Gary Kelsberg, MD

Evidence summary

Thrombotic complications are common in lowerlimb fractures. In 1968, a prospective observational study evaluated the natural history of DVT and pulmonary embolism (PE) in tibial fractures treated with open reduction and internal fixation with early mobilization. Seventy-six consecutive patients with 79 tibial fractures were evaluated with venograms, most within 1 month of injury. The overall incidence of thrombosis was 45%. Half were minor, involving 1 to 3 of the paired deep venous trunks of the lower leg without clinical signs of embolism. Twelve patients (16%) had extensive thrombosis, involving 4 to 6 of the deep venous trunks. Three of these had nonfatal PE diagnosed clinically, and 1 had a fatal PE confirmed at autopsy. The mean age of those with extensive thrombosis or PE was 54 years, and these events were uncommon below age 25 years.¹

Incidence of DVT and PE was also evaluated in a cohort of 102 unselected patients who underwent operative fixation for lower-limb fractures, excluding patella, ankle, and foot fractures. All underwent venography approximately 9 days after fixation and were followed clinically for 6 weeks. The overall incidence of DVT was 28% (40% with femoral shaft, 43% with tibial plateau, 22% with tibial shaft, and 12% with tibial plafond [distal articular tibia]). Four developed clinical evidence of PE during hospitalization but only 1 had objective confirmation. None of the patients showed clinical evidence of PE as outpatients.²

LMWH prophylaxis significantly reduced thrombosis in patients with lower-limb fractures in 3 out of 4 RCTs. The first RCT evaluated 253 patients with lower-limb fractures immobilized in plaster casts after surgical fixation. Half the patients received subcutaneous LMWH (nadroparin [Fraxiparin], a European LMWH similar to enoxaparin), and half received no thrombosis prophylaxis. Based on compression ultrasound at the time of cast removal (17 days postinjury, on average), the overall DVT incidence was 11%. Six patients (5%) receiving LMWH had DVTs vs 21 (17%) in the control group (number needed to treat [NNT]=8 to prevent 1 DVT detectible by compression ultrasound). Two thirds of patients with DVT were asymptomatic. One third had clinical signs of DVT, including 1 patient diagnosed with PE on clinical grounds. There was no difference in bleeding complications between the treatment groups.³

A second RCT evaluated LMWH (Mono-Embolex, a European LMWH) prophylaxis in 328 outpatients with lower limb injuries, which included fractures, severe contusions, and ligamentous injuries. All were treated nonsurgically with cast immobilization (mean=18.8 days, range=2–72 days) and 176 patients used daily LMWH injections. All underwent Doppler evaluation for leg thromboses after cast removal, and positive results were confirmed with venograms. Overall, there were no DVTs among the LMWH prophylaxis group and 7 DVTs (4.3%) in the group without LMWH prophylaxis (P<.006). Among those with fractures, the untreated DVT rate was 5.9% (vs 0% with LMWH prophylaxis). Those over age 40 who did not use LMWH had a DVT rate of 11.4% (vs 1.7% in younger patients). Without LMWH prophylaxis, casting for more than 10 days approximately doubled the risk of DVT compared with less than 10 days (6.1% vs 3.1%). This study did not report on the anatomic location of DVTs or if they were clinically evident.⁴

The third RCT evaluated reviparin (another European LMWH) vs placebo in 440 outpatients with lower limb injuries, of whom 293 had fractures. About half had surgical management and all were treated with a plaster cast or brace for an average of 44 days. Most were ambulatory with crutches. All underwent venography within a week of cast removal. The DVT rate for fracture patients using reviparin was 10.4%, vs 18.2% among those without LMWH prophylaxis (absolute risk reduction=7.8%; NNT=12.8). Three fourths of the DVTs were in distal veins, and 21% of the DVTs in the LMWH patients occurred in deep veins compared with 34% in patients without. Two pulmonary emboli occurred, both in patients without LMWH prophylaxis.⁵

The final RCT evaluated tinzaparin (yet another European LMWH) in 300 adult outpatients immobilized in plaster for at least 3 weeks. Most patients (205 out of 300) underwent venography, and the overall DVT rate was 10% (tinzaparin) vs 17% (controls). Among the 150 fracture patients who underwent venography, the DVT rate was 11% (tinzaparin) vs 13% (controls). This difference was not significant, probably due to insufficient numbers. None of the DVTs was clinically detectable.⁶

In hip fracture and hip arthroplasty, warfarin and LMWH are both effective in preventing thrombosis. No studies have specifically evaluated warfarin prophylaxis in lower extremity fractures or compared it with LMWH.

Recommendations from others

The American College of Chest Physicians (ACCP) says that LMWH prophylaxis reduces the risk of asymptomatic DVTs and is standard of care in Europe. The ACCP does not recommend thromboprophylaxis for isolated lower extremity fractures in the US because of cost and insufficient evidence of clinically important reduction in venous thromboembolism (VTE). However, ACCP lists unspecified “lower extremity or pelvic fracture” as a risk factor for VTE, and does recommend that trauma patients with at least 1 risk factor for VTE receive thromboprophylaxis. They make no recommendation about the use of warfarin.⁷

Evidence summary

Thrombotic complications are common in lowerlimb fractures. In 1968, a prospective observational study evaluated the natural history of DVT and pulmonary embolism (PE) in tibial fractures treated with open reduction and internal fixation with early mobilization. Seventy-six consecutive patients with 79 tibial fractures were evaluated with venograms, most within 1 month of injury. The overall incidence of thrombosis was 45%. Half were minor, involving 1 to 3 of the paired deep venous trunks of the lower leg without clinical signs of embolism. Twelve patients (16%) had extensive thrombosis, involving 4 to 6 of the deep venous trunks. Three of these had nonfatal PE diagnosed clinically, and 1 had a fatal PE confirmed at autopsy. The mean age of those with extensive thrombosis or PE was 54 years, and these events were uncommon below age 25 years.¹

Incidence of DVT and PE was also evaluated in a cohort of 102 unselected patients who underwent operative fixation for lower-limb fractures, excluding patella, ankle, and foot fractures. All underwent venography approximately 9 days after fixation and were followed clinically for 6 weeks. The overall incidence of DVT was 28% (40% with femoral shaft, 43% with tibial plateau, 22% with tibial shaft, and 12% with tibial plafond [distal articular tibia]). Four developed clinical evidence of PE during hospitalization but only 1 had objective confirmation. None of the patients showed clinical evidence of PE as outpatients.²

LMWH prophylaxis significantly reduced thrombosis in patients with lower-limb fractures in 3 out of 4 RCTs. The first RCT evaluated 253 patients with lower-limb fractures immobilized in plaster casts after surgical fixation. Half the patients received subcutaneous LMWH (nadroparin [Fraxiparin], a European LMWH similar to enoxaparin), and half received no thrombosis prophylaxis. Based on compression ultrasound at the time of cast removal (17 days postinjury, on average), the overall DVT incidence was 11%. Six patients (5%) receiving LMWH had DVTs vs 21 (17%) in the control group (number needed to treat [NNT]=8 to prevent 1 DVT detectible by compression ultrasound). Two thirds of patients with DVT were asymptomatic. One third had clinical signs of DVT, including 1 patient diagnosed with PE on clinical grounds. There was no difference in bleeding complications between the treatment groups.³

A second RCT evaluated LMWH (Mono-Embolex, a European LMWH) prophylaxis in 328 outpatients with lower limb injuries, which included fractures, severe contusions, and ligamentous injuries. All were treated nonsurgically with cast immobilization (mean=18.8 days, range=2–72 days) and 176 patients used daily LMWH injections. All underwent Doppler evaluation for leg thromboses after cast removal, and positive results were confirmed with venograms. Overall, there were no DVTs among the LMWH prophylaxis group and 7 DVTs (4.3%) in the group without LMWH prophylaxis (P<.006). Among those with fractures, the untreated DVT rate was 5.9% (vs 0% with LMWH prophylaxis). Those over age 40 who did not use LMWH had a DVT rate of 11.4% (vs 1.7% in younger patients). Without LMWH prophylaxis, casting for more than 10 days approximately doubled the risk of DVT compared with less than 10 days (6.1% vs 3.1%). This study did not report on the anatomic location of DVTs or if they were clinically evident.⁴

The third RCT evaluated reviparin (another European LMWH) vs placebo in 440 outpatients with lower limb injuries, of whom 293 had fractures. About half had surgical management and all were treated with a plaster cast or brace for an average of 44 days. Most were ambulatory with crutches. All underwent venography within a week of cast removal. The DVT rate for fracture patients using reviparin was 10.4%, vs 18.2% among those without LMWH prophylaxis (absolute risk reduction=7.8%; NNT=12.8). Three fourths of the DVTs were in distal veins, and 21% of the DVTs in the LMWH patients occurred in deep veins compared with 34% in patients without. Two pulmonary emboli occurred, both in patients without LMWH prophylaxis.⁵

The final RCT evaluated tinzaparin (yet another European LMWH) in 300 adult outpatients immobilized in plaster for at least 3 weeks. Most patients (205 out of 300) underwent venography, and the overall DVT rate was 10% (tinzaparin) vs 17% (controls). Among the 150 fracture patients who underwent venography, the DVT rate was 11% (tinzaparin) vs 13% (controls). This difference was not significant, probably due to insufficient numbers. None of the DVTs was clinically detectable.⁶

In hip fracture and hip arthroplasty, warfarin and LMWH are both effective in preventing thrombosis. No studies have specifically evaluated warfarin prophylaxis in lower extremity fractures or compared it with LMWH.

