Q&A

BACKGROUND: Amiodarone, a class III antiarrhythmic agent, is effective in the conversion of AF to sinus rhythm. It has been used successfully when administered by either intravenous (IV) or high-dose oral routes. No randomized placebo-controlled studies have been done to determine if a single oral dose of amiodarone may work as effectively.

POPULATION STUDIED: Patients older than 18 years were eligible if 4 criteria were met: recent onset AF (<48 hours) that lasted more than 3 hours; ventricular rate >50 beats per minute (bpm) and <150 bpm; hemodynamic stability, defined as systolic blood pressure >95 mm Hg; and a normal serum potassium level. Patients were excluded for the following conditions: history of acute myocardial infarction, acute pulmonary edema, sick sinus syndrome, high-degree atrioventricular block, or stroke. Women with childbearing potential were ineligible. The final study population was 60% men, and the average age was 60 years.

STUDY DESIGN AND VALIDITY: In this randomized placebo-controlled trial, all medications affecting cardiac rhythm and conduction were discontinued before randomization. Patients received either high-dose oral amiodarone (30 mg/kg) or placebo. Electrocardiogram, echocardiogram, and 24-hour Holter monitoring were performed. Blood pressure was measured at frequent regular intervals for 24 hours. In the event of rapid ventricular response rate (100 to 150 bpm) or patient discomfort, patients in the placebo group were given intravenous verapamil, and those in the amiodarone group received saline in a blinded fashion. Electrocardioversion was administered for hemodynamic deterioration.

OUTCOMES MEASURED: The primary outcome was the percentage of patients successfully converted from AF to sinus rhythm at 24 hours. Proarrhythmic events and other adverse drug effects were recorded.

RESULTS: Of the 72 patients enrolled in the study, 10 were excluded from the final analysis because of technical failure or sinus rhythm at the start of Holter monitoring. Eight hours after drug administration more patients in the amiodarone group had converted to sinus rhythm than in the placebo group (50% vs 20%, P <.001; number needed to treat [NNT]=3.3). Amiodarone was also more effective than placebo for conversion to sinus rhythm at 24 hours (87% vs 35%, P <.001; NNT=2.0). There was no difference in the ventricular response rates, heart rates, or blood pressures between the groups. No proarrhythmic events occurred in either group. One patient in the amiodarone group received IV saline because of a rapid ventricular response, and one had a syncopal episode with a valsalva maneuver. One patient in the placebo group had 2 episodes of sinus arrest with syncope. None of the patients required electrocardioversion. Other side effects, such as headache, diarrhea, and nausea, were similar in each group.

BACKGROUND: Amiodarone, a class III antiarrhythmic agent, is effective in the conversion of AF to sinus rhythm. It has been used successfully when administered by either intravenous (IV) or high-dose oral routes. No randomized placebo-controlled studies have been done to determine if a single oral dose of amiodarone may work as effectively.

POPULATION STUDIED: Patients older than 18 years were eligible if 4 criteria were met: recent onset AF (<48 hours) that lasted more than 3 hours; ventricular rate >50 beats per minute (bpm) and <150 bpm; hemodynamic stability, defined as systolic blood pressure >95 mm Hg; and a normal serum potassium level. Patients were excluded for the following conditions: history of acute myocardial infarction, acute pulmonary edema, sick sinus syndrome, high-degree atrioventricular block, or stroke. Women with childbearing potential were ineligible. The final study population was 60% men, and the average age was 60 years.

STUDY DESIGN AND VALIDITY: In this randomized placebo-controlled trial, all medications affecting cardiac rhythm and conduction were discontinued before randomization. Patients received either high-dose oral amiodarone (30 mg/kg) or placebo. Electrocardiogram, echocardiogram, and 24-hour Holter monitoring were performed. Blood pressure was measured at frequent regular intervals for 24 hours. In the event of rapid ventricular response rate (100 to 150 bpm) or patient discomfort, patients in the placebo group were given intravenous verapamil, and those in the amiodarone group received saline in a blinded fashion. Electrocardioversion was administered for hemodynamic deterioration.

OUTCOMES MEASURED: The primary outcome was the percentage of patients successfully converted from AF to sinus rhythm at 24 hours. Proarrhythmic events and other adverse drug effects were recorded.

RESULTS: Of the 72 patients enrolled in the study, 10 were excluded from the final analysis because of technical failure or sinus rhythm at the start of Holter monitoring. Eight hours after drug administration more patients in the amiodarone group had converted to sinus rhythm than in the placebo group (50% vs 20%, P <.001; number needed to treat [NNT]=3.3). Amiodarone was also more effective than placebo for conversion to sinus rhythm at 24 hours (87% vs 35%, P <.001; NNT=2.0). There was no difference in the ventricular response rates, heart rates, or blood pressures between the groups. No proarrhythmic events occurred in either group. One patient in the amiodarone group received IV saline because of a rapid ventricular response, and one had a syncopal episode with a valsalva maneuver. One patient in the placebo group had 2 episodes of sinus arrest with syncope. None of the patients required electrocardioversion. Other side effects, such as headache, diarrhea, and nausea, were similar in each group.

BACKGROUND: Amiodarone, a class III antiarrhythmic agent, is effective in the conversion of AF to sinus rhythm. It has been used successfully when administered by either intravenous (IV) or high-dose oral routes. No randomized placebo-controlled studies have been done to determine if a single oral dose of amiodarone may work as effectively.

POPULATION STUDIED: Patients older than 18 years were eligible if 4 criteria were met: recent onset AF (<48 hours) that lasted more than 3 hours; ventricular rate >50 beats per minute (bpm) and <150 bpm; hemodynamic stability, defined as systolic blood pressure >95 mm Hg; and a normal serum potassium level. Patients were excluded for the following conditions: history of acute myocardial infarction, acute pulmonary edema, sick sinus syndrome, high-degree atrioventricular block, or stroke. Women with childbearing potential were ineligible. The final study population was 60% men, and the average age was 60 years.

STUDY DESIGN AND VALIDITY: In this randomized placebo-controlled trial, all medications affecting cardiac rhythm and conduction were discontinued before randomization. Patients received either high-dose oral amiodarone (30 mg/kg) or placebo. Electrocardiogram, echocardiogram, and 24-hour Holter monitoring were performed. Blood pressure was measured at frequent regular intervals for 24 hours. In the event of rapid ventricular response rate (100 to 150 bpm) or patient discomfort, patients in the placebo group were given intravenous verapamil, and those in the amiodarone group received saline in a blinded fashion. Electrocardioversion was administered for hemodynamic deterioration.

OUTCOMES MEASURED: The primary outcome was the percentage of patients successfully converted from AF to sinus rhythm at 24 hours. Proarrhythmic events and other adverse drug effects were recorded.

RESULTS: Of the 72 patients enrolled in the study, 10 were excluded from the final analysis because of technical failure or sinus rhythm at the start of Holter monitoring. Eight hours after drug administration more patients in the amiodarone group had converted to sinus rhythm than in the placebo group (50% vs 20%, P <.001; number needed to treat [NNT]=3.3). Amiodarone was also more effective than placebo for conversion to sinus rhythm at 24 hours (87% vs 35%, P <.001; NNT=2.0). There was no difference in the ventricular response rates, heart rates, or blood pressures between the groups. No proarrhythmic events occurred in either group. One patient in the amiodarone group received IV saline because of a rapid ventricular response, and one had a syncopal episode with a valsalva maneuver. One patient in the placebo group had 2 episodes of sinus arrest with syncope. None of the patients required electrocardioversion. Other side effects, such as headache, diarrhea, and nausea, were similar in each group.

BACKGROUND: An estimated 175,000 Americans have a pulmonary embolism (PE) each year. Pulmonary angiography is the accepted gold standard for diagnosing PE, but it is invasive, expensive, and causes cardiopulmonary complications in 3% to 4% of patients. A ventilation-perfusion (V/Q) scan is less invasive, but also less accurate. Used in combination with clinical assessment, it fails to find 20% of PEs.¹ Recent studies evaluating the use of spiral computed tomography (CT) have reported favorable results in diagnosing PE. However, the role of CT for this use is not yet fully defined.

POPULATION STUDIED: In this systematic review, neither specific patient characteristics nor exclusion criteria were mentioned. Enrollment criteria were described as inconsistent.

STUDY DESIGN AND VALIDITY: The authors conducted a systematic review of the literature evaluating the use of spiral CT in diagnosing PE. They searched MEDLINE and Current Contents through July 1998 and reviewed pertinent references. Eleven articles met their preset inclusion criteria. The articles were rated by using a set of 11 basic methodologic standards for addressing diagnostic test research. None of the 11 studies met all of the criteria; only 5 studies met 5 or more criteria. All studies compared CT with either pulmonary angiography or another reference standard (high-probability V/Q scan plus high clinical suspicion) to confirm the diagnosis of PE. The studies were not methodologically similar enough to perform a meta-analysis.

