trial and assessed its quality. Quality was determined by randomization that included concealed allocation assignment, adequate follow-up, and blinded outcome assessment. Treatments included operative (using a similar surgical protocol), casting for 6 weeks, and different types of functional intervention (bracing, wrapping, orthoses such as air casts, special shoes, and cast immobilization for 3 weeks). Three methods employing minimal treatment (less than 3 weeks of socks, braces, wraps, or casts) were also included because no trials of nonintervention were identified. Data were analyzed for homogeneity by calculating the Q statistic.

OUTCOMES MEASURED: The authors evaluated 2 long-term outcomes (residual pain and giving way) and one short-term outcome (time lost from work).

RESULTS: The natural history of untreated lateral ankle ligament ruptures is unknown. Treatments of short duration or inadequate ankle joint support are associated with more frequent residual symptoms (pain and giving way). Operative treatment followed by functional treatment resulted in less giving way than functional treatment alone (relative risk [RR]=0.23; 95% confidence interval [CI], 0.17-0.31). Functional treatment alone led to less giving way than 6-week cast treatment (RR=0.69; 95% CI, 0.50-0.94). Functional treatment was also associated with less pain than 6-week cast treatment (RR=0.67; 95% CI, 0.50-0.90). No other differences between interventions were found with regard to pain. Time lost from work varied greatly. Approximately 10% of patients undergoing operative treatment developed surgical complications. Results of a subgroup analysis of the high-quality studies only were not different from the results of the corresponding analysis of all studies.

BACKGROUND: The nearly 23,000 daily ankle injuries in the United States account for approximately 25% of all musculoskeletal injuries. The anterior talofibular ligament (a lateral supporting ligament) is most often involved. Current management options include casting, surgery, functional treatment, or minimal-to-no treatment. Despite recently published reviews suggesting that functional treatment and early mobilization provide the best results, other studies recommend operative treatment. This meta-analysis was designed to systematically determine the best treatment approach.

POPULATION STUDIED: More than 3300 patients with acute lateral ankle ligament ruptures enrolled in 27 randomized controlled trials were evaluated. Fifteen of the 42 trials initially identified were excluded because of poor follow-up (<40% dropout), republication of the same trial, or lack of relevant outcome variables. Diagnosis based on imaging by an arthrogram or stress radiograph was required. Study duration ranged from 6 to 46 months. Articles were included regardless of published language. Patients were largely recruited from the general population, so the results likely apply to those managed by family physicians.

STUDY DESIGN AND VALIDITY: The authors of this meta-analysis reviewed randomized controlled trials found by searching the MEDLINE, Cochrane, and EMBASE databases from 1966 to 1998. Three independent investigators blinded to author and institution reviewed each trial and assessed its quality. Quality was determined by randomization that included concealed allocation assignment, adequate follow-up, and blinded outcome assessment. Treatments included operative (using a similar surgical protocol), casting for 6 weeks, and different types of functional intervention (bracing, wrapping, orthoses such as air casts, special shoes, and cast immobilization for 3 weeks). Three methods employing minimal treatment (less than 3 weeks of socks, braces, wraps, or casts) were also included because no trials of nonintervention were identified. Data were analyzed for homogeneity by calculating the Q statistic.

OUTCOMES MEASURED: The authors evaluated 2 long-term outcomes (residual pain and giving way) and one short-term outcome (time lost from work).

RESULTS: The natural history of untreated lateral ankle ligament ruptures is unknown. Treatments of short duration or inadequate ankle joint support are associated with more frequent residual symptoms (pain and giving way). Operative treatment followed by functional treatment resulted in less giving way than functional treatment alone (relative risk [RR]=0.23; 95% confidence interval [CI], 0.17-0.31). Functional treatment alone led to less giving way than 6-week cast treatment (RR=0.69; 95% CI, 0.50-0.94). Functional treatment was also associated with less pain than 6-week cast treatment (RR=0.67; 95% CI, 0.50-0.90). No other differences between interventions were found with regard to pain. Time lost from work varied greatly. Approximately 10% of patients undergoing operative treatment developed surgical complications. Results of a subgroup analysis of the high-quality studies only were not different from the results of the corresponding analysis of all studies.