Recommendations from others

The American College of Chest Physicians (ACCP) says that LMWH prophylaxis reduces the risk of asymptomatic DVTs and is standard of care in Europe. The ACCP does not recommend thromboprophylaxis for isolated lower extremity fractures in the US because of cost and insufficient evidence of clinically important reduction in venous thromboembolism (VTE). However, ACCP lists unspecified “lower extremity or pelvic fracture” as a risk factor for VTE, and does recommend that trauma patients with at least 1 risk factor for VTE receive thromboprophylaxis. They make no recommendation about the use of warfarin.⁷

Evidence summary

Thrombotic complications are common in lowerlimb fractures. In 1968, a prospective observational study evaluated the natural history of DVT and pulmonary embolism (PE) in tibial fractures treated with open reduction and internal fixation with early mobilization. Seventy-six consecutive patients with 79 tibial fractures were evaluated with venograms, most within 1 month of injury. The overall incidence of thrombosis was 45%. Half were minor, involving 1 to 3 of the paired deep venous trunks of the lower leg without clinical signs of embolism. Twelve patients (16%) had extensive thrombosis, involving 4 to 6 of the deep venous trunks. Three of these had nonfatal PE diagnosed clinically, and 1 had a fatal PE confirmed at autopsy. The mean age of those with extensive thrombosis or PE was 54 years, and these events were uncommon below age 25 years.¹

Incidence of DVT and PE was also evaluated in a cohort of 102 unselected patients who underwent operative fixation for lower-limb fractures, excluding patella, ankle, and foot fractures. All underwent venography approximately 9 days after fixation and were followed clinically for 6 weeks. The overall incidence of DVT was 28% (40% with femoral shaft, 43% with tibial plateau, 22% with tibial shaft, and 12% with tibial plafond [distal articular tibia]). Four developed clinical evidence of PE during hospitalization but only 1 had objective confirmation. None of the patients showed clinical evidence of PE as outpatients.²

LMWH prophylaxis significantly reduced thrombosis in patients with lower-limb fractures in 3 out of 4 RCTs. The first RCT evaluated 253 patients with lower-limb fractures immobilized in plaster casts after surgical fixation. Half the patients received subcutaneous LMWH (nadroparin [Fraxiparin], a European LMWH similar to enoxaparin), and half received no thrombosis prophylaxis. Based on compression ultrasound at the time of cast removal (17 days postinjury, on average), the overall DVT incidence was 11%. Six patients (5%) receiving LMWH had DVTs vs 21 (17%) in the control group (number needed to treat [NNT]=8 to prevent 1 DVT detectible by compression ultrasound). Two thirds of patients with DVT were asymptomatic. One third had clinical signs of DVT, including 1 patient diagnosed with PE on clinical grounds. There was no difference in bleeding complications between the treatment groups.³

A second RCT evaluated LMWH (Mono-Embolex, a European LMWH) prophylaxis in 328 outpatients with lower limb injuries, which included fractures, severe contusions, and ligamentous injuries. All were treated nonsurgically with cast immobilization (mean=18.8 days, range=2–72 days) and 176 patients used daily LMWH injections. All underwent Doppler evaluation for leg thromboses after cast removal, and positive results were confirmed with venograms. Overall, there were no DVTs among the LMWH prophylaxis group and 7 DVTs (4.3%) in the group without LMWH prophylaxis (P<.006). Among those with fractures, the untreated DVT rate was 5.9% (vs 0% with LMWH prophylaxis). Those over age 40 who did not use LMWH had a DVT rate of 11.4% (vs 1.7% in younger patients). Without LMWH prophylaxis, casting for more than 10 days approximately doubled the risk of DVT compared with less than 10 days (6.1% vs 3.1%). This study did not report on the anatomic location of DVTs or if they were clinically evident.⁴

The third RCT evaluated reviparin (another European LMWH) vs placebo in 440 outpatients with lower limb injuries, of whom 293 had fractures. About half had surgical management and all were treated with a plaster cast or brace for an average of 44 days. Most were ambulatory with crutches. All underwent venography within a week of cast removal. The DVT rate for fracture patients using reviparin was 10.4%, vs 18.2% among those without LMWH prophylaxis (absolute risk reduction=7.8%; NNT=12.8). Three fourths of the DVTs were in distal veins, and 21% of the DVTs in the LMWH patients occurred in deep veins compared with 34% in patients without. Two pulmonary emboli occurred, both in patients without LMWH prophylaxis.⁵

The final RCT evaluated tinzaparin (yet another European LMWH) in 300 adult outpatients immobilized in plaster for at least 3 weeks. Most patients (205 out of 300) underwent venography, and the overall DVT rate was 10% (tinzaparin) vs 17% (controls). Among the 150 fracture patients who underwent venography, the DVT rate was 11% (tinzaparin) vs 13% (controls). This difference was not significant, probably due to insufficient numbers. None of the DVTs was clinically detectable.⁶

In hip fracture and hip arthroplasty, warfarin and LMWH are both effective in preventing thrombosis. No studies have specifically evaluated warfarin prophylaxis in lower extremity fractures or compared it with LMWH.

Recommendations from others

The American College of Chest Physicians (ACCP) says that LMWH prophylaxis reduces the risk of asymptomatic DVTs and is standard of care in Europe. The ACCP does not recommend thromboprophylaxis for isolated lower extremity fractures in the US because of cost and insufficient evidence of clinically important reduction in venous thromboembolism (VTE). However, ACCP lists unspecified “lower extremity or pelvic fracture” as a risk factor for VTE, and does recommend that trauma patients with at least 1 risk factor for VTE receive thromboprophylaxis. They make no recommendation about the use of warfarin.⁷

Evidence summary

Three large prospective RCTs evaluated the effect of dietary and exercise interventions in populations at risk for developing diabetes.

The Diabetes Prevention Program Research Group¹ randomized 3234 patients age >24 years without diabetes but with IGT and a BMI >24 to 1 of 3 groups: intensive lifestyle modification, metformin, or control; they then compared the incidence of diabetes over 3 years. Patients were men and women from primary care populations and represented diverse ethnic backgrounds. Investigators defined IGT as plasma glucose of 140 to 200 mg/dL 2 hours after a 75-g glucose bolus when the fasting glucose was <140 mg/dL. Intensive lifestyle intervention comprised individual training sessions on a low-calorie, low-fat diet, aerobic exercise (such as brisk walking), and behavior modification. Case managers met with each participant for at least 16 sessions during the first 24 weeks and at least monthly thereafter. The control group received lifestyle change recommendations without individualized attention.

After 24 weeks, 50% of the lifestyle group met the 7% weight loss goal and 74% were exercising at least 150 minutes per week. At the final visit, 38% maintained their target weight and 58% met their exercise goal. Lifestyle intervention produced greater weight reduction and increased activity compared with the metformin and control groups, with a corresponding decreased incidence of diabetes (TABLE). Subgroup analysis found that lifestyle intervention produced the greatest reduction in diabetes (71%) for patients aged >60 years.

The Finnish Diabetes Prevention Study² similarly randomized 522 patients, aged 40 to 65 years, with IGT and obesity (mean BMI=31) to either intensive lifestyle intervention or control and followed them for 3.2 years. The lifestyle intervention included moderate exercise for at least 150 minutes per week and weight loss of at least 5%. Patients were offered an individualized exercise plan with supervised aerobic exercise plus circuit-type resistance sessions 3 times a week. Nutritionists met with patients 7 times in the first year and every 3 months after that. Patients were counseled to increase fiber intake, reduce total fat below 30% of total calories, and reduce saturated fat below 10%. The control group was given general information on diet and exercise without individualized programs. Most patients (86%) in the intervention group met their exercise goal, and 25% met the fiber requirement.

Compared with the control group, the intervention group had greater success rate for each category. Intensive lifestyle intervention reduced the incidence of diabetes by 58% (number needed to treat=5 for 5 years; (see TABLE).

The Da Qing IGT and Diabetes Study³ divided 577 patients with IGT into 1 control and 3 intervention groups: diet, aerobic exercise, and combined diet plus aerobic exercise. Patients in this study had the lowest average BMI (25.8) of the 3 studies. The intervention group received individual and group counseling sessions at weekly intervals for 1 month, then monthly for 3 months, and then every 3 months. The control group received generalized information on IGT and diabetes but individual or group instruction was not included.

At the 6-year follow-up, the quantity of exercise was significantly higher in the exercise intervention groups, but no significant difference in caloric intake was seen among all 4 groups. The incidence of diabetes in the exercise intervention group was approximately half that in the control group overall (TABLE 1). Exercise was more effective in reducing diabetes in lean patients (BMI <25), but both lean and overweight patients benefited. The combination of diet plus exercise and diet changes also significantly reduced diabetes, although to a lesser degree.

TABLE
Incidence of diabetes among patients with impaired glucose tolerance participating in diet and exercise programs

Recommendations from others

The American Diabetes Association recommends structured programs that emphasize lifestyle changes, including education, reduced fat and energy intake, regular physical activity, and regular participant contact. These changes can produce long-term weight loss of 5% to 7% of starting weight and reduce the risk for developing diabetes.⁴ They also stress the importance of promoting exercise as a vital component of the prevention as well as management of type 2 diabetes. The benefit of exercise in improving the metabolic abnormalities of type 2 diabetes is probably greatest when it is used early in its progression from insulin resistance to impaired glucose tolerance to overt hyperglycemia.⁵ The Exercise was more effective in reducing diabetes in lean patients, but overweight patients also benefited World Health Organization states that increased physical activity and maintaining a healthy weight play critical roles in the prevention and treatment of diabetes.⁶

Evidence summary

Three large prospective RCTs evaluated the effect of dietary and exercise interventions in populations at risk for developing diabetes.

The Diabetes Prevention Program Research Group¹ randomized 3234 patients age >24 years without diabetes but with IGT and a BMI >24 to 1 of 3 groups: intensive lifestyle modification, metformin, or control; they then compared the incidence of diabetes over 3 years. Patients were men and women from primary care populations and represented diverse ethnic backgrounds. Investigators defined IGT as plasma glucose of 140 to 200 mg/dL 2 hours after a 75-g glucose bolus when the fasting glucose was <140 mg/dL. Intensive lifestyle intervention comprised individual training sessions on a low-calorie, low-fat diet, aerobic exercise (such as brisk walking), and behavior modification. Case managers met with each participant for at least 16 sessions during the first 24 weeks and at least monthly thereafter. The control group received lifestyle change recommendations without individualized attention.

After 24 weeks, 50% of the lifestyle group met the 7% weight loss goal and 74% were exercising at least 150 minutes per week. At the final visit, 38% maintained their target weight and 58% met their exercise goal. Lifestyle intervention produced greater weight reduction and increased activity compared with the metformin and control groups, with a corresponding decreased incidence of diabetes (TABLE). Subgroup analysis found that lifestyle intervention produced the greatest reduction in diabetes (71%) for patients aged >60 years.

The Finnish Diabetes Prevention Study² similarly randomized 522 patients, aged 40 to 65 years, with IGT and obesity (mean BMI=31) to either intensive lifestyle intervention or control and followed them for 3.2 years. The lifestyle intervention included moderate exercise for at least 150 minutes per week and weight loss of at least 5%. Patients were offered an individualized exercise plan with supervised aerobic exercise plus circuit-type resistance sessions 3 times a week. Nutritionists met with patients 7 times in the first year and every 3 months after that. Patients were counseled to increase fiber intake, reduce total fat below 30% of total calories, and reduce saturated fat below 10%. The control group was given general information on diet and exercise without individualized programs. Most patients (86%) in the intervention group met their exercise goal, and 25% met the fiber requirement.

Compared with the control group, the intervention group had greater success rate for each category. Intensive lifestyle intervention reduced the incidence of diabetes by 58% (number needed to treat=5 for 5 years; (see TABLE).

The Da Qing IGT and Diabetes Study³ divided 577 patients with IGT into 1 control and 3 intervention groups: diet, aerobic exercise, and combined diet plus aerobic exercise. Patients in this study had the lowest average BMI (25.8) of the 3 studies. The intervention group received individual and group counseling sessions at weekly intervals for 1 month, then monthly for 3 months, and then every 3 months. The control group received generalized information on IGT and diabetes but individual or group instruction was not included.

At the 6-year follow-up, the quantity of exercise was significantly higher in the exercise intervention groups, but no significant difference in caloric intake was seen among all 4 groups. The incidence of diabetes in the exercise intervention group was approximately half that in the control group overall (TABLE 1). Exercise was more effective in reducing diabetes in lean patients (BMI <25), but both lean and overweight patients benefited. The combination of diet plus exercise and diet changes also significantly reduced diabetes, although to a lesser degree.