OUTCOMES MEASURED: The primary outcome was the presence of a PE.

RESULTS: Compared with the gold standard of pulmonary angiography, the sensitivity of spiral CT ranged from 64% to 93%. If a PE is present, the probability of a positive CT scan is 64% to 93%. That means up to one third of PEs could be missed. The reported specificity ranged from 89% to 100%, which corresponds to a false-positive rate of 0% to 11%. These results are similar to those of another recent systematic review in which the authors reported a sensitivity range of 53% to 100% and a specificity range of 81% to 100%.¹ Nine of the studies differentiated between large central and small subsegmental vessel embolism. When stratified by site, the sensitivity for spiral CT was much higher for central vessel PE (83% to 100%) than for subsegmental vessel PE (29%).

BACKGROUND: An estimated 175,000 Americans have a pulmonary embolism (PE) each year. Pulmonary angiography is the accepted gold standard for diagnosing PE, but it is invasive, expensive, and causes cardiopulmonary complications in 3% to 4% of patients. A ventilation-perfusion (V/Q) scan is less invasive, but also less accurate. Used in combination with clinical assessment, it fails to find 20% of PEs.¹ Recent studies evaluating the use of spiral computed tomography (CT) have reported favorable results in diagnosing PE. However, the role of CT for this use is not yet fully defined.

POPULATION STUDIED: In this systematic review, neither specific patient characteristics nor exclusion criteria were mentioned. Enrollment criteria were described as inconsistent.

STUDY DESIGN AND VALIDITY: The authors conducted a systematic review of the literature evaluating the use of spiral CT in diagnosing PE. They searched MEDLINE and Current Contents through July 1998 and reviewed pertinent references. Eleven articles met their preset inclusion criteria. The articles were rated by using a set of 11 basic methodologic standards for addressing diagnostic test research. None of the 11 studies met all of the criteria; only 5 studies met 5 or more criteria. All studies compared CT with either pulmonary angiography or another reference standard (high-probability V/Q scan plus high clinical suspicion) to confirm the diagnosis of PE. The studies were not methodologically similar enough to perform a meta-analysis.

OUTCOMES MEASURED: The primary outcome was the presence of a PE.

RESULTS: Compared with the gold standard of pulmonary angiography, the sensitivity of spiral CT ranged from 64% to 93%. If a PE is present, the probability of a positive CT scan is 64% to 93%. That means up to one third of PEs could be missed. The reported specificity ranged from 89% to 100%, which corresponds to a false-positive rate of 0% to 11%. These results are similar to those of another recent systematic review in which the authors reported a sensitivity range of 53% to 100% and a specificity range of 81% to 100%.¹ Nine of the studies differentiated between large central and small subsegmental vessel embolism. When stratified by site, the sensitivity for spiral CT was much higher for central vessel PE (83% to 100%) than for subsegmental vessel PE (29%).

BACKGROUND: An estimated 175,000 Americans have a pulmonary embolism (PE) each year. Pulmonary angiography is the accepted gold standard for diagnosing PE, but it is invasive, expensive, and causes cardiopulmonary complications in 3% to 4% of patients. A ventilation-perfusion (V/Q) scan is less invasive, but also less accurate. Used in combination with clinical assessment, it fails to find 20% of PEs.¹ Recent studies evaluating the use of spiral computed tomography (CT) have reported favorable results in diagnosing PE. However, the role of CT for this use is not yet fully defined.

POPULATION STUDIED: In this systematic review, neither specific patient characteristics nor exclusion criteria were mentioned. Enrollment criteria were described as inconsistent.

STUDY DESIGN AND VALIDITY: The authors conducted a systematic review of the literature evaluating the use of spiral CT in diagnosing PE. They searched MEDLINE and Current Contents through July 1998 and reviewed pertinent references. Eleven articles met their preset inclusion criteria. The articles were rated by using a set of 11 basic methodologic standards for addressing diagnostic test research. None of the 11 studies met all of the criteria; only 5 studies met 5 or more criteria. All studies compared CT with either pulmonary angiography or another reference standard (high-probability V/Q scan plus high clinical suspicion) to confirm the diagnosis of PE. The studies were not methodologically similar enough to perform a meta-analysis.

OUTCOMES MEASURED: The primary outcome was the presence of a PE.

RESULTS: Compared with the gold standard of pulmonary angiography, the sensitivity of spiral CT ranged from 64% to 93%. If a PE is present, the probability of a positive CT scan is 64% to 93%. That means up to one third of PEs could be missed. The reported specificity ranged from 89% to 100%, which corresponds to a false-positive rate of 0% to 11%. These results are similar to those of another recent systematic review in which the authors reported a sensitivity range of 53% to 100% and a specificity range of 81% to 100%.¹ Nine of the studies differentiated between large central and small subsegmental vessel embolism. When stratified by site, the sensitivity for spiral CT was much higher for central vessel PE (83% to 100%) than for subsegmental vessel PE (29%).

BACKGROUND: Osteoarthritis affects 16 million people in the United States, and the prevalence of osteoarthritis of the knee is 6 out of 100 people older than 30 years.¹ Mainstays of therapy include analgesics, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgery. Varying data indicate that exercise reduces pain and improves function in patients with osteoarthritis of the knee; however, the optimal exercise regimen is yet to be determined.

POPULATION STUDIED: Study subjects included 83 adults with osteoarthritis of the knee from various military clinics in Texas who were referred for physical therapy. Osteoarthritis of the knee was defined as knee pain plus 1 of the following criteria: (1) aged 38 years or younger and bony enlargement; (2) aged 38 years or older, morning stiffness for longer than 30 minutes, and bony enlargement; (3) crepitus on active motion, morning stiffness for longer than 30 minutes, and bony enlargement; or (4) crepitus on active motion, morning stiffness for longer than 30 minutes, bony enlargement, and aged 38 years or older. Mean age in the treatment group was 60±11 years and 62±10 years in the placebo group. Thirty-four participants were men and 49 were women. Exclusion criteria included a surgical procedure to either lower extremity within the previous 6 months, physical impairment unrelated to the knee restricting the ability to perform the 6-minute walk test, a lack of minimal English skills, corticosteroid injection in the knee within 30 days, inability to attend the required number of visits, and new medical therapy for knee osteoarthritis. Baseline characteristics were homogeneous.

STUDY DESIGN AND VALIDITY: Using techniques to conceal allocation assignment, eligible patients were randomly assigned to 1 of 2 groups. The treatment group (n=42) underwent manual physical therapy (passive movement, muscle stretching and strengthening, and soft tissue mobilization) and supervised exercise (range of motion exercise, stretching, and stationary bicycling) 2 times a week for a total of 8 sessions. They also received therapy directed at the lower back, hip, and ankles as indicated. Treatment group participants also performed a home exercise program. Patients in the placebo group (n=41) received sham ultrasound therapy for the same number of sessions and were instructed to continue their normal activities. Neither group was aware of the treatment that the other group was receiving. All outcome measurements were obtained by an observer blinded to group assignment. Intention-to-treat analysis was used to determine group differences in the number of surgical interventions at 1 year.

OUTCOMES MEASURED: The primary outcomes measured were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and 6-minute walk distances, both of which were obtained at baseline, 4 weeks, 8 weeks, and 1 year. The numbers of participants in each group requiring corticosteroid injection or surgical intervention were also recorded.

RESULTS: Included for analysis were the 33 patients (79%) in the treatment group and 36 patients (88%) in the placebo group who completed all treatment and testing through 8 weeks. By 8 weeks, WOMAC scores had improved by 56% over baseline in the treatment group and 15% in the placebo group (P <.001; number needed to treat [NNT]=2.4). Six-minute walk times improved by 13% in the treatment group; there was minimal change in the placebo group (P=.001; NNT=8). Follow-up in the treatment group at 1 year compared with 8-week testing revealed 6-minute walk times essentially unchanged and WOMAC scores still well below baseline. At 1-year follow-up, 5% of treated participants and 20% of those in the placebo group had undergone a total knee arthroplasty (P=.04%; NNT=6.7), and 5% of treated participants and 15% of those in the placebo group had received corticosteroid injections into the knee.

BACKGROUND: Osteoarthritis affects 16 million people in the United States, and the prevalence of osteoarthritis of the knee is 6 out of 100 people older than 30 years.¹ Mainstays of therapy include analgesics, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgery. Varying data indicate that exercise reduces pain and improves function in patients with osteoarthritis of the knee; however, the optimal exercise regimen is yet to be determined.