TABLE
Incidence of diabetes among patients with impaired glucose tolerance participating in diet and exercise programs

Recommendations from others

The American Diabetes Association recommends structured programs that emphasize lifestyle changes, including education, reduced fat and energy intake, regular physical activity, and regular participant contact. These changes can produce long-term weight loss of 5% to 7% of starting weight and reduce the risk for developing diabetes.⁴ They also stress the importance of promoting exercise as a vital component of the prevention as well as management of type 2 diabetes. The benefit of exercise in improving the metabolic abnormalities of type 2 diabetes is probably greatest when it is used early in its progression from insulin resistance to impaired glucose tolerance to overt hyperglycemia.⁵ The Exercise was more effective in reducing diabetes in lean patients, but overweight patients also benefited World Health Organization states that increased physical activity and maintaining a healthy weight play critical roles in the prevention and treatment of diabetes.⁶

Evidence summary

Three large prospective RCTs evaluated the effect of dietary and exercise interventions in populations at risk for developing diabetes.

The Diabetes Prevention Program Research Group¹ randomized 3234 patients age >24 years without diabetes but with IGT and a BMI >24 to 1 of 3 groups: intensive lifestyle modification, metformin, or control; they then compared the incidence of diabetes over 3 years. Patients were men and women from primary care populations and represented diverse ethnic backgrounds. Investigators defined IGT as plasma glucose of 140 to 200 mg/dL 2 hours after a 75-g glucose bolus when the fasting glucose was <140 mg/dL. Intensive lifestyle intervention comprised individual training sessions on a low-calorie, low-fat diet, aerobic exercise (such as brisk walking), and behavior modification. Case managers met with each participant for at least 16 sessions during the first 24 weeks and at least monthly thereafter. The control group received lifestyle change recommendations without individualized attention.

After 24 weeks, 50% of the lifestyle group met the 7% weight loss goal and 74% were exercising at least 150 minutes per week. At the final visit, 38% maintained their target weight and 58% met their exercise goal. Lifestyle intervention produced greater weight reduction and increased activity compared with the metformin and control groups, with a corresponding decreased incidence of diabetes (TABLE). Subgroup analysis found that lifestyle intervention produced the greatest reduction in diabetes (71%) for patients aged >60 years.

The Finnish Diabetes Prevention Study² similarly randomized 522 patients, aged 40 to 65 years, with IGT and obesity (mean BMI=31) to either intensive lifestyle intervention or control and followed them for 3.2 years. The lifestyle intervention included moderate exercise for at least 150 minutes per week and weight loss of at least 5%. Patients were offered an individualized exercise plan with supervised aerobic exercise plus circuit-type resistance sessions 3 times a week. Nutritionists met with patients 7 times in the first year and every 3 months after that. Patients were counseled to increase fiber intake, reduce total fat below 30% of total calories, and reduce saturated fat below 10%. The control group was given general information on diet and exercise without individualized programs. Most patients (86%) in the intervention group met their exercise goal, and 25% met the fiber requirement.

Compared with the control group, the intervention group had greater success rate for each category. Intensive lifestyle intervention reduced the incidence of diabetes by 58% (number needed to treat=5 for 5 years; (see TABLE).

The Da Qing IGT and Diabetes Study³ divided 577 patients with IGT into 1 control and 3 intervention groups: diet, aerobic exercise, and combined diet plus aerobic exercise. Patients in this study had the lowest average BMI (25.8) of the 3 studies. The intervention group received individual and group counseling sessions at weekly intervals for 1 month, then monthly for 3 months, and then every 3 months. The control group received generalized information on IGT and diabetes but individual or group instruction was not included.

At the 6-year follow-up, the quantity of exercise was significantly higher in the exercise intervention groups, but no significant difference in caloric intake was seen among all 4 groups. The incidence of diabetes in the exercise intervention group was approximately half that in the control group overall (TABLE 1). Exercise was more effective in reducing diabetes in lean patients (BMI <25), but both lean and overweight patients benefited. The combination of diet plus exercise and diet changes also significantly reduced diabetes, although to a lesser degree.

TABLE
Incidence of diabetes among patients with impaired glucose tolerance participating in diet and exercise programs

Recommendations from others

The American Diabetes Association recommends structured programs that emphasize lifestyle changes, including education, reduced fat and energy intake, regular physical activity, and regular participant contact. These changes can produce long-term weight loss of 5% to 7% of starting weight and reduce the risk for developing diabetes.⁴ They also stress the importance of promoting exercise as a vital component of the prevention as well as management of type 2 diabetes. The benefit of exercise in improving the metabolic abnormalities of type 2 diabetes is probably greatest when it is used early in its progression from insulin resistance to impaired glucose tolerance to overt hyperglycemia.⁵ The Exercise was more effective in reducing diabetes in lean patients, but overweight patients also benefited World Health Organization states that increased physical activity and maintaining a healthy weight play critical roles in the prevention and treatment of diabetes.⁶

Evidence summary

A systematic review of antibiotic prophylaxis for recurrent AOM examined 9 RCTs with a total of 958 children. Recurrent AOM was defined as 3 or more episodes per 6 to 18 months. The studies were low to moderate in quality (mean methodologic quality score of 11.8 out of 29 possible points). The most commonly used antibiotics were amoxicillin, cotrimoxazole, and sulfamethoxazole, given for 3 to 24 months (dosing not reported).

Children taking antibiotics had 0.11 (95% confidence interval [CI], 0.03–0.19) fewer episodes of recurrent AOM per patient-month than those taking placebo. The rate in the control group was 0.19 (95% CI, 0.13–0.26). Nine children would have to be treated per month to prevent 1 ear infection (NNT=9; 95% CI, 5–33). Only 2 of the 9 studies had statistically significant results; both used sulfisoxazole for 10 to 12 weeks and were of similar methodologic quality (12.5 out 29 points).

A trend towards a better outcome in studies that used sulfisoxazole did not reach significance compared with those using other medications (ie, ampicillin, amoxicillin, cotrimoxazole). Shorter treatment intervals (<6 months) trended toward being more effective than longer intervals, but this also did not reach significance. Children with more frequent episodes of AOM did no better than those with less frequent episodes.¹

Since that review was published, another study of prophylaxis for ear infections had been published. This randomized, double blind, placebo-controlled study enrolled 194 children aged 3 months to 6 years with at least 3 documented AOM episodes in the preceding 6 months. The children were given amoxicillin (20 mg/kg/d) either once daily (n=55) or divided twice daily (n=44) or placebo (n=59). Excluding 36 noncompliant subjects, the percentages without a recurrent episode were 63% for the placebo group, 64% for the once-daily amoxicillin group, and 61% for the twice-daily amoxicillin group. There was no significant difference in the incidence of new AOM episodes among the children in the 3 groups.²

A review article states: “Many children with acute otitis media do not benefit from antimicrobial therapy because the cause of their illness is not bacterial or the infection is cleared by the immune system without use of a drug. At present, we do not have clinical criteria for distinguishing which children are in need of antibiotic therapy for AOM.”³ The lack of criteria for determining which children need antibiotic therapy for AOM makes it more difficult to select children for antibiotic prophylaxis against recurrent AOM.

Recommendations from others

The American Academy of Pediatrics and the American Academy of Family Physicians do not address antibiotic prophylaxis for recurrent episodes of otitis media in their guidelines. Both groups recommend modification of risk factors to decrease recurrent AOM, including promoting breastfeeding during the first 6 months, avoiding bottle-propping, reducing or eliminating pacifier use in the second 6 months of life, and eliminating exposure to secondhand smoke.

They also recommend pneumococcal conjugate vaccine to reduce vaccine-serotype pneumococcal otitis and live-attenuated influenza vaccine during respiratory virus season for children aged >2 years.

Evidence summary

A systematic review of antibiotic prophylaxis for recurrent AOM examined 9 RCTs with a total of 958 children. Recurrent AOM was defined as 3 or more episodes per 6 to 18 months. The studies were low to moderate in quality (mean methodologic quality score of 11.8 out of 29 possible points). The most commonly used antibiotics were amoxicillin, cotrimoxazole, and sulfamethoxazole, given for 3 to 24 months (dosing not reported).

Children taking antibiotics had 0.11 (95% confidence interval [CI], 0.03–0.19) fewer episodes of recurrent AOM per patient-month than those taking placebo. The rate in the control group was 0.19 (95% CI, 0.13–0.26). Nine children would have to be treated per month to prevent 1 ear infection (NNT=9; 95% CI, 5–33). Only 2 of the 9 studies had statistically significant results; both used sulfisoxazole for 10 to 12 weeks and were of similar methodologic quality (12.5 out 29 points).

A trend towards a better outcome in studies that used sulfisoxazole did not reach significance compared with those using other medications (ie, ampicillin, amoxicillin, cotrimoxazole). Shorter treatment intervals (<6 months) trended toward being more effective than longer intervals, but this also did not reach significance. Children with more frequent episodes of AOM did no better than those with less frequent episodes.¹

Since that review was published, another study of prophylaxis for ear infections had been published. This randomized, double blind, placebo-controlled study enrolled 194 children aged 3 months to 6 years with at least 3 documented AOM episodes in the preceding 6 months. The children were given amoxicillin (20 mg/kg/d) either once daily (n=55) or divided twice daily (n=44) or placebo (n=59). Excluding 36 noncompliant subjects, the percentages without a recurrent episode were 63% for the placebo group, 64% for the once-daily amoxicillin group, and 61% for the twice-daily amoxicillin group. There was no significant difference in the incidence of new AOM episodes among the children in the 3 groups.²

A review article states: “Many children with acute otitis media do not benefit from antimicrobial therapy because the cause of their illness is not bacterial or the infection is cleared by the immune system without use of a drug. At present, we do not have clinical criteria for distinguishing which children are in need of antibiotic therapy for AOM.”³ The lack of criteria for determining which children need antibiotic therapy for AOM makes it more difficult to select children for antibiotic prophylaxis against recurrent AOM.

Recommendations from others

The American Academy of Pediatrics and the American Academy of Family Physicians do not address antibiotic prophylaxis for recurrent episodes of otitis media in their guidelines. Both groups recommend modification of risk factors to decrease recurrent AOM, including promoting breastfeeding during the first 6 months, avoiding bottle-propping, reducing or eliminating pacifier use in the second 6 months of life, and eliminating exposure to secondhand smoke.

They also recommend pneumococcal conjugate vaccine to reduce vaccine-serotype pneumococcal otitis and live-attenuated influenza vaccine during respiratory virus season for children aged >2 years.

Evidence summary

A systematic review of antibiotic prophylaxis for recurrent AOM examined 9 RCTs with a total of 958 children. Recurrent AOM was defined as 3 or more episodes per 6 to 18 months. The studies were low to moderate in quality (mean methodologic quality score of 11.8 out of 29 possible points). The most commonly used antibiotics were amoxicillin, cotrimoxazole, and sulfamethoxazole, given for 3 to 24 months (dosing not reported).

Children taking antibiotics had 0.11 (95% confidence interval [CI], 0.03–0.19) fewer episodes of recurrent AOM per patient-month than those taking placebo. The rate in the control group was 0.19 (95% CI, 0.13–0.26). Nine children would have to be treated per month to prevent 1 ear infection (NNT=9; 95% CI, 5–33). Only 2 of the 9 studies had statistically significant results; both used sulfisoxazole for 10 to 12 weeks and were of similar methodologic quality (12.5 out 29 points).

A trend towards a better outcome in studies that used sulfisoxazole did not reach significance compared with those using other medications (ie, ampicillin, amoxicillin, cotrimoxazole). Shorter treatment intervals (<6 months) trended toward being more effective than longer intervals, but this also did not reach significance. Children with more frequent episodes of AOM did no better than those with less frequent episodes.¹

Since that review was published, another study of prophylaxis for ear infections had been published. This randomized, double blind, placebo-controlled study enrolled 194 children aged 3 months to 6 years with at least 3 documented AOM episodes in the preceding 6 months. The children were given amoxicillin (20 mg/kg/d) either once daily (n=55) or divided twice daily (n=44) or placebo (n=59). Excluding 36 noncompliant subjects, the percentages without a recurrent episode were 63% for the placebo group, 64% for the once-daily amoxicillin group, and 61% for the twice-daily amoxicillin group. There was no significant difference in the incidence of new AOM episodes among the children in the 3 groups.²

A review article states: “Many children with acute otitis media do not benefit from antimicrobial therapy because the cause of their illness is not bacterial or the infection is cleared by the immune system without use of a drug. At present, we do not have clinical criteria for distinguishing which children are in need of antibiotic therapy for AOM.”³ The lack of criteria for determining which children need antibiotic therapy for AOM makes it more difficult to select children for antibiotic prophylaxis against recurrent AOM.

Recommendations from others

The American Academy of Pediatrics and the American Academy of Family Physicians do not address antibiotic prophylaxis for recurrent episodes of otitis media in their guidelines. Both groups recommend modification of risk factors to decrease recurrent AOM, including promoting breastfeeding during the first 6 months, avoiding bottle-propping, reducing or eliminating pacifier use in the second 6 months of life, and eliminating exposure to secondhand smoke.

They also recommend pneumococcal conjugate vaccine to reduce vaccine-serotype pneumococcal otitis and live-attenuated influenza vaccine during respiratory virus season for children aged >2 years.

FIGURE 1
Bariatric surgical techniques for weight loss

Evidence summary

A systematic review comparing bariatric surgery with conventional medical therapy for obesity included 1 randomized controlled trial and the Swedish Obesity Study, a large cohort study with matched controls. Surgery produced 23 to 28 kg more weight loss at 2 years.¹ The study demonstrated 33% ± 10% weight loss for gastric bypass and 0% for medical therapy (not described) at 2 years,² and 25% ± 6% loss vs 0.9% gain at 8 years.³ Among bariatric surgical techniques, patients undergoing gastric bypass lost more weight than those with gastroplasty (using staples to partition the stomach, either horizontally or vertically ( Figure 1 ) (P=.057, not significant) or gastric banding (placing a constricting ring around the stomach) (P<.05) at 8 years.³

The same systematic review assessed multiple randomized controlled trials comparing gastric bypass with gastroplasty and found greater weight loss, fewer revisions, and more side effects from gastric bypass ( Figure 2 ).¹ Five trials comparing gastric bypass with horizontal gastroplasty demonstrated significantly greater weight loss from gastric bypass. Five other trials comparing weight loss from gastric bypass with vertical gastroplasty produced mixed results, with 3 trials favoring gastric bypass and 2 showing no difference.¹ Fewer patients required revision after gastric bypass (0%–4%) compared with vertical gastroplasty (9%) or horizontal gastroplasty (19%–40%). One included trial found that postoperative dumping syndrome (28% vs 0%, P<0.05) and heartburn (59% vs 32%, P<.05) were more common with gastric bypass than with gastroplasty.¹

Bariatric surgery, including gastric bypass, improves a variety of obesity-related comorbid conditions. Diabetes prevalence decreased among gastric bypass patients at 2 years (0.0% vs 4.7%, P<0.005) and 8 years (3.6% vs 18.5%, P<.0005) compared with those receiving medical therapy.^2,3 In a case series involving 154 diabetic gastric bypass patients, diabetes resolved for 83% by 1 year, and for 86% at 5 to 7 years.⁴ In several case series, most patients became euglycemic and discontinued insulin or oral agents.

In the Swedish Obesity Study, hypertriglyceridemia decreased postoperatively but hypercholesterolemia did not.⁵ In a case series, bariatric surgery reduced triglycerides (50%) as well as total cholesterol (15%) (P<.05 for both) at 6 months and significantly increased high-density lipoprotein cholesterol levels at 1 and 5 years.⁶

Bariatric surgery significantly lowered the incidence of hypertension at 2 years (3.2%) compared with conventional treatment (9.9%), but after 8 years this difference disappeared.^2,3,5 However, in multiple large case series with morbidly obese patients, hypertension resolved or improved. The largest study showed resolution of hypertension for 69% at 1 to 2 years (91% follow-up), 66% at 5 to 7 years (50% follow-up), and 51% at 10 to 12 years (37% follow-up).⁴

Bariatric surgery improved obstructive sleep apnea and obesity hypoventilation syndrome in 2 case series. In one, Epworth Sleepiness Scale scores, minimum O₂ saturation, and other measures improved significantly (P<.001) by 3 to 21 months after surgery.⁷

In another case series, menstrual irregularities decreased from 40.4% to 4.6% following surgery (P<.001) among women who lost 50% of their excess weight.⁸ The incidence of urinary stress incontinence also decreased significantly (61.2% to 11.6%, P<.001 in this study⁸ ). The Swedish Obesity Study found significant improvements in Health-Related Quality of Life scores at 2 years with surgery vs conventional treatment.⁹

Bariatric surgery, including gastric bypass, has significant postoperative morbidity and mortality. Thirteen percent of patients in the Swedish Obesity Study experienced peri-operative complications, including pulmonary symptoms (6.2%), abdominal infection (2.1%), wound complications (1.8%), bleeding (0.9%), thromboembolic events (0.8%), and other miscellaneous complications (4.8%). Postoperative complications required reoperation for 2.2% of surgical patients, and there were 4 postoperative deaths (0.2% of the operative patients; 3 due to leakage, and 1 due to a technical laparoscopic error).²

Nutritional and vitamin deficiencies are common following gastric bypass, including deficiencies of vitamin B12, iron, folate, and calcium. Lifelong nutritional supplementation is generally necessary following this procedure.¹⁰

FIGURE 2
Long-term weight loss with bariatric surgery

Recommendations from others

A 1991 National Institutes of Health consensus conference suggested consideration of obesity surgery for patients with a body-mass index ≥40, or ≥35 plus severe obesity-related medical comorbidities (such as severe sleep apnea, obesity hypoventilation syndrome, obesity-related cardiomyopathy, or severe diabetes) who have not been successfully treated with non-surgical attempts at weight reduction.

Selected patients should be well-informed and motivated, with acceptable operative risk. A multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise should evaluate patients who are candidates for surgery. An experienced surgeon, working in a clinical setting with adequate support for all aspects of management and assessment, should perform the surgery.

Lifelong medical surveillance is necessary after surgery, and patients should be selected who are likely to comply with this.¹¹

FIGURE 1
Bariatric surgical techniques for weight loss

Evidence summary

A systematic review comparing bariatric surgery with conventional medical therapy for obesity included 1 randomized controlled trial and the Swedish Obesity Study, a large cohort study with matched controls. Surgery produced 23 to 28 kg more weight loss at 2 years.¹ The study demonstrated 33% ± 10% weight loss for gastric bypass and 0% for medical therapy (not described) at 2 years,² and 25% ± 6% loss vs 0.9% gain at 8 years.³ Among bariatric surgical techniques, patients undergoing gastric bypass lost more weight than those with gastroplasty (using staples to partition the stomach, either horizontally or vertically ( Figure 1 ) (P=.057, not significant) or gastric banding (placing a constricting ring around the stomach) (P<.05) at 8 years.³

The same systematic review assessed multiple randomized controlled trials comparing gastric bypass with gastroplasty and found greater weight loss, fewer revisions, and more side effects from gastric bypass ( Figure 2 ).¹ Five trials comparing gastric bypass with horizontal gastroplasty demonstrated significantly greater weight loss from gastric bypass. Five other trials comparing weight loss from gastric bypass with vertical gastroplasty produced mixed results, with 3 trials favoring gastric bypass and 2 showing no difference.¹ Fewer patients required revision after gastric bypass (0%–4%) compared with vertical gastroplasty (9%) or horizontal gastroplasty (19%–40%). One included trial found that postoperative dumping syndrome (28% vs 0%, P<0.05) and heartburn (59% vs 32%, P<.05) were more common with gastric bypass than with gastroplasty.¹

Bariatric surgery, including gastric bypass, improves a variety of obesity-related comorbid conditions. Diabetes prevalence decreased among gastric bypass patients at 2 years (0.0% vs 4.7%, P<0.005) and 8 years (3.6% vs 18.5%, P<.0005) compared with those receiving medical therapy.^2,3 In a case series involving 154 diabetic gastric bypass patients, diabetes resolved for 83% by 1 year, and for 86% at 5 to 7 years.⁴ In several case series, most patients became euglycemic and discontinued insulin or oral agents.

In the Swedish Obesity Study, hypertriglyceridemia decreased postoperatively but hypercholesterolemia did not.⁵ In a case series, bariatric surgery reduced triglycerides (50%) as well as total cholesterol (15%) (P<.05 for both) at 6 months and significantly increased high-density lipoprotein cholesterol levels at 1 and 5 years.⁶

Bariatric surgery significantly lowered the incidence of hypertension at 2 years (3.2%) compared with conventional treatment (9.9%), but after 8 years this difference disappeared.^2,3,5 However, in multiple large case series with morbidly obese patients, hypertension resolved or improved. The largest study showed resolution of hypertension for 69% at 1 to 2 years (91% follow-up), 66% at 5 to 7 years (50% follow-up), and 51% at 10 to 12 years (37% follow-up).⁴

Bariatric surgery improved obstructive sleep apnea and obesity hypoventilation syndrome in 2 case series. In one, Epworth Sleepiness Scale scores, minimum O₂ saturation, and other measures improved significantly (P<.001) by 3 to 21 months after surgery.⁷

In another case series, menstrual irregularities decreased from 40.4% to 4.6% following surgery (P<.001) among women who lost 50% of their excess weight.⁸ The incidence of urinary stress incontinence also decreased significantly (61.2% to 11.6%, P<.001 in this study⁸ ). The Swedish Obesity Study found significant improvements in Health-Related Quality of Life scores at 2 years with surgery vs conventional treatment.⁹

Bariatric surgery, including gastric bypass, has significant postoperative morbidity and mortality. Thirteen percent of patients in the Swedish Obesity Study experienced peri-operative complications, including pulmonary symptoms (6.2%), abdominal infection (2.1%), wound complications (1.8%), bleeding (0.9%), thromboembolic events (0.8%), and other miscellaneous complications (4.8%). Postoperative complications required reoperation for 2.2% of surgical patients, and there were 4 postoperative deaths (0.2% of the operative patients; 3 due to leakage, and 1 due to a technical laparoscopic error).²

Nutritional and vitamin deficiencies are common following gastric bypass, including deficiencies of vitamin B12, iron, folate, and calcium. Lifelong nutritional supplementation is generally necessary following this procedure.¹⁰

FIGURE 2
Long-term weight loss with bariatric surgery

Recommendations from others

A 1991 National Institutes of Health consensus conference suggested consideration of obesity surgery for patients with a body-mass index ≥40, or ≥35 plus severe obesity-related medical comorbidities (such as severe sleep apnea, obesity hypoventilation syndrome, obesity-related cardiomyopathy, or severe diabetes) who have not been successfully treated with non-surgical attempts at weight reduction.