POPULATION STUDIED: Study subjects included 83 adults with osteoarthritis of the knee from various military clinics in Texas who were referred for physical therapy. Osteoarthritis of the knee was defined as knee pain plus 1 of the following criteria: (1) aged 38 years or younger and bony enlargement; (2) aged 38 years or older, morning stiffness for longer than 30 minutes, and bony enlargement; (3) crepitus on active motion, morning stiffness for longer than 30 minutes, and bony enlargement; or (4) crepitus on active motion, morning stiffness for longer than 30 minutes, bony enlargement, and aged 38 years or older. Mean age in the treatment group was 60±11 years and 62±10 years in the placebo group. Thirty-four participants were men and 49 were women. Exclusion criteria included a surgical procedure to either lower extremity within the previous 6 months, physical impairment unrelated to the knee restricting the ability to perform the 6-minute walk test, a lack of minimal English skills, corticosteroid injection in the knee within 30 days, inability to attend the required number of visits, and new medical therapy for knee osteoarthritis. Baseline characteristics were homogeneous.

STUDY DESIGN AND VALIDITY: Using techniques to conceal allocation assignment, eligible patients were randomly assigned to 1 of 2 groups. The treatment group (n=42) underwent manual physical therapy (passive movement, muscle stretching and strengthening, and soft tissue mobilization) and supervised exercise (range of motion exercise, stretching, and stationary bicycling) 2 times a week for a total of 8 sessions. They also received therapy directed at the lower back, hip, and ankles as indicated. Treatment group participants also performed a home exercise program. Patients in the placebo group (n=41) received sham ultrasound therapy for the same number of sessions and were instructed to continue their normal activities. Neither group was aware of the treatment that the other group was receiving. All outcome measurements were obtained by an observer blinded to group assignment. Intention-to-treat analysis was used to determine group differences in the number of surgical interventions at 1 year.

OUTCOMES MEASURED: The primary outcomes measured were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and 6-minute walk distances, both of which were obtained at baseline, 4 weeks, 8 weeks, and 1 year. The numbers of participants in each group requiring corticosteroid injection or surgical intervention were also recorded.

RESULTS: Included for analysis were the 33 patients (79%) in the treatment group and 36 patients (88%) in the placebo group who completed all treatment and testing through 8 weeks. By 8 weeks, WOMAC scores had improved by 56% over baseline in the treatment group and 15% in the placebo group (P <.001; number needed to treat [NNT]=2.4). Six-minute walk times improved by 13% in the treatment group; there was minimal change in the placebo group (P=.001; NNT=8). Follow-up in the treatment group at 1 year compared with 8-week testing revealed 6-minute walk times essentially unchanged and WOMAC scores still well below baseline. At 1-year follow-up, 5% of treated participants and 20% of those in the placebo group had undergone a total knee arthroplasty (P=.04%; NNT=6.7), and 5% of treated participants and 15% of those in the placebo group had received corticosteroid injections into the knee.

BACKGROUND: Osteoarthritis affects 16 million people in the United States, and the prevalence of osteoarthritis of the knee is 6 out of 100 people older than 30 years.¹ Mainstays of therapy include analgesics, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgery. Varying data indicate that exercise reduces pain and improves function in patients with osteoarthritis of the knee; however, the optimal exercise regimen is yet to be determined.

POPULATION STUDIED: Study subjects included 83 adults with osteoarthritis of the knee from various military clinics in Texas who were referred for physical therapy. Osteoarthritis of the knee was defined as knee pain plus 1 of the following criteria: (1) aged 38 years or younger and bony enlargement; (2) aged 38 years or older, morning stiffness for longer than 30 minutes, and bony enlargement; (3) crepitus on active motion, morning stiffness for longer than 30 minutes, and bony enlargement; or (4) crepitus on active motion, morning stiffness for longer than 30 minutes, bony enlargement, and aged 38 years or older. Mean age in the treatment group was 60±11 years and 62±10 years in the placebo group. Thirty-four participants were men and 49 were women. Exclusion criteria included a surgical procedure to either lower extremity within the previous 6 months, physical impairment unrelated to the knee restricting the ability to perform the 6-minute walk test, a lack of minimal English skills, corticosteroid injection in the knee within 30 days, inability to attend the required number of visits, and new medical therapy for knee osteoarthritis. Baseline characteristics were homogeneous.

STUDY DESIGN AND VALIDITY: Using techniques to conceal allocation assignment, eligible patients were randomly assigned to 1 of 2 groups. The treatment group (n=42) underwent manual physical therapy (passive movement, muscle stretching and strengthening, and soft tissue mobilization) and supervised exercise (range of motion exercise, stretching, and stationary bicycling) 2 times a week for a total of 8 sessions. They also received therapy directed at the lower back, hip, and ankles as indicated. Treatment group participants also performed a home exercise program. Patients in the placebo group (n=41) received sham ultrasound therapy for the same number of sessions and were instructed to continue their normal activities. Neither group was aware of the treatment that the other group was receiving. All outcome measurements were obtained by an observer blinded to group assignment. Intention-to-treat analysis was used to determine group differences in the number of surgical interventions at 1 year.

OUTCOMES MEASURED: The primary outcomes measured were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and 6-minute walk distances, both of which were obtained at baseline, 4 weeks, 8 weeks, and 1 year. The numbers of participants in each group requiring corticosteroid injection or surgical intervention were also recorded.

RESULTS: Included for analysis were the 33 patients (79%) in the treatment group and 36 patients (88%) in the placebo group who completed all treatment and testing through 8 weeks. By 8 weeks, WOMAC scores had improved by 56% over baseline in the treatment group and 15% in the placebo group (P <.001; number needed to treat [NNT]=2.4). Six-minute walk times improved by 13% in the treatment group; there was minimal change in the placebo group (P=.001; NNT=8). Follow-up in the treatment group at 1 year compared with 8-week testing revealed 6-minute walk times essentially unchanged and WOMAC scores still well below baseline. At 1-year follow-up, 5% of treated participants and 20% of those in the placebo group had undergone a total knee arthroplasty (P=.04%; NNT=6.7), and 5% of treated participants and 15% of those in the placebo group had received corticosteroid injections into the knee.

BACKGROUND: Antibiotics are of limited effectiveness in treating acute otitis media in children aged older than 2 years. Antibiotic treatment, however, is widely prescribed in children younger than 2 years because they are thought to be at greater risk for complications. Widespread use of antibiotics is not benign, as side effects are common, and antibiotic resistance is a concern. Moreover, the benefit of antibiotics in children younger than 2 years has not been demonstrated in clinical studies.

POPULATION STUDIED: Children with acute otitis media were included if they were aged between 6 months and 2 years. They were selected from general practices in the Netherlands. Children were excluded if they had taken antibiotics in the preceding 4 weeks; had documented penicillin allergy, compromised immunity, craniofacial abnormalities, or Down syndrome; or had been entered in the study before.

STUDY DESIGN AND VALIDITY: This is a practice-based double-blind randomized controlled trial. Patients received either placebo or amoxicillin 40 mg per kg daily for 10 days. In addition, all patients used decongestant nasal drops and analgesics, as needed. Parents of patients kept a 10-day diary documenting symptoms and medication use. Assessment of response to therapy occurred at 4 and 11 days after the start of therapy, with a home visit after 6 weeks. This is a well-designed randomized controlled trial. To standardize the diagnosis of acute otitis media, participating physicians received special training. The authors did not describe the methods used to prevent researchers from knowing to which group the patient would be assigned (concealed allocation). This lack of concealment could introduce selective enrollment of patients. Follow-up was frequent and nearly complete. One concern: Otitis media resolves within 2 days in 90% of children older than 2 years.¹ The later assessment time used in this study (4 days) may be less clinically relevant and may favor the placebo. The authors of this study focused on short-term outcomes and did not report on the incidence of chronic otitis media, hearing loss, and any unpleasant effects from antibiotics.

OUTCOMES MEASURED: The primary outcome was the presence of symptoms after 4 days of therapy, including earache, fever (>38 °C), crying, irritability, or the prescription of another antibiotic because of worsening symptoms. Secondary outcome measures included clinical treatment failure at day 11.

RESULTS: Persistent symptoms at day 4 were present in 59% of the children in the amoxicillin group and 72% in the placebo group (P=.03) . Between 7 and 8 children aged 6 to 24 months with acute otitis media need to be treated to improve symptoms in 1 child on day 4 (number needed to treat=7.7; 95% confidence interval, 4-100). There was a high rate of treatment failure in both groups after therapy was completed: 64% in the treated group and 70% in the placebo group.