Selected patients should be well-informed and motivated, with acceptable operative risk. A multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise should evaluate patients who are candidates for surgery. An experienced surgeon, working in a clinical setting with adequate support for all aspects of management and assessment, should perform the surgery.

Lifelong medical surveillance is necessary after surgery, and patients should be selected who are likely to comply with this.¹¹

FIGURE 1
Bariatric surgical techniques for weight loss

Evidence summary

A systematic review comparing bariatric surgery with conventional medical therapy for obesity included 1 randomized controlled trial and the Swedish Obesity Study, a large cohort study with matched controls. Surgery produced 23 to 28 kg more weight loss at 2 years.¹ The study demonstrated 33% ± 10% weight loss for gastric bypass and 0% for medical therapy (not described) at 2 years,² and 25% ± 6% loss vs 0.9% gain at 8 years.³ Among bariatric surgical techniques, patients undergoing gastric bypass lost more weight than those with gastroplasty (using staples to partition the stomach, either horizontally or vertically ( Figure 1 ) (P=.057, not significant) or gastric banding (placing a constricting ring around the stomach) (P<.05) at 8 years.³

The same systematic review assessed multiple randomized controlled trials comparing gastric bypass with gastroplasty and found greater weight loss, fewer revisions, and more side effects from gastric bypass ( Figure 2 ).¹ Five trials comparing gastric bypass with horizontal gastroplasty demonstrated significantly greater weight loss from gastric bypass. Five other trials comparing weight loss from gastric bypass with vertical gastroplasty produced mixed results, with 3 trials favoring gastric bypass and 2 showing no difference.¹ Fewer patients required revision after gastric bypass (0%–4%) compared with vertical gastroplasty (9%) or horizontal gastroplasty (19%–40%). One included trial found that postoperative dumping syndrome (28% vs 0%, P<0.05) and heartburn (59% vs 32%, P<.05) were more common with gastric bypass than with gastroplasty.¹

Bariatric surgery, including gastric bypass, improves a variety of obesity-related comorbid conditions. Diabetes prevalence decreased among gastric bypass patients at 2 years (0.0% vs 4.7%, P<0.005) and 8 years (3.6% vs 18.5%, P<.0005) compared with those receiving medical therapy.^2,3 In a case series involving 154 diabetic gastric bypass patients, diabetes resolved for 83% by 1 year, and for 86% at 5 to 7 years.⁴ In several case series, most patients became euglycemic and discontinued insulin or oral agents.

In the Swedish Obesity Study, hypertriglyceridemia decreased postoperatively but hypercholesterolemia did not.⁵ In a case series, bariatric surgery reduced triglycerides (50%) as well as total cholesterol (15%) (P<.05 for both) at 6 months and significantly increased high-density lipoprotein cholesterol levels at 1 and 5 years.⁶

Bariatric surgery significantly lowered the incidence of hypertension at 2 years (3.2%) compared with conventional treatment (9.9%), but after 8 years this difference disappeared.^2,3,5 However, in multiple large case series with morbidly obese patients, hypertension resolved or improved. The largest study showed resolution of hypertension for 69% at 1 to 2 years (91% follow-up), 66% at 5 to 7 years (50% follow-up), and 51% at 10 to 12 years (37% follow-up).⁴

Bariatric surgery improved obstructive sleep apnea and obesity hypoventilation syndrome in 2 case series. In one, Epworth Sleepiness Scale scores, minimum O₂ saturation, and other measures improved significantly (P<.001) by 3 to 21 months after surgery.⁷

In another case series, menstrual irregularities decreased from 40.4% to 4.6% following surgery (P<.001) among women who lost 50% of their excess weight.⁸ The incidence of urinary stress incontinence also decreased significantly (61.2% to 11.6%, P<.001 in this study⁸ ). The Swedish Obesity Study found significant improvements in Health-Related Quality of Life scores at 2 years with surgery vs conventional treatment.⁹

Bariatric surgery, including gastric bypass, has significant postoperative morbidity and mortality. Thirteen percent of patients in the Swedish Obesity Study experienced peri-operative complications, including pulmonary symptoms (6.2%), abdominal infection (2.1%), wound complications (1.8%), bleeding (0.9%), thromboembolic events (0.8%), and other miscellaneous complications (4.8%). Postoperative complications required reoperation for 2.2% of surgical patients, and there were 4 postoperative deaths (0.2% of the operative patients; 3 due to leakage, and 1 due to a technical laparoscopic error).²

Nutritional and vitamin deficiencies are common following gastric bypass, including deficiencies of vitamin B12, iron, folate, and calcium. Lifelong nutritional supplementation is generally necessary following this procedure.¹⁰

FIGURE 2
Long-term weight loss with bariatric surgery

Recommendations from others

A 1991 National Institutes of Health consensus conference suggested consideration of obesity surgery for patients with a body-mass index ≥40, or ≥35 plus severe obesity-related medical comorbidities (such as severe sleep apnea, obesity hypoventilation syndrome, obesity-related cardiomyopathy, or severe diabetes) who have not been successfully treated with non-surgical attempts at weight reduction.

Selected patients should be well-informed and motivated, with acceptable operative risk. A multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise should evaluate patients who are candidates for surgery. An experienced surgeon, working in a clinical setting with adequate support for all aspects of management and assessment, should perform the surgery.

Lifelong medical surveillance is necessary after surgery, and patients should be selected who are likely to comply with this.¹¹

Evidence summary

In the US, GABHS is the cause of acute pharyn-gitis in 5% to 10% of adults and 15% to 30% of children. It is the only commonly occurring cause of pharyngitis with an indication for antibiotic therapy.¹ The main benefit of antibiotic treatment in adults is earlier symptom relief—1 fewer day of fever and pain if antibiotics are begun within 3 days of onset.

Antibiotic treatment also reduces the incidence of acute rheumatic fever, which complicates 1 case per 100,000 in most of the US and Europe (relative risk reduction [RRR]=0.28).² The risk of acute rheumatic fever is higher in some populaHawaiians (13–45 per 100,000).³ Treatment may also reduce suppurative complications (peritonsil-tions, particularly Native Americans and lar or retropharyngeal abscess), which occur in 1 case out of 1000.^2,4

A systematic review of the diagnosis of GABHS evaluated the accuracy of history and physical exam elements.⁵ Clinical prediction rules based on selected symptoms and signs can identify patients at low risk for GABHS. The 4 Centor criteria (history of fever, anterior cervical adenopathy, tonsillar exudates, absence of cough) are well validated in adult populations ( Table 1 ), while other clinical prediction rules (such as McIssac) are validated in populations with children and adults ( Table 2 ). The number of criteria present determines the likelihood ratio (LR), with which to calculate the posttest probability of GABHS.

The usefulness of clinical prediction rules depends on knowing how prevalent GABHS is among cases of pharyngitis in a particular community. In a typical US adult population, GABHS comprises 5% to 10% of cases. The presence of only 1 Centor criterion would reduce the probability of GABHS pharyngitis to 2% to 3%, while meeting all 4 criteria would raise the probability to 25% to 40%, an intermediate value ( Table 1 ). If the prevalence of GABHS pharyngitis were 50%, as in some Native communities in Alaska, meeting all 4 criteria would predict an 86% probability of pharyngitis due to GABHS. Performing additional testing for patients with intermediate or high probability based on clinical prediction rules reduces the likelihood of unnecessary antibiotic treatment.¹

A systematic review⁶ of RAD testing demonstrates that the newer techniques (optical immunoassay, chemiluminescent DNA probes) have a sensitivity of 80% to 90%, which compares closely with that of throat culture (90%–95%). Both have a specificity greater than 95%, so false-positive test results are uncommon (LR+ =16–19). Treatment based on a positive RAD test would result in few unnecessary antibiotic prescriptions.¹

A retrospective outcome study⁴ reviewed the frequency of suppurative complications of GABHS among 30,036 patients with pharyngitis diagnosed with either RAD testing or throat culture. Patients included adults and children in a primary care setting. Complication rates were identical. A prospective study of 465 suburban outpatients with pharyngitis assessed the accuracy of RAD diagnosis using throat culture as a reference. The RAD accuracy was 93% for pediatric patients and 97% for adults.⁵ In another retrospective review of RAD testing, investigators performed 11,427 RAD tests over 3 years in a private pediatric group. There were 8385 negative tests, among which follow-up cultures detected 200 (2.4%) that were positive for GABHS. In the second half of the study, a newer RAD test produced a false-negative rate of 1.4%.⁷ Because of the possibility of higher false-negative RAD test rates in some settings, unless the physician has ascertained that RAD testing is comparable to throat culture in their own setting, expert opinion recommends confirming a negative RAD test in children or adolescents with a throat culture.¹ Patients at higher risk of GABHS or GABHS complications may also warrant throat culture back up of RAD testing.¹

TABLE 1
Centor clinical prediction rules for diagnosis of GABHS (for adults)

TABLE 2
McIssac clinical prediction rules for diagnosis of GABHS (for adults and children)

Recommendations from others

The Infectious Diseases Society of America recommends that if the physician is unable to exclude the diagnosis of GABHS on epidemiological or clinical grounds, either RAD testing or throat culture should be done. A positive result warrants treatment for patients with signs and symptoms of acute pharyngitis. A negative RAD result for a child or adolescent should be confirmed by throat culture unless the physician has ascertained that the sensitivity of RAD testing and throat culture are comparable in his or her practice setting.¹

The American Academy of Pediatrics also recommends laboratory confirmation of GABHS pharyngitis in children with throat culture or RAD testing. If a patient suspected clinically of GABHS has a negative RAD test, a throat culture should be done. Since some experts believe RAD tests using optical immunoassay are sufficiently sensitive to be used without throat culture backup, physicians who wish to use them should validate them by comparison to throat culture in their practice.⁸

Evidence summary

In the US, GABHS is the cause of acute pharyn-gitis in 5% to 10% of adults and 15% to 30% of children. It is the only commonly occurring cause of pharyngitis with an indication for antibiotic therapy.¹ The main benefit of antibiotic treatment in adults is earlier symptom relief—1 fewer day of fever and pain if antibiotics are begun within 3 days of onset.

Antibiotic treatment also reduces the incidence of acute rheumatic fever, which complicates 1 case per 100,000 in most of the US and Europe (relative risk reduction [RRR]=0.28).² The risk of acute rheumatic fever is higher in some populaHawaiians (13–45 per 100,000).³ Treatment may also reduce suppurative complications (peritonsil-tions, particularly Native Americans and lar or retropharyngeal abscess), which occur in 1 case out of 1000.^2,4

A systematic review of the diagnosis of GABHS evaluated the accuracy of history and physical exam elements.⁵ Clinical prediction rules based on selected symptoms and signs can identify patients at low risk for GABHS. The 4 Centor criteria (history of fever, anterior cervical adenopathy, tonsillar exudates, absence of cough) are well validated in adult populations ( Table 1 ), while other clinical prediction rules (such as McIssac) are validated in populations with children and adults ( Table 2 ). The number of criteria present determines the likelihood ratio (LR), with which to calculate the posttest probability of GABHS.

The usefulness of clinical prediction rules depends on knowing how prevalent GABHS is among cases of pharyngitis in a particular community. In a typical US adult population, GABHS comprises 5% to 10% of cases. The presence of only 1 Centor criterion would reduce the probability of GABHS pharyngitis to 2% to 3%, while meeting all 4 criteria would raise the probability to 25% to 40%, an intermediate value ( Table 1 ). If the prevalence of GABHS pharyngitis were 50%, as in some Native communities in Alaska, meeting all 4 criteria would predict an 86% probability of pharyngitis due to GABHS. Performing additional testing for patients with intermediate or high probability based on clinical prediction rules reduces the likelihood of unnecessary antibiotic treatment.¹

A systematic review⁶ of RAD testing demonstrates that the newer techniques (optical immunoassay, chemiluminescent DNA probes) have a sensitivity of 80% to 90%, which compares closely with that of throat culture (90%–95%). Both have a specificity greater than 95%, so false-positive test results are uncommon (LR+ =16–19). Treatment based on a positive RAD test would result in few unnecessary antibiotic prescriptions.¹

A retrospective outcome study⁴ reviewed the frequency of suppurative complications of GABHS among 30,036 patients with pharyngitis diagnosed with either RAD testing or throat culture. Patients included adults and children in a primary care setting. Complication rates were identical. A prospective study of 465 suburban outpatients with pharyngitis assessed the accuracy of RAD diagnosis using throat culture as a reference. The RAD accuracy was 93% for pediatric patients and 97% for adults.⁵ In another retrospective review of RAD testing, investigators performed 11,427 RAD tests over 3 years in a private pediatric group. There were 8385 negative tests, among which follow-up cultures detected 200 (2.4%) that were positive for GABHS. In the second half of the study, a newer RAD test produced a false-negative rate of 1.4%.⁷ Because of the possibility of higher false-negative RAD test rates in some settings, unless the physician has ascertained that RAD testing is comparable to throat culture in their own setting, expert opinion recommends confirming a negative RAD test in children or adolescents with a throat culture.¹ Patients at higher risk of GABHS or GABHS complications may also warrant throat culture back up of RAD testing.¹

TABLE 1
Centor clinical prediction rules for diagnosis of GABHS (for adults)

TABLE 2
McIssac clinical prediction rules for diagnosis of GABHS (for adults and children)

Recommendations from others

The Infectious Diseases Society of America recommends that if the physician is unable to exclude the diagnosis of GABHS on epidemiological or clinical grounds, either RAD testing or throat culture should be done. A positive result warrants treatment for patients with signs and symptoms of acute pharyngitis. A negative RAD result for a child or adolescent should be confirmed by throat culture unless the physician has ascertained that the sensitivity of RAD testing and throat culture are comparable in his or her practice setting.¹

The American Academy of Pediatrics also recommends laboratory confirmation of GABHS pharyngitis in children with throat culture or RAD testing. If a patient suspected clinically of GABHS has a negative RAD test, a throat culture should be done. Since some experts believe RAD tests using optical immunoassay are sufficiently sensitive to be used without throat culture backup, physicians who wish to use them should validate them by comparison to throat culture in their practice.⁸

Evidence summary

In the US, GABHS is the cause of acute pharyn-gitis in 5% to 10% of adults and 15% to 30% of children. It is the only commonly occurring cause of pharyngitis with an indication for antibiotic therapy.¹ The main benefit of antibiotic treatment in adults is earlier symptom relief—1 fewer day of fever and pain if antibiotics are begun within 3 days of onset.

Antibiotic treatment also reduces the incidence of acute rheumatic fever, which complicates 1 case per 100,000 in most of the US and Europe (relative risk reduction [RRR]=0.28).² The risk of acute rheumatic fever is higher in some populaHawaiians (13–45 per 100,000).³ Treatment may also reduce suppurative complications (peritonsil-tions, particularly Native Americans and lar or retropharyngeal abscess), which occur in 1 case out of 1000.^2,4

A systematic review of the diagnosis of GABHS evaluated the accuracy of history and physical exam elements.⁵ Clinical prediction rules based on selected symptoms and signs can identify patients at low risk for GABHS. The 4 Centor criteria (history of fever, anterior cervical adenopathy, tonsillar exudates, absence of cough) are well validated in adult populations ( Table 1 ), while other clinical prediction rules (such as McIssac) are validated in populations with children and adults ( Table 2 ). The number of criteria present determines the likelihood ratio (LR), with which to calculate the posttest probability of GABHS.

The usefulness of clinical prediction rules depends on knowing how prevalent GABHS is among cases of pharyngitis in a particular community. In a typical US adult population, GABHS comprises 5% to 10% of cases. The presence of only 1 Centor criterion would reduce the probability of GABHS pharyngitis to 2% to 3%, while meeting all 4 criteria would raise the probability to 25% to 40%, an intermediate value ( Table 1 ). If the prevalence of GABHS pharyngitis were 50%, as in some Native communities in Alaska, meeting all 4 criteria would predict an 86% probability of pharyngitis due to GABHS. Performing additional testing for patients with intermediate or high probability based on clinical prediction rules reduces the likelihood of unnecessary antibiotic treatment.¹

A systematic review⁶ of RAD testing demonstrates that the newer techniques (optical immunoassay, chemiluminescent DNA probes) have a sensitivity of 80% to 90%, which compares closely with that of throat culture (90%–95%). Both have a specificity greater than 95%, so false-positive test results are uncommon (LR+ =16–19). Treatment based on a positive RAD test would result in few unnecessary antibiotic prescriptions.¹

A retrospective outcome study⁴ reviewed the frequency of suppurative complications of GABHS among 30,036 patients with pharyngitis diagnosed with either RAD testing or throat culture. Patients included adults and children in a primary care setting. Complication rates were identical. A prospective study of 465 suburban outpatients with pharyngitis assessed the accuracy of RAD diagnosis using throat culture as a reference. The RAD accuracy was 93% for pediatric patients and 97% for adults.⁵ In another retrospective review of RAD testing, investigators performed 11,427 RAD tests over 3 years in a private pediatric group. There were 8385 negative tests, among which follow-up cultures detected 200 (2.4%) that were positive for GABHS. In the second half of the study, a newer RAD test produced a false-negative rate of 1.4%.⁷ Because of the possibility of higher false-negative RAD test rates in some settings, unless the physician has ascertained that RAD testing is comparable to throat culture in their own setting, expert opinion recommends confirming a negative RAD test in children or adolescents with a throat culture.¹ Patients at higher risk of GABHS or GABHS complications may also warrant throat culture back up of RAD testing.¹

TABLE 1
Centor clinical prediction rules for diagnosis of GABHS (for adults)

TABLE 2
McIssac clinical prediction rules for diagnosis of GABHS (for adults and children)

Recommendations from others

The Infectious Diseases Society of America recommends that if the physician is unable to exclude the diagnosis of GABHS on epidemiological or clinical grounds, either RAD testing or throat culture should be done. A positive result warrants treatment for patients with signs and symptoms of acute pharyngitis. A negative RAD result for a child or adolescent should be confirmed by throat culture unless the physician has ascertained that the sensitivity of RAD testing and throat culture are comparable in his or her practice setting.¹

The American Academy of Pediatrics also recommends laboratory confirmation of GABHS pharyngitis in children with throat culture or RAD testing. If a patient suspected clinically of GABHS has a negative RAD test, a throat culture should be done. Since some experts believe RAD tests using optical immunoassay are sufficiently sensitive to be used without throat culture backup, physicians who wish to use them should validate them by comparison to throat culture in their practice.⁸

Evidence Summary

Screening for hypothyroidism is more likely to detect the elevated TSH and normal free thyroxine level (FT4) of subclinical hypothyroidism than it is to detect overt hypothyroidism with a high TSH and a low FT4. We reviewed the accuracy of detection, natural history, and benefits and harms of treating subclinical hypothyroidism.

Detection. Subclinical hypothyroidism is found in 7% to 26% of women (with increasing prevalence as women reach age 60 and 70 years); overt hypothyroidism occurs in approximately 5%.^1-4 Two studies assessed the ability of the history and physical to detect hypothyroidism.

The first study evaluated 1154 women (aged 50–72) in a primary care setting using both history and physical and TSH testing. TSH testing found 3 women with overt hypothyroidism not identified by history and physical. History and physical identified 286 women with indications for TSH testing, 2 of whom had mild hypothyroidism and 1 with mild hyperthyroidism.⁵

In the second study, 2000 adults from a primary care population underwent history and physical and TSH testing. The TSH screen identified 19 cases of hypothyroidism not found by history and physical, while the history and physical prompted evaluation of 35 patients without abnormal TSH.⁶

Natural history of subclinical hypothyroidism. Among 1210 primary care patients (700 women) aged >60 years, 73 women with subclinical hypothyroidism were identified and followed for 12 months. Of these, 13 (18%) progressed to overt disease.⁷ Another prospective study of 30 patients (6 women) with subclinical hypothyroidism found 16 (3 women) who progressed to overt disease within 24 months. The remaining patients maintained normal FT4 levels for at least 15 years despite persistently elevated TSH.⁸ A third study followed 2779 adults (1494 women) with all types of thyroid disease for 20 years and found that 55% of women with TSH >6 and a positive antibody test developed overt hypothyroidism. Ninety percent of patients with an initial TSH >10 eventually progressed to overt disease.²

Serum lipid reduction. A retrospective study of 709 women referred to an endocrine clinic for evaluation of abnormal lipoprotein levels identified 34 (4.8%) with undiagnosed hypothyroidism. Thyroid hormone treatment significantly reduced total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with initial TSH >10, but not in those with a TSH <10.⁹

A randomized trial involving 42 women with subclinical hypothyroidism measured lipid levels before and after 6 months of levothyroxine treatment. Levothyroxine reduced total cholesterol and LDL significantly compared with placebo. Additionally, the subclinical hypothyroidism patients had higher baseline lipid levels when compared with 27 euthyroid controls.¹⁰

A meta-analysis combined 13 studies, involving 247 patients with subclinical hypothyroidism, all of whom were given thyroid replacement. All studies reported a decrease in total cholesterol (mean –7.9 mg/dL), and 9 reported a decrease in LDL (mean –10 mg/dL).¹¹ A second meta-analysis with 278 hypothyroid patients given thyroid replacement also found a reduction of total cholesterol (mean –15 mg/dL). LDL effects were not reported.¹² The clinical significance of lipid changes in these circumstances is unknown.