BACKGROUND: Antibiotics are of limited effectiveness in treating acute otitis media in children aged older than 2 years. Antibiotic treatment, however, is widely prescribed in children younger than 2 years because they are thought to be at greater risk for complications. Widespread use of antibiotics is not benign, as side effects are common, and antibiotic resistance is a concern. Moreover, the benefit of antibiotics in children younger than 2 years has not been demonstrated in clinical studies.

POPULATION STUDIED: Children with acute otitis media were included if they were aged between 6 months and 2 years. They were selected from general practices in the Netherlands. Children were excluded if they had taken antibiotics in the preceding 4 weeks; had documented penicillin allergy, compromised immunity, craniofacial abnormalities, or Down syndrome; or had been entered in the study before.

STUDY DESIGN AND VALIDITY: This is a practice-based double-blind randomized controlled trial. Patients received either placebo or amoxicillin 40 mg per kg daily for 10 days. In addition, all patients used decongestant nasal drops and analgesics, as needed. Parents of patients kept a 10-day diary documenting symptoms and medication use. Assessment of response to therapy occurred at 4 and 11 days after the start of therapy, with a home visit after 6 weeks. This is a well-designed randomized controlled trial. To standardize the diagnosis of acute otitis media, participating physicians received special training. The authors did not describe the methods used to prevent researchers from knowing to which group the patient would be assigned (concealed allocation). This lack of concealment could introduce selective enrollment of patients. Follow-up was frequent and nearly complete. One concern: Otitis media resolves within 2 days in 90% of children older than 2 years.¹ The later assessment time used in this study (4 days) may be less clinically relevant and may favor the placebo. The authors of this study focused on short-term outcomes and did not report on the incidence of chronic otitis media, hearing loss, and any unpleasant effects from antibiotics.

OUTCOMES MEASURED: The primary outcome was the presence of symptoms after 4 days of therapy, including earache, fever (>38 °C), crying, irritability, or the prescription of another antibiotic because of worsening symptoms. Secondary outcome measures included clinical treatment failure at day 11.

RESULTS: Persistent symptoms at day 4 were present in 59% of the children in the amoxicillin group and 72% in the placebo group (P=.03) . Between 7 and 8 children aged 6 to 24 months with acute otitis media need to be treated to improve symptoms in 1 child on day 4 (number needed to treat=7.7; 95% confidence interval, 4-100). There was a high rate of treatment failure in both groups after therapy was completed: 64% in the treated group and 70% in the placebo group.

BACKGROUND: Antibiotics are of limited effectiveness in treating acute otitis media in children aged older than 2 years. Antibiotic treatment, however, is widely prescribed in children younger than 2 years because they are thought to be at greater risk for complications. Widespread use of antibiotics is not benign, as side effects are common, and antibiotic resistance is a concern. Moreover, the benefit of antibiotics in children younger than 2 years has not been demonstrated in clinical studies.

POPULATION STUDIED: Children with acute otitis media were included if they were aged between 6 months and 2 years. They were selected from general practices in the Netherlands. Children were excluded if they had taken antibiotics in the preceding 4 weeks; had documented penicillin allergy, compromised immunity, craniofacial abnormalities, or Down syndrome; or had been entered in the study before.

STUDY DESIGN AND VALIDITY: This is a practice-based double-blind randomized controlled trial. Patients received either placebo or amoxicillin 40 mg per kg daily for 10 days. In addition, all patients used decongestant nasal drops and analgesics, as needed. Parents of patients kept a 10-day diary documenting symptoms and medication use. Assessment of response to therapy occurred at 4 and 11 days after the start of therapy, with a home visit after 6 weeks. This is a well-designed randomized controlled trial. To standardize the diagnosis of acute otitis media, participating physicians received special training. The authors did not describe the methods used to prevent researchers from knowing to which group the patient would be assigned (concealed allocation). This lack of concealment could introduce selective enrollment of patients. Follow-up was frequent and nearly complete. One concern: Otitis media resolves within 2 days in 90% of children older than 2 years.¹ The later assessment time used in this study (4 days) may be less clinically relevant and may favor the placebo. The authors of this study focused on short-term outcomes and did not report on the incidence of chronic otitis media, hearing loss, and any unpleasant effects from antibiotics.

OUTCOMES MEASURED: The primary outcome was the presence of symptoms after 4 days of therapy, including earache, fever (>38 °C), crying, irritability, or the prescription of another antibiotic because of worsening symptoms. Secondary outcome measures included clinical treatment failure at day 11.

RESULTS: Persistent symptoms at day 4 were present in 59% of the children in the amoxicillin group and 72% in the placebo group (P=.03) . Between 7 and 8 children aged 6 to 24 months with acute otitis media need to be treated to improve symptoms in 1 child on day 4 (number needed to treat=7.7; 95% confidence interval, 4-100). There was a high rate of treatment failure in both groups after therapy was completed: 64% in the treated group and 70% in the placebo group.

BACKGROUND: Lyme disease is the most common vector-borne illness diagnosed in the United States. Following a period of latent infection, long-term sequelae of untreated disease may involve the neurologic, cardiac, and musculoskeletal systems. Diagnosis is often difficult, as serologic testing is not standardized and patients with early disease may be antibody-negative. Vaccination confuses the issue by converting patients to seropositivity but protecting only 76% against symptomatic Lyme disease.¹ Because it is primarily a clinical diagnosis, there are concerns about inadequate detection and treatment resulting in insidious progression of symptoms. Additionally, concern has been raised regarding possible long-term sequelae of the disease despite accepted treatment.

POPULATION STUDIED: Of the 8764 suspected cases of Lyme disease reported to the Connecticut Department of Public Health between 1984 and 1991, 1325 patients were randomly selected and 678 were included in this study. Of these, 52% were female, 34% were children, and 99% were white. The median age was 36 years. Patients were excluded if they reported that they had never had Lyme disease, did not speak English, or did not reside in Connecticut at the time of diagnosis.

STUDY DESIGN AND VALIDITY: This 2-part study consisted of a prospective longitudinal study and a case-control substudy to determine the frequency of long-term symptoms. In the longitudinal group, the median time from diagnosis was 51 months (range=15-135 months). A random subsample of 212 patients was selected from the longitudinal study. These patients were matched and compared with a person without Lyme disease of similar age and area of residence (control group). Patients and control subjects were interviewed by telephone using a standardized questionnaire to evaluate increased frequency of symptoms and increased difficulty in ability to perform activities. Adults also completed a study of general health and well-being (the Medical Outcomes Study Short Form-36 [SF-36]) and the Center for Epidemiologic Studies-Depression (CES-D) questionnaire. Parents were interviewed if the patient was a child.

OUTCOMES MEASURED: The primary outcome was a change in frequency of specifically identified symptoms and ability to perform certain typical daily activities. Patients were also screened for depression, and their health-related quality of life was evaluated.

RESULTS: Of patients with Lyme disease, 69% reported an increase in symptoms and difficulty with daily activities. Patients who did not meet the case definition for Lyme disease were significantly more likely to report joint or muscle pain (relative risk [RR]= 0.71; 95% CI, 0.57-0.88), numbness (RR=0.65; 95% CI, 0.48-0.88), fatigue (RR=0.66; 95% CI, 0.48-0.89), and headaches (RR=0.67; 95% CI, 0.47-0.96). Symptom reports were similar when patients were stratified by whether they had received antibiotic therapy, with the exception of joint or muscle aches, which were reported less often in the antibiotic-treated patients (RR=0.71; 95% CI, 0.6-0.9). Comparing patients with a diagnosis of Lyme disease with their matched control subjects, only joint or muscle pain (RR=1.4; 95% CI, 1.03-1.89) and difficulty formulating ideas (RR=2.96; 95% CI, 1.36-6.43) were reported more frequently. There were no statistically significant differences in the health and well-being (SF-36) and depression (CES-D) scores among the longitudinal and matched cohorts.

BACKGROUND: Lyme disease is the most common vector-borne illness diagnosed in the United States. Following a period of latent infection, long-term sequelae of untreated disease may involve the neurologic, cardiac, and musculoskeletal systems. Diagnosis is often difficult, as serologic testing is not standardized and patients with early disease may be antibody-negative. Vaccination confuses the issue by converting patients to seropositivity but protecting only 76% against symptomatic Lyme disease.¹ Because it is primarily a clinical diagnosis, there are concerns about inadequate detection and treatment resulting in insidious progression of symptoms. Additionally, concern has been raised regarding possible long-term sequelae of the disease despite accepted treatment.

POPULATION STUDIED: Of the 8764 suspected cases of Lyme disease reported to the Connecticut Department of Public Health between 1984 and 1991, 1325 patients were randomly selected and 678 were included in this study. Of these, 52% were female, 34% were children, and 99% were white. The median age was 36 years. Patients were excluded if they reported that they had never had Lyme disease, did not speak English, or did not reside in Connecticut at the time of diagnosis.

STUDY DESIGN AND VALIDITY: This 2-part study consisted of a prospective longitudinal study and a case-control substudy to determine the frequency of long-term symptoms. In the longitudinal group, the median time from diagnosis was 51 months (range=15-135 months). A random subsample of 212 patients was selected from the longitudinal study. These patients were matched and compared with a person without Lyme disease of similar age and area of residence (control group). Patients and control subjects were interviewed by telephone using a standardized questionnaire to evaluate increased frequency of symptoms and increased difficulty in ability to perform activities. Adults also completed a study of general health and well-being (the Medical Outcomes Study Short Form-36 [SF-36]) and the Center for Epidemiologic Studies-Depression (CES-D) questionnaire. Parents were interviewed if the patient was a child.

OUTCOMES MEASURED: The primary outcome was a change in frequency of specifically identified symptoms and ability to perform certain typical daily activities. Patients were also screened for depression, and their health-related quality of life was evaluated.

RESULTS: Of patients with Lyme disease, 69% reported an increase in symptoms and difficulty with daily activities. Patients who did not meet the case definition for Lyme disease were significantly more likely to report joint or muscle pain (relative risk [RR]= 0.71; 95% CI, 0.57-0.88), numbness (RR=0.65; 95% CI, 0.48-0.88), fatigue (RR=0.66; 95% CI, 0.48-0.89), and headaches (RR=0.67; 95% CI, 0.47-0.96). Symptom reports were similar when patients were stratified by whether they had received antibiotic therapy, with the exception of joint or muscle aches, which were reported less often in the antibiotic-treated patients (RR=0.71; 95% CI, 0.6-0.9). Comparing patients with a diagnosis of Lyme disease with their matched control subjects, only joint or muscle pain (RR=1.4; 95% CI, 1.03-1.89) and difficulty formulating ideas (RR=2.96; 95% CI, 1.36-6.43) were reported more frequently. There were no statistically significant differences in the health and well-being (SF-36) and depression (CES-D) scores among the longitudinal and matched cohorts.

BACKGROUND: Lyme disease is the most common vector-borne illness diagnosed in the United States. Following a period of latent infection, long-term sequelae of untreated disease may involve the neurologic, cardiac, and musculoskeletal systems. Diagnosis is often difficult, as serologic testing is not standardized and patients with early disease may be antibody-negative. Vaccination confuses the issue by converting patients to seropositivity but protecting only 76% against symptomatic Lyme disease.¹ Because it is primarily a clinical diagnosis, there are concerns about inadequate detection and treatment resulting in insidious progression of symptoms. Additionally, concern has been raised regarding possible long-term sequelae of the disease despite accepted treatment.

POPULATION STUDIED: Of the 8764 suspected cases of Lyme disease reported to the Connecticut Department of Public Health between 1984 and 1991, 1325 patients were randomly selected and 678 were included in this study. Of these, 52% were female, 34% were children, and 99% were white. The median age was 36 years. Patients were excluded if they reported that they had never had Lyme disease, did not speak English, or did not reside in Connecticut at the time of diagnosis.

STUDY DESIGN AND VALIDITY: This 2-part study consisted of a prospective longitudinal study and a case-control substudy to determine the frequency of long-term symptoms. In the longitudinal group, the median time from diagnosis was 51 months (range=15-135 months). A random subsample of 212 patients was selected from the longitudinal study. These patients were matched and compared with a person without Lyme disease of similar age and area of residence (control group). Patients and control subjects were interviewed by telephone using a standardized questionnaire to evaluate increased frequency of symptoms and increased difficulty in ability to perform activities. Adults also completed a study of general health and well-being (the Medical Outcomes Study Short Form-36 [SF-36]) and the Center for Epidemiologic Studies-Depression (CES-D) questionnaire. Parents were interviewed if the patient was a child.

OUTCOMES MEASURED: The primary outcome was a change in frequency of specifically identified symptoms and ability to perform certain typical daily activities. Patients were also screened for depression, and their health-related quality of life was evaluated.

RESULTS: Of patients with Lyme disease, 69% reported an increase in symptoms and difficulty with daily activities. Patients who did not meet the case definition for Lyme disease were significantly more likely to report joint or muscle pain (relative risk [RR]= 0.71; 95% CI, 0.57-0.88), numbness (RR=0.65; 95% CI, 0.48-0.88), fatigue (RR=0.66; 95% CI, 0.48-0.89), and headaches (RR=0.67; 95% CI, 0.47-0.96). Symptom reports were similar when patients were stratified by whether they had received antibiotic therapy, with the exception of joint or muscle aches, which were reported less often in the antibiotic-treated patients (RR=0.71; 95% CI, 0.6-0.9). Comparing patients with a diagnosis of Lyme disease with their matched control subjects, only joint or muscle pain (RR=1.4; 95% CI, 1.03-1.89) and difficulty formulating ideas (RR=2.96; 95% CI, 1.36-6.43) were reported more frequently. There were no statistically significant differences in the health and well-being (SF-36) and depression (CES-D) scores among the longitudinal and matched cohorts.

BACKGROUND: Losartan (Cozaar, Hyzaar), a specific angiotensin-II receptor antagonist (ACE-II), is associated with hemodynamic, symptomatic, and neurohormonal improvement in heart failure. In the Evaluation of Losartan in the Elderly (ELITE) study, an unexpected reduction in mortality was observed in patients randomized to losartan compared with captopril. This meta-analysis is an attempt to put this result into perspective with other studies.

POPULATION STUDIED: Most of the patients studied were white men, with a mean age of approximately 60 years. Most had ischemic heart disease and had been given a diagnosis of heart failure within the last 5 years. Their mean left ventricular ejection fractions ranged from 23% to 31% in the studies.

STUDY DESIGN AND VALIDITY: This was a meta-analysis of 8 studies in the Losartan Heart Failure Program. Two of those studies did not meet the criteria for inclusion (one was a pharmacokinetic study; the other was a single-dose study). This left 6 multicenter randomized double-blinded controlled trials for analysis. A total of 1894 patients were enrolled in these 6 studies, of whom 1154 were randomized to receive losartan and 740 to a control (274 to placebo, 96 to enalapril, 370 to captopril). There were no significant differences between groups regarding any demographic or clinical characteristics. Concurrent use of an ACE inhibitor was not permitted.

OUTCOMES MEASURED: The primary outcome was all-cause mortality.

RESULTS: There was a total of 47 deaths (6.35%) in the control groups compared with 36 (3.12%) in the losartan groups during double-blinded therapy (mean follow-up time=25.4 weeks, P=.004). The combined odds ratio of observed mortality was 0.50 (95% confidence interval [CI], 0.32-0.81), indicating a 50% relative reduction in the risk of death for patients with heart failure taking losartan (absolute risk reduction=3.23%, number needed to treat=31). A number of subgroups of studies did not reach significance; that is, the group that switched from ACE to ACE-II (odds ratio [OR]=1.07; 95% CI, 0.23-4.89), the ACE inhibitor controlled studies (OR=0.6; 95% CI, 0.34-1.04), and the group in which patients had previously received an ACE inhibitor (OR=0.76; 95% CI, 0.3-1.96).

BACKGROUND: Losartan (Cozaar, Hyzaar), a specific angiotensin-II receptor antagonist (ACE-II), is associated with hemodynamic, symptomatic, and neurohormonal improvement in heart failure. In the Evaluation of Losartan in the Elderly (ELITE) study, an unexpected reduction in mortality was observed in patients randomized to losartan compared with captopril. This meta-analysis is an attempt to put this result into perspective with other studies.

POPULATION STUDIED: Most of the patients studied were white men, with a mean age of approximately 60 years. Most had ischemic heart disease and had been given a diagnosis of heart failure within the last 5 years. Their mean left ventricular ejection fractions ranged from 23% to 31% in the studies.

STUDY DESIGN AND VALIDITY: This was a meta-analysis of 8 studies in the Losartan Heart Failure Program. Two of those studies did not meet the criteria for inclusion (one was a pharmacokinetic study; the other was a single-dose study). This left 6 multicenter randomized double-blinded controlled trials for analysis. A total of 1894 patients were enrolled in these 6 studies, of whom 1154 were randomized to receive losartan and 740 to a control (274 to placebo, 96 to enalapril, 370 to captopril). There were no significant differences between groups regarding any demographic or clinical characteristics. Concurrent use of an ACE inhibitor was not permitted.

OUTCOMES MEASURED: The primary outcome was all-cause mortality.

RESULTS: There was a total of 47 deaths (6.35%) in the control groups compared with 36 (3.12%) in the losartan groups during double-blinded therapy (mean follow-up time=25.4 weeks, P=.004). The combined odds ratio of observed mortality was 0.50 (95% confidence interval [CI], 0.32-0.81), indicating a 50% relative reduction in the risk of death for patients with heart failure taking losartan (absolute risk reduction=3.23%, number needed to treat=31). A number of subgroups of studies did not reach significance; that is, the group that switched from ACE to ACE-II (odds ratio [OR]=1.07; 95% CI, 0.23-4.89), the ACE inhibitor controlled studies (OR=0.6; 95% CI, 0.34-1.04), and the group in which patients had previously received an ACE inhibitor (OR=0.76; 95% CI, 0.3-1.96).

BACKGROUND: Losartan (Cozaar, Hyzaar), a specific angiotensin-II receptor antagonist (ACE-II), is associated with hemodynamic, symptomatic, and neurohormonal improvement in heart failure. In the Evaluation of Losartan in the Elderly (ELITE) study, an unexpected reduction in mortality was observed in patients randomized to losartan compared with captopril. This meta-analysis is an attempt to put this result into perspective with other studies.

POPULATION STUDIED: Most of the patients studied were white men, with a mean age of approximately 60 years. Most had ischemic heart disease and had been given a diagnosis of heart failure within the last 5 years. Their mean left ventricular ejection fractions ranged from 23% to 31% in the studies.

STUDY DESIGN AND VALIDITY: This was a meta-analysis of 8 studies in the Losartan Heart Failure Program. Two of those studies did not meet the criteria for inclusion (one was a pharmacokinetic study; the other was a single-dose study). This left 6 multicenter randomized double-blinded controlled trials for analysis. A total of 1894 patients were enrolled in these 6 studies, of whom 1154 were randomized to receive losartan and 740 to a control (274 to placebo, 96 to enalapril, 370 to captopril). There were no significant differences between groups regarding any demographic or clinical characteristics. Concurrent use of an ACE inhibitor was not permitted.

OUTCOMES MEASURED: The primary outcome was all-cause mortality.

RESULTS: There was a total of 47 deaths (6.35%) in the control groups compared with 36 (3.12%) in the losartan groups during double-blinded therapy (mean follow-up time=25.4 weeks, P=.004). The combined odds ratio of observed mortality was 0.50 (95% confidence interval [CI], 0.32-0.81), indicating a 50% relative reduction in the risk of death for patients with heart failure taking losartan (absolute risk reduction=3.23%, number needed to treat=31). A number of subgroups of studies did not reach significance; that is, the group that switched from ACE to ACE-II (odds ratio [OR]=1.07; 95% CI, 0.23-4.89), the ACE inhibitor controlled studies (OR=0.6; 95% CI, 0.34-1.04), and the group in which patients had previously received an ACE inhibitor (OR=0.76; 95% CI, 0.3-1.96).

BACKGROUND: Functional gastrointestinal disorders, such as irritable bowel syndrome and nonulcer dyspepsia, are difficult for primary care physicians to treat. These conditions result in frequent referrals and are frustrating for both patients and physicians. Because of their usefulness for other painful chronic conditions, antidepressants have been suggested as a therapeutic alternative.

POPULATION STUDIED: This meta-analysis included 12 studies of the use of antidepressant medications for the treatment of functional gastrointestinal disorders. Most only included adults, with a range of mean ages of 33 to 48 years.

STUDY DESIGN AND VALIDITY: The authors obtained articles through a MEDLINE, PsycLIT, and EMBASE search covering 1966 through 1998. They also searched the Cochrane Controlled Trials Register and Federal Research in Progress to identify unpublished research. Of 90 articles, 12 met their inclusion criteria. The quality of each study was formally evaluated using a standard instrument. In a meta-analysis, the validity of the study depends on the validity of the individual studies, as well as the authors’ ability to group the data in a reasonable fashion. Because each study was listed in a table, we are able to assess quality independent of the meta-analysis.

OUTCOMES MEASURED: The primary outcome was a subjective decrease in gastrointestinal symptoms.

RESULTS: Most of the studies were of low quality. Only 2 studies had a quality rating of 7 (out of 8), and most were in the 2 to 4 range. The authors acknowledge the difficulty of blinding patients in these studies because of the noticeable side effects of most of the drugs tested. In addition, the size of the individual studies was small (only 1 included more than 100 patients), and the duration of follow-up was usually only 4 to 8 weeks. However, the findings were consistent. All studies demonstrated an improvement in both abdominal pain scores and the likelihood of overall improvement in gastrointestinal symptoms among patients treated with antidepressants when compared with placebo. The authors estimate that 3 patients have to be treated for 1 to benefit, which would compare favorably with other widely used interventions for this and other problems. Improvements were seen with both tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs).

BACKGROUND: Functional gastrointestinal disorders, such as irritable bowel syndrome and nonulcer dyspepsia, are difficult for primary care physicians to treat. These conditions result in frequent referrals and are frustrating for both patients and physicians. Because of their usefulness for other painful chronic conditions, antidepressants have been suggested as a therapeutic alternative.

POPULATION STUDIED: This meta-analysis included 12 studies of the use of antidepressant medications for the treatment of functional gastrointestinal disorders. Most only included adults, with a range of mean ages of 33 to 48 years.

STUDY DESIGN AND VALIDITY: The authors obtained articles through a MEDLINE, PsycLIT, and EMBASE search covering 1966 through 1998. They also searched the Cochrane Controlled Trials Register and Federal Research in Progress to identify unpublished research. Of 90 articles, 12 met their inclusion criteria. The quality of each study was formally evaluated using a standard instrument. In a meta-analysis, the validity of the study depends on the validity of the individual studies, as well as the authors’ ability to group the data in a reasonable fashion. Because each study was listed in a table, we are able to assess quality independent of the meta-analysis.

OUTCOMES MEASURED: The primary outcome was a subjective decrease in gastrointestinal symptoms.

RESULTS: Most of the studies were of low quality. Only 2 studies had a quality rating of 7 (out of 8), and most were in the 2 to 4 range. The authors acknowledge the difficulty of blinding patients in these studies because of the noticeable side effects of most of the drugs tested. In addition, the size of the individual studies was small (only 1 included more than 100 patients), and the duration of follow-up was usually only 4 to 8 weeks. However, the findings were consistent. All studies demonstrated an improvement in both abdominal pain scores and the likelihood of overall improvement in gastrointestinal symptoms among patients treated with antidepressants when compared with placebo. The authors estimate that 3 patients have to be treated for 1 to benefit, which would compare favorably with other widely used interventions for this and other problems. Improvements were seen with both tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs).

BACKGROUND: Functional gastrointestinal disorders, such as irritable bowel syndrome and nonulcer dyspepsia, are difficult for primary care physicians to treat. These conditions result in frequent referrals and are frustrating for both patients and physicians. Because of their usefulness for other painful chronic conditions, antidepressants have been suggested as a therapeutic alternative.

POPULATION STUDIED: This meta-analysis included 12 studies of the use of antidepressant medications for the treatment of functional gastrointestinal disorders. Most only included adults, with a range of mean ages of 33 to 48 years.

STUDY DESIGN AND VALIDITY: The authors obtained articles through a MEDLINE, PsycLIT, and EMBASE search covering 1966 through 1998. They also searched the Cochrane Controlled Trials Register and Federal Research in Progress to identify unpublished research. Of 90 articles, 12 met their inclusion criteria. The quality of each study was formally evaluated using a standard instrument. In a meta-analysis, the validity of the study depends on the validity of the individual studies, as well as the authors’ ability to group the data in a reasonable fashion. Because each study was listed in a table, we are able to assess quality independent of the meta-analysis.

OUTCOMES MEASURED: The primary outcome was a subjective decrease in gastrointestinal symptoms.

RESULTS: Most of the studies were of low quality. Only 2 studies had a quality rating of 7 (out of 8), and most were in the 2 to 4 range. The authors acknowledge the difficulty of blinding patients in these studies because of the noticeable side effects of most of the drugs tested. In addition, the size of the individual studies was small (only 1 included more than 100 patients), and the duration of follow-up was usually only 4 to 8 weeks. However, the findings were consistent. All studies demonstrated an improvement in both abdominal pain scores and the likelihood of overall improvement in gastrointestinal symptoms among patients treated with antidepressants when compared with placebo. The authors estimate that 3 patients have to be treated for 1 to benefit, which would compare favorably with other widely used interventions for this and other problems. Improvements were seen with both tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs).

BACKGROUND: Strong evidence supports the efficacy of laser treatment for diabetic retinopathy; however, compliance with screening has been disappointing, and the optimum frequency of screening remains controversial. This cost-utility analysis compares cost, duration of blindness, and quality-adjusted life years (QALYs) for several intervals of screening.

POPULATION STUDIED: A hypothetical cohort of people 40 years and older with diabetes was modeled on the Third National Health and Nutrition Examination Survey. Estimates for retinopathy development and progression were taken from the United Kingdom Prospective Diabetes Study. Thus, the study population is probably similar to that seen by the typical family physician, though caution should be exercised in generalizing results to practices with higher proportions of Hispanics, African Americans, or other ethnic populations for whom the prevalence and rate of progression of retinopathy may be different from the reference populations.

STUDY DESIGN AND VALIDITY: This cost-utility study used a Markhov model to compare the impact of annual versus less frequent screening on the progression of diabetic retinopathy and macular edema. The perspective was that of a payer; costs included an ophthalmology visit, laser photocoagulation, and fluorescein angiogram. Age and hemoglobin (Hb) A1C levels were used to define patient groups at high, medium, and low risk. Predictions for life expectancy were adjusted for time spent blind on the basis of a utility of 0.69. A 3% discount was applied to all costs and years of life. The methodology of this study was strong. The authors defined alternatives explicitly and calculated incremental analysis of cost. Their model addressed accuracy of diagnosis, and they performed thorough univariate and multivariate sensitivity analyses. Weaknesses included the lacks of evidence for effectiveness of population screening for diabetic retinopathy, attention to the rate of poor follow-up, and recognition of the impact of visual impairment without blindness.

OUTCOMES MEASURED: The primary outcomes measured were costs, days of blindness, and QALYs. Costs directly due to blindness, the impact of labeling, and patient satisfaction were not addressed.

RESULTS: The effectiveness of screening is dramatically greater for patients at a higher risk of retinopathy; increasing screening frequency modestly decreases time spent blind. For example, for a low-risk patient (eg, 75 years old with a Hb A1C of 7%) screening every third year prevents 1 day of blindness during the patient’s lifetime, and annual screening prevents an additional 2 days of blindness (compared with no screening). For a high-risk patient (eg, 45 years old with a Hb A1C of 11%), screening every third year prevents 188 days of blindness, and annual screening saves an additional 21 days of blindness. Within any given risk group, the cost of screening increases dramatically with increasing frequency. For example, even for the high-risk patient for whom screening is most cost-effective, the marginal cost-effectiveness of increasing screening from every other year to every year was $181,850 per QALY gained. Extrapolating the results to the whole population and using $50,000 per QALY as a criterion of cost-effectiveness, screening every second year is cost-effective ($49,760/QALY), while annual screening is not ($107,510/QALY). Sensitivity analysis did not change the results substantially, except that lowering the utility score for blindness increased the cost-effectiveness of all screening.

BACKGROUND: Strong evidence supports the efficacy of laser treatment for diabetic retinopathy; however, compliance with screening has been disappointing, and the optimum frequency of screening remains controversial. This cost-utility analysis compares cost, duration of blindness, and quality-adjusted life years (QALYs) for several intervals of screening.

POPULATION STUDIED: A hypothetical cohort of people 40 years and older with diabetes was modeled on the Third National Health and Nutrition Examination Survey. Estimates for retinopathy development and progression were taken from the United Kingdom Prospective Diabetes Study. Thus, the study population is probably similar to that seen by the typical family physician, though caution should be exercised in generalizing results to practices with higher proportions of Hispanics, African Americans, or other ethnic populations for whom the prevalence and rate of progression of retinopathy may be different from the reference populations.

STUDY DESIGN AND VALIDITY: This cost-utility study used a Markhov model to compare the impact of annual versus less frequent screening on the progression of diabetic retinopathy and macular edema. The perspective was that of a payer; costs included an ophthalmology visit, laser photocoagulation, and fluorescein angiogram. Age and hemoglobin (Hb) A1C levels were used to define patient groups at high, medium, and low risk. Predictions for life expectancy were adjusted for time spent blind on the basis of a utility of 0.69. A 3% discount was applied to all costs and years of life. The methodology of this study was strong. The authors defined alternatives explicitly and calculated incremental analysis of cost. Their model addressed accuracy of diagnosis, and they performed thorough univariate and multivariate sensitivity analyses. Weaknesses included the lacks of evidence for effectiveness of population screening for diabetic retinopathy, attention to the rate of poor follow-up, and recognition of the impact of visual impairment without blindness.

OUTCOMES MEASURED: The primary outcomes measured were costs, days of blindness, and QALYs. Costs directly due to blindness, the impact of labeling, and patient satisfaction were not addressed.

RESULTS: The effectiveness of screening is dramatically greater for patients at a higher risk of retinopathy; increasing screening frequency modestly decreases time spent blind. For example, for a low-risk patient (eg, 75 years old with a Hb A1C of 7%) screening every third year prevents 1 day of blindness during the patient’s lifetime, and annual screening prevents an additional 2 days of blindness (compared with no screening). For a high-risk patient (eg, 45 years old with a Hb A1C of 11%), screening every third year prevents 188 days of blindness, and annual screening saves an additional 21 days of blindness. Within any given risk group, the cost of screening increases dramatically with increasing frequency. For example, even for the high-risk patient for whom screening is most cost-effective, the marginal cost-effectiveness of increasing screening from every other year to every year was $181,850 per QALY gained. Extrapolating the results to the whole population and using $50,000 per QALY as a criterion of cost-effectiveness, screening every second year is cost-effective ($49,760/QALY), while annual screening is not ($107,510/QALY). Sensitivity analysis did not change the results substantially, except that lowering the utility score for blindness increased the cost-effectiveness of all screening.

BACKGROUND: Strong evidence supports the efficacy of laser treatment for diabetic retinopathy; however, compliance with screening has been disappointing, and the optimum frequency of screening remains controversial. This cost-utility analysis compares cost, duration of blindness, and quality-adjusted life years (QALYs) for several intervals of screening.

POPULATION STUDIED: A hypothetical cohort of people 40 years and older with diabetes was modeled on the Third National Health and Nutrition Examination Survey. Estimates for retinopathy development and progression were taken from the United Kingdom Prospective Diabetes Study. Thus, the study population is probably similar to that seen by the typical family physician, though caution should be exercised in generalizing results to practices with higher proportions of Hispanics, African Americans, or other ethnic populations for whom the prevalence and rate of progression of retinopathy may be different from the reference populations.

STUDY DESIGN AND VALIDITY: This cost-utility study used a Markhov model to compare the impact of annual versus less frequent screening on the progression of diabetic retinopathy and macular edema. The perspective was that of a payer; costs included an ophthalmology visit, laser photocoagulation, and fluorescein angiogram. Age and hemoglobin (Hb) A1C levels were used to define patient groups at high, medium, and low risk. Predictions for life expectancy were adjusted for time spent blind on the basis of a utility of 0.69. A 3% discount was applied to all costs and years of life. The methodology of this study was strong. The authors defined alternatives explicitly and calculated incremental analysis of cost. Their model addressed accuracy of diagnosis, and they performed thorough univariate and multivariate sensitivity analyses. Weaknesses included the lacks of evidence for effectiveness of population screening for diabetic retinopathy, attention to the rate of poor follow-up, and recognition of the impact of visual impairment without blindness.

OUTCOMES MEASURED: The primary outcomes measured were costs, days of blindness, and QALYs. Costs directly due to blindness, the impact of labeling, and patient satisfaction were not addressed.

RESULTS: The effectiveness of screening is dramatically greater for patients at a higher risk of retinopathy; increasing screening frequency modestly decreases time spent blind. For example, for a low-risk patient (eg, 75 years old with a Hb A1C of 7%) screening every third year prevents 1 day of blindness during the patient’s lifetime, and annual screening prevents an additional 2 days of blindness (compared with no screening). For a high-risk patient (eg, 45 years old with a Hb A1C of 11%), screening every third year prevents 188 days of blindness, and annual screening saves an additional 21 days of blindness. Within any given risk group, the cost of screening increases dramatically with increasing frequency. For example, even for the high-risk patient for whom screening is most cost-effective, the marginal cost-effectiveness of increasing screening from every other year to every year was $181,850 per QALY gained. Extrapolating the results to the whole population and using $50,000 per QALY as a criterion of cost-effectiveness, screening every second year is cost-effective ($49,760/QALY), while annual screening is not ($107,510/QALY). Sensitivity analysis did not change the results substantially, except that lowering the utility score for blindness increased the cost-effectiveness of all screening.

CLINICAL QUESTION: Does therapy with an angiotensin-converting-enzyme (ACE) inhibitor reduce the rate of cardiovascular events in high-risk patients with no known left ventricular (LV) dysfunction or heart failure?

BACKGROUND: The renin-angiotensin-aldosterone system is an important contributor to the pathogenesis of cardiovascular disease. ACE inhibitors improve outcomes in patients with LV dysfunction (with or without heart failure). This study assessed whether therapy with an ACE inhibitor, ramipril, reduced the rate of cardiovascular events in high-risk patients with no known LV dysfunction or heart failure.

POPULATION STUDIED: From December 1993 through June 1995, the Heart Outcomes Prevention Evaluation (HOPE) investigators recruited patients from 277 centers in Canada, the United States, Argentina, Brazil, Mexico, and 14 western European countries. The final study population included 9297 patients at high risk for a cardiovascular event. All patients were aged 55 years or older and had either evidence of vascular disease or diabetes mellitus plus one other cardiovascular risk factor. Exclusion criteria included known history of heart failure or low LV ejection fraction (<40%), use of an ACE inhibitor or vitamin E, uncontrolled hypertension, overt nephropathy, and myocardial infarction or stroke in the 4 weeks before the study began.

STUDY DESIGN AND VALIDITY: The study was part of a double-blinded 2-by-2 factorial randomized trial evaluating both ramipril and vitamin E. This paper reports the placebo-controlled study of ramipril 10 mg per day compared with placebo. Allocation of patients to ramipril or placebo was adequately concealed. Treatments were compared using the log-rank test, and subgroup analyses were conducted using tests for interactions in the Cox regression model. Treatment was scheduled to last 5 years, but an independent monitoring board recommended termination of the study after 4 years because of clear evidence of a beneficial effect of ramipril.

OUTCOMES MEASURED: The primary study outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Secondary outcomes were death from any cause, the need for revascularization, hospitalization for unstable angina or heart failure, diabetes-related complications, and each of the primary outcomes reported individually.

RESULTS: Compared with controls, treatment with ramipril reduced the combined rate of myocardial infarction, stroke, or death from cardiovascular causes (relative risk reduction [RRR]=21%, absolute risk reduction [ARR]=3.8%, number needed to treat [NNT]=27). It also reduced the rates of the secondary outcomes, including death from any cause (RRR=15%, ARR=1.9%, NNT=54), revascularization procedures (RRR=13%, ARR=2.3%, NNT=43), cardiac arrest (RRR=38%, ARR=0.5%, NNT=200), heart failure (RRR=22%, ARR=2.5%, NNT=40), and complications related to diabetes (RRR=16%, ARR=1.2%, NNT=83). All these reductions in risk were statistically significant. Reduction in blood pressure was not felt to be a major factor in the improved outcomes; the majority of patients did not have underlying hypertension and the treatment group’s mean reduction in blood pressure was minimal (3/2 mm Hg).

CLINICAL QUESTION: Does therapy with an angiotensin-converting-enzyme (ACE) inhibitor reduce the rate of cardiovascular events in high-risk patients with no known left ventricular (LV) dysfunction or heart failure?

BACKGROUND: The renin-angiotensin-aldosterone system is an important contributor to the pathogenesis of cardiovascular disease. ACE inhibitors improve outcomes in patients with LV dysfunction (with or without heart failure). This study assessed whether therapy with an ACE inhibitor, ramipril, reduced the rate of cardiovascular events in high-risk patients with no known LV dysfunction or heart failure.

POPULATION STUDIED: From December 1993 through June 1995, the Heart Outcomes Prevention Evaluation (HOPE) investigators recruited patients from 277 centers in Canada, the United States, Argentina, Brazil, Mexico, and 14 western European countries. The final study population included 9297 patients at high risk for a cardiovascular event. All patients were aged 55 years or older and had either evidence of vascular disease or diabetes mellitus plus one other cardiovascular risk factor. Exclusion criteria included known history of heart failure or low LV ejection fraction (<40%), use of an ACE inhibitor or vitamin E, uncontrolled hypertension, overt nephropathy, and myocardial infarction or stroke in the 4 weeks before the study began.

STUDY DESIGN AND VALIDITY: The study was part of a double-blinded 2-by-2 factorial randomized trial evaluating both ramipril and vitamin E. This paper reports the placebo-controlled study of ramipril 10 mg per day compared with placebo. Allocation of patients to ramipril or placebo was adequately concealed. Treatments were compared using the log-rank test, and subgroup analyses were conducted using tests for interactions in the Cox regression model. Treatment was scheduled to last 5 years, but an independent monitoring board recommended termination of the study after 4 years because of clear evidence of a beneficial effect of ramipril.

OUTCOMES MEASURED: The primary study outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Secondary outcomes were death from any cause, the need for revascularization, hospitalization for unstable angina or heart failure, diabetes-related complications, and each of the primary outcomes reported individually.

RESULTS: Compared with controls, treatment with ramipril reduced the combined rate of myocardial infarction, stroke, or death from cardiovascular causes (relative risk reduction [RRR]=21%, absolute risk reduction [ARR]=3.8%, number needed to treat [NNT]=27). It also reduced the rates of the secondary outcomes, including death from any cause (RRR=15%, ARR=1.9%, NNT=54), revascularization procedures (RRR=13%, ARR=2.3%, NNT=43), cardiac arrest (RRR=38%, ARR=0.5%, NNT=200), heart failure (RRR=22%, ARR=2.5%, NNT=40), and complications related to diabetes (RRR=16%, ARR=1.2%, NNT=83). All these reductions in risk were statistically significant. Reduction in blood pressure was not felt to be a major factor in the improved outcomes; the majority of patients did not have underlying hypertension and the treatment group’s mean reduction in blood pressure was minimal (3/2 mm Hg).

CLINICAL QUESTION: Does therapy with an angiotensin-converting-enzyme (ACE) inhibitor reduce the rate of cardiovascular events in high-risk patients with no known left ventricular (LV) dysfunction or heart failure?

BACKGROUND: The renin-angiotensin-aldosterone system is an important contributor to the pathogenesis of cardiovascular disease. ACE inhibitors improve outcomes in patients with LV dysfunction (with or without heart failure). This study assessed whether therapy with an ACE inhibitor, ramipril, reduced the rate of cardiovascular events in high-risk patients with no known LV dysfunction or heart failure.

POPULATION STUDIED: From December 1993 through June 1995, the Heart Outcomes Prevention Evaluation (HOPE) investigators recruited patients from 277 centers in Canada, the United States, Argentina, Brazil, Mexico, and 14 western European countries. The final study population included 9297 patients at high risk for a cardiovascular event. All patients were aged 55 years or older and had either evidence of vascular disease or diabetes mellitus plus one other cardiovascular risk factor. Exclusion criteria included known history of heart failure or low LV ejection fraction (<40%), use of an ACE inhibitor or vitamin E, uncontrolled hypertension, overt nephropathy, and myocardial infarction or stroke in the 4 weeks before the study began.

STUDY DESIGN AND VALIDITY: The study was part of a double-blinded 2-by-2 factorial randomized trial evaluating both ramipril and vitamin E. This paper reports the placebo-controlled study of ramipril 10 mg per day compared with placebo. Allocation of patients to ramipril or placebo was adequately concealed. Treatments were compared using the log-rank test, and subgroup analyses were conducted using tests for interactions in the Cox regression model. Treatment was scheduled to last 5 years, but an independent monitoring board recommended termination of the study after 4 years because of clear evidence of a beneficial effect of ramipril.

OUTCOMES MEASURED: The primary study outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Secondary outcomes were death from any cause, the need for revascularization, hospitalization for unstable angina or heart failure, diabetes-related complications, and each of the primary outcomes reported individually.

RESULTS: Compared with controls, treatment with ramipril reduced the combined rate of myocardial infarction, stroke, or death from cardiovascular causes (relative risk reduction [RRR]=21%, absolute risk reduction [ARR]=3.8%, number needed to treat [NNT]=27). It also reduced the rates of the secondary outcomes, including death from any cause (RRR=15%, ARR=1.9%, NNT=54), revascularization procedures (RRR=13%, ARR=2.3%, NNT=43), cardiac arrest (RRR=38%, ARR=0.5%, NNT=200), heart failure (RRR=22%, ARR=2.5%, NNT=40), and complications related to diabetes (RRR=16%, ARR=1.2%, NNT=83). All these reductions in risk were statistically significant. Reduction in blood pressure was not felt to be a major factor in the improved outcomes; the majority of patients did not have underlying hypertension and the treatment group’s mean reduction in blood pressure was minimal (3/2 mm Hg).