Symptom relief. Four small randomized controlled trials used symptom-rating scales to measure symptom relief with treatment of subclinical hypothyroidism. One study involved patients found by screening; the other 3 did not indicate means of diagnosis. Three studies found no significant improvement.^13-15 The most recent, involving 33 unblinded patients, found that those taking thyroid replacement had lower symptom scores (number needed to treat [NNT]=3.5).¹⁶

Cardiac manifestations. Subclinical hypothyroidism may be associated with ventricular dysfunction, myocardial infarction, and atherosclerosis.^18-20 A randomized controlled trial of 20 people with subclinical hypothyroidism found significantly improved left ventricular function assessed by echocardiography after 6 months of treatment with levothyroxine vs placebo.¹⁸ Whether treatment prevents myocardial infarction and atherosclerosis is unknown.^19,20 A cohort study, involving 2779 adults studied aged >20 years, did not find an association between subclinical hypothyroidism and ischemic heart disease.²

Risks of replacement. A meta-analysis of 41 controlled, cross-sectional studies involving 1250 women treated with thyroid replacement for all causes (ie, not specifically subclinical hypothyroidism) found that replacement therapy (mean duration of treatment, 7 to 9 years) was associated with bone loss in premenopausal women, but not in postmenopausal women.¹⁷

A randomized trial of 37 patients over 55 with subclinical hypothyroidism (28 of whom were women), found that thyroid hormone reduced bone mineral density, as assessed by dual-energy x-ray absorptiometry (DEXA) scans over a 10-month period.¹⁴ In several trials, patients withdrew due to adverse effects. Two of 37 patients receiving L-thyroxine in 1 study withdrew because of new atrial fibrillation and worsened angina, and 2 of 20 patients in another study withdrew because of nervousness and palpitations.^13,14

Recommendations from others

The US Preventive Services Task Force concluded the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults. The yield of screening is greater in high-risk groups such as postpartum women, people with Down syndrome, and the elderly; however, there is poor evidence that screening these groups leads to clinically important benefits.²¹

The American Thyroid Association recommends screening men and women beginning at age 35 and every 5 years thereafter.²² The American Academy of Family Physicians recommends screening for men and women over age 60.²³ The American College of Physicians states screening may be indicated in women over age 50.²⁴

Evidence Summary

Screening for hypothyroidism is more likely to detect the elevated TSH and normal free thyroxine level (FT4) of subclinical hypothyroidism than it is to detect overt hypothyroidism with a high TSH and a low FT4. We reviewed the accuracy of detection, natural history, and benefits and harms of treating subclinical hypothyroidism.

Detection. Subclinical hypothyroidism is found in 7% to 26% of women (with increasing prevalence as women reach age 60 and 70 years); overt hypothyroidism occurs in approximately 5%.^1-4 Two studies assessed the ability of the history and physical to detect hypothyroidism.

The first study evaluated 1154 women (aged 50–72) in a primary care setting using both history and physical and TSH testing. TSH testing found 3 women with overt hypothyroidism not identified by history and physical. History and physical identified 286 women with indications for TSH testing, 2 of whom had mild hypothyroidism and 1 with mild hyperthyroidism.⁵

In the second study, 2000 adults from a primary care population underwent history and physical and TSH testing. The TSH screen identified 19 cases of hypothyroidism not found by history and physical, while the history and physical prompted evaluation of 35 patients without abnormal TSH.⁶

Natural history of subclinical hypothyroidism. Among 1210 primary care patients (700 women) aged >60 years, 73 women with subclinical hypothyroidism were identified and followed for 12 months. Of these, 13 (18%) progressed to overt disease.⁷ Another prospective study of 30 patients (6 women) with subclinical hypothyroidism found 16 (3 women) who progressed to overt disease within 24 months. The remaining patients maintained normal FT4 levels for at least 15 years despite persistently elevated TSH.⁸ A third study followed 2779 adults (1494 women) with all types of thyroid disease for 20 years and found that 55% of women with TSH >6 and a positive antibody test developed overt hypothyroidism. Ninety percent of patients with an initial TSH >10 eventually progressed to overt disease.²

Serum lipid reduction. A retrospective study of 709 women referred to an endocrine clinic for evaluation of abnormal lipoprotein levels identified 34 (4.8%) with undiagnosed hypothyroidism. Thyroid hormone treatment significantly reduced total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with initial TSH >10, but not in those with a TSH <10.⁹

A randomized trial involving 42 women with subclinical hypothyroidism measured lipid levels before and after 6 months of levothyroxine treatment. Levothyroxine reduced total cholesterol and LDL significantly compared with placebo. Additionally, the subclinical hypothyroidism patients had higher baseline lipid levels when compared with 27 euthyroid controls.¹⁰

A meta-analysis combined 13 studies, involving 247 patients with subclinical hypothyroidism, all of whom were given thyroid replacement. All studies reported a decrease in total cholesterol (mean –7.9 mg/dL), and 9 reported a decrease in LDL (mean –10 mg/dL).¹¹ A second meta-analysis with 278 hypothyroid patients given thyroid replacement also found a reduction of total cholesterol (mean –15 mg/dL). LDL effects were not reported.¹² The clinical significance of lipid changes in these circumstances is unknown.

Symptom relief. Four small randomized controlled trials used symptom-rating scales to measure symptom relief with treatment of subclinical hypothyroidism. One study involved patients found by screening; the other 3 did not indicate means of diagnosis. Three studies found no significant improvement.^13-15 The most recent, involving 33 unblinded patients, found that those taking thyroid replacement had lower symptom scores (number needed to treat [NNT]=3.5).¹⁶

Cardiac manifestations. Subclinical hypothyroidism may be associated with ventricular dysfunction, myocardial infarction, and atherosclerosis.^18-20 A randomized controlled trial of 20 people with subclinical hypothyroidism found significantly improved left ventricular function assessed by echocardiography after 6 months of treatment with levothyroxine vs placebo.¹⁸ Whether treatment prevents myocardial infarction and atherosclerosis is unknown.^19,20 A cohort study, involving 2779 adults studied aged >20 years, did not find an association between subclinical hypothyroidism and ischemic heart disease.²

Risks of replacement. A meta-analysis of 41 controlled, cross-sectional studies involving 1250 women treated with thyroid replacement for all causes (ie, not specifically subclinical hypothyroidism) found that replacement therapy (mean duration of treatment, 7 to 9 years) was associated with bone loss in premenopausal women, but not in postmenopausal women.¹⁷

A randomized trial of 37 patients over 55 with subclinical hypothyroidism (28 of whom were women), found that thyroid hormone reduced bone mineral density, as assessed by dual-energy x-ray absorptiometry (DEXA) scans over a 10-month period.¹⁴ In several trials, patients withdrew due to adverse effects. Two of 37 patients receiving L-thyroxine in 1 study withdrew because of new atrial fibrillation and worsened angina, and 2 of 20 patients in another study withdrew because of nervousness and palpitations.^13,14

Recommendations from others

The US Preventive Services Task Force concluded the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults. The yield of screening is greater in high-risk groups such as postpartum women, people with Down syndrome, and the elderly; however, there is poor evidence that screening these groups leads to clinically important benefits.²¹

The American Thyroid Association recommends screening men and women beginning at age 35 and every 5 years thereafter.²² The American Academy of Family Physicians recommends screening for men and women over age 60.²³ The American College of Physicians states screening may be indicated in women over age 50.²⁴

Evidence Summary

Screening for hypothyroidism is more likely to detect the elevated TSH and normal free thyroxine level (FT4) of subclinical hypothyroidism than it is to detect overt hypothyroidism with a high TSH and a low FT4. We reviewed the accuracy of detection, natural history, and benefits and harms of treating subclinical hypothyroidism.

Detection. Subclinical hypothyroidism is found in 7% to 26% of women (with increasing prevalence as women reach age 60 and 70 years); overt hypothyroidism occurs in approximately 5%.^1-4 Two studies assessed the ability of the history and physical to detect hypothyroidism.

The first study evaluated 1154 women (aged 50–72) in a primary care setting using both history and physical and TSH testing. TSH testing found 3 women with overt hypothyroidism not identified by history and physical. History and physical identified 286 women with indications for TSH testing, 2 of whom had mild hypothyroidism and 1 with mild hyperthyroidism.⁵

In the second study, 2000 adults from a primary care population underwent history and physical and TSH testing. The TSH screen identified 19 cases of hypothyroidism not found by history and physical, while the history and physical prompted evaluation of 35 patients without abnormal TSH.⁶

Natural history of subclinical hypothyroidism. Among 1210 primary care patients (700 women) aged >60 years, 73 women with subclinical hypothyroidism were identified and followed for 12 months. Of these, 13 (18%) progressed to overt disease.⁷ Another prospective study of 30 patients (6 women) with subclinical hypothyroidism found 16 (3 women) who progressed to overt disease within 24 months. The remaining patients maintained normal FT4 levels for at least 15 years despite persistently elevated TSH.⁸ A third study followed 2779 adults (1494 women) with all types of thyroid disease for 20 years and found that 55% of women with TSH >6 and a positive antibody test developed overt hypothyroidism. Ninety percent of patients with an initial TSH >10 eventually progressed to overt disease.²

Serum lipid reduction. A retrospective study of 709 women referred to an endocrine clinic for evaluation of abnormal lipoprotein levels identified 34 (4.8%) with undiagnosed hypothyroidism. Thyroid hormone treatment significantly reduced total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with initial TSH >10, but not in those with a TSH <10.⁹

A randomized trial involving 42 women with subclinical hypothyroidism measured lipid levels before and after 6 months of levothyroxine treatment. Levothyroxine reduced total cholesterol and LDL significantly compared with placebo. Additionally, the subclinical hypothyroidism patients had higher baseline lipid levels when compared with 27 euthyroid controls.¹⁰

A meta-analysis combined 13 studies, involving 247 patients with subclinical hypothyroidism, all of whom were given thyroid replacement. All studies reported a decrease in total cholesterol (mean –7.9 mg/dL), and 9 reported a decrease in LDL (mean –10 mg/dL).¹¹ A second meta-analysis with 278 hypothyroid patients given thyroid replacement also found a reduction of total cholesterol (mean –15 mg/dL). LDL effects were not reported.¹² The clinical significance of lipid changes in these circumstances is unknown.

Symptom relief. Four small randomized controlled trials used symptom-rating scales to measure symptom relief with treatment of subclinical hypothyroidism. One study involved patients found by screening; the other 3 did not indicate means of diagnosis. Three studies found no significant improvement.^13-15 The most recent, involving 33 unblinded patients, found that those taking thyroid replacement had lower symptom scores (number needed to treat [NNT]=3.5).¹⁶

Cardiac manifestations. Subclinical hypothyroidism may be associated with ventricular dysfunction, myocardial infarction, and atherosclerosis.^18-20 A randomized controlled trial of 20 people with subclinical hypothyroidism found significantly improved left ventricular function assessed by echocardiography after 6 months of treatment with levothyroxine vs placebo.¹⁸ Whether treatment prevents myocardial infarction and atherosclerosis is unknown.^19,20 A cohort study, involving 2779 adults studied aged >20 years, did not find an association between subclinical hypothyroidism and ischemic heart disease.²

Risks of replacement. A meta-analysis of 41 controlled, cross-sectional studies involving 1250 women treated with thyroid replacement for all causes (ie, not specifically subclinical hypothyroidism) found that replacement therapy (mean duration of treatment, 7 to 9 years) was associated with bone loss in premenopausal women, but not in postmenopausal women.¹⁷

A randomized trial of 37 patients over 55 with subclinical hypothyroidism (28 of whom were women), found that thyroid hormone reduced bone mineral density, as assessed by dual-energy x-ray absorptiometry (DEXA) scans over a 10-month period.¹⁴ In several trials, patients withdrew due to adverse effects. Two of 37 patients receiving L-thyroxine in 1 study withdrew because of new atrial fibrillation and worsened angina, and 2 of 20 patients in another study withdrew because of nervousness and palpitations.^13,14

Recommendations from others

The US Preventive Services Task Force concluded the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults. The yield of screening is greater in high-risk groups such as postpartum women, people with Down syndrome, and the elderly; however, there is poor evidence that screening these groups leads to clinically important benefits.²¹

The American Thyroid Association recommends screening men and women beginning at age 35 and every 5 years thereafter.²² The American Academy of Family Physicians recommends screening for men and women over age 60.²³ The American College of Physicians states screening may be indicated in women over age 50.²⁴

Evidence summary

A systematic review of cardiac rehabilitation programs evaluated 14 randomized controlled trials with exercise-based interventions.¹ An updated review added 5 more for a total of 2984 patients with coronary heart disease.² Patients with coronary heart disease comprised those with prior MI, prior coronary artery bypass graft surgery, or PTCA, and those with angina pectoris and angiographically confirmed coronary heart disease.

Exercise-based cardiac rehabilitation significantly reduced all-cause mortality (relative risk [RR]=0.76; 95% confidence interval [CI], 0.59–0.98) compared with usual care (NNT=66; 95% CI, 35–273). Cardiac mortality also decreased significantly with exercise (RR=0.73; 95% CI, 0.56–0.96) compared with usual care (NNT=49; 95% CI, 26–120).

Six studies showed particularly significant improvement in total cardiac mortality.^3-8 Exercise was variably defined. Training sessions lasted 30 minutes and occurred on 2 to 5 days per week. Intensity was typically 75% to 85% of a maximum work capacity determined on an exercise test before initiating the training sessions. The type of exercise ranged from cycling alone to circuit training with 6 stationary devices. Patients were trained with supervision 1 to 36 months and followed for a mean of 24 months (range, 6–60 months).

A trend was observed toward decreased recurrence of nonfatal MI with exercise-based cardiac rehabilitation, which did not reach significance (RR=0.78; 95% CI, 0.59–1.03). An inadequate number of subjects is the most likely reason; however, other possibilities include an increase in the frequency of nonfatal MI after rehabilitation, or an increased rate of survival after MI for patients undergoing exercise-based rehabilitation.

The studies included in these reviews had several limitations. The population appears skewed in age (mean=54 years, with patients aged >65 years excluded from most studies) and gender (4.9% female); ethnicity was rarely reported. The adequacy of randomization was poor or unclear in 71% of studies, and only 4 trials reported blind assessment of outcomes. Finally, in 34% of studies the loss of participants to follow-up was more than 20%.

A well-done study randomized 101 male patients (age <70 years) with stable angina to either a daily exercise program or standard PTCA with stenting.⁹ After 12 months, event-free survival was significantly greater among patients randomized to exercise than in those randomized to PTCA with stenting (88% vs 70%; P=.023; NNT=5.5). Cardiovascular events were defined as percutaneous interventions, hospitalizations, acute MI, cerebrovascular accidents, coronary artery bypass graft operation, and death.

Recommendation from others

The American Heart Association (AHA) supports aggressive risk factor management for patients with coronary heart disease, and recommends a minimum of 30 minutes of exercise 3 to 4 days per week as well as an increase in daily lifestyle activities.¹⁰ The American College of Cardiology endorses the position of the AHA.

Evidence summary

A systematic review of cardiac rehabilitation programs evaluated 14 randomized controlled trials with exercise-based interventions.¹ An updated review added 5 more for a total of 2984 patients with coronary heart disease.² Patients with coronary heart disease comprised those with prior MI, prior coronary artery bypass graft surgery, or PTCA, and those with angina pectoris and angiographically confirmed coronary heart disease.

Exercise-based cardiac rehabilitation significantly reduced all-cause mortality (relative risk [RR]=0.76; 95% confidence interval [CI], 0.59–0.98) compared with usual care (NNT=66; 95% CI, 35–273). Cardiac mortality also decreased significantly with exercise (RR=0.73; 95% CI, 0.56–0.96) compared with usual care (NNT=49; 95% CI, 26–120).

Six studies showed particularly significant improvement in total cardiac mortality.^3-8 Exercise was variably defined. Training sessions lasted 30 minutes and occurred on 2 to 5 days per week. Intensity was typically 75% to 85% of a maximum work capacity determined on an exercise test before initiating the training sessions. The type of exercise ranged from cycling alone to circuit training with 6 stationary devices. Patients were trained with supervision 1 to 36 months and followed for a mean of 24 months (range, 6–60 months).

A trend was observed toward decreased recurrence of nonfatal MI with exercise-based cardiac rehabilitation, which did not reach significance (RR=0.78; 95% CI, 0.59–1.03). An inadequate number of subjects is the most likely reason; however, other possibilities include an increase in the frequency of nonfatal MI after rehabilitation, or an increased rate of survival after MI for patients undergoing exercise-based rehabilitation.

The studies included in these reviews had several limitations. The population appears skewed in age (mean=54 years, with patients aged >65 years excluded from most studies) and gender (4.9% female); ethnicity was rarely reported. The adequacy of randomization was poor or unclear in 71% of studies, and only 4 trials reported blind assessment of outcomes. Finally, in 34% of studies the loss of participants to follow-up was more than 20%.

A well-done study randomized 101 male patients (age <70 years) with stable angina to either a daily exercise program or standard PTCA with stenting.⁹ After 12 months, event-free survival was significantly greater among patients randomized to exercise than in those randomized to PTCA with stenting (88% vs 70%; P=.023; NNT=5.5). Cardiovascular events were defined as percutaneous interventions, hospitalizations, acute MI, cerebrovascular accidents, coronary artery bypass graft operation, and death.

Recommendation from others

The American Heart Association (AHA) supports aggressive risk factor management for patients with coronary heart disease, and recommends a minimum of 30 minutes of exercise 3 to 4 days per week as well as an increase in daily lifestyle activities.¹⁰ The American College of Cardiology endorses the position of the AHA.

Evidence summary

A systematic review of cardiac rehabilitation programs evaluated 14 randomized controlled trials with exercise-based interventions.¹ An updated review added 5 more for a total of 2984 patients with coronary heart disease.² Patients with coronary heart disease comprised those with prior MI, prior coronary artery bypass graft surgery, or PTCA, and those with angina pectoris and angiographically confirmed coronary heart disease.

Exercise-based cardiac rehabilitation significantly reduced all-cause mortality (relative risk [RR]=0.76; 95% confidence interval [CI], 0.59–0.98) compared with usual care (NNT=66; 95% CI, 35–273). Cardiac mortality also decreased significantly with exercise (RR=0.73; 95% CI, 0.56–0.96) compared with usual care (NNT=49; 95% CI, 26–120).

Six studies showed particularly significant improvement in total cardiac mortality.^3-8 Exercise was variably defined. Training sessions lasted 30 minutes and occurred on 2 to 5 days per week. Intensity was typically 75% to 85% of a maximum work capacity determined on an exercise test before initiating the training sessions. The type of exercise ranged from cycling alone to circuit training with 6 stationary devices. Patients were trained with supervision 1 to 36 months and followed for a mean of 24 months (range, 6–60 months).

A trend was observed toward decreased recurrence of nonfatal MI with exercise-based cardiac rehabilitation, which did not reach significance (RR=0.78; 95% CI, 0.59–1.03). An inadequate number of subjects is the most likely reason; however, other possibilities include an increase in the frequency of nonfatal MI after rehabilitation, or an increased rate of survival after MI for patients undergoing exercise-based rehabilitation.

The studies included in these reviews had several limitations. The population appears skewed in age (mean=54 years, with patients aged >65 years excluded from most studies) and gender (4.9% female); ethnicity was rarely reported. The adequacy of randomization was poor or unclear in 71% of studies, and only 4 trials reported blind assessment of outcomes. Finally, in 34% of studies the loss of participants to follow-up was more than 20%.

A well-done study randomized 101 male patients (age <70 years) with stable angina to either a daily exercise program or standard PTCA with stenting.⁹ After 12 months, event-free survival was significantly greater among patients randomized to exercise than in those randomized to PTCA with stenting (88% vs 70%; P=.023; NNT=5.5). Cardiovascular events were defined as percutaneous interventions, hospitalizations, acute MI, cerebrovascular accidents, coronary artery bypass graft operation, and death.

Recommendation from others

The American Heart Association (AHA) supports aggressive risk factor management for patients with coronary heart disease, and recommends a minimum of 30 minutes of exercise 3 to 4 days per week as well as an increase in daily lifestyle activities.¹⁰ The American College of Cardiology endorses the position of the AHA.

Evidence summary

We found no studies evaluating statins for the primary prevention of stroke. An observational study of 433 patients with ischemic stroke found that patients who were taking statins before hospital admission more often had better outcomes (51%) than those who were not taking statins (38%). However, the groups differed in many respects.¹ Many coronary event prevention and treatment trials using statins include the risk of primary and recurrent ischemic stroke as secondary endpoints for patients with high cardiac risk.

Primary prevention of stroke in vascular disease. The Heart Protection Study followed 20,536 patients in the United Kingdom (aged 40–80 years), 3280 with a history of cerebrovascular disease (defined as nondisabling stroke, transient cerebral ischemic attack, or carotid endarterectomy or angioplasty) and 17,256 with other occlusive arterial disease, coronary artery disease, or diabetes. Patients were randomized to receive either simvastatin 40 mg or placebo for an average of 5 years. The endpoint was major vascular events: myocardial infarction, stroke of any type, and revascularization procedure.

Simvastatin reduced the combined risk of non-fatal or fatal ischemic stroke for patients with no history of cerebrovascular disease (3.2% for simvastatin vs 4.8% with placebo; relative risk reduction=33%, number needed to treat [NNT]=63; P=.0001).² As noted in other well-done studies, the Heart Protection Study showed no difference in the number of hemorrhagic strokes between treatment and placebo groups. There were 3500 subjects with pretreatment low-density lipoprotein (LDL) cholesterol <100 mg/dL; lowering LDL to 65 mg/dL reduced major vascular event risk by about 25%.³

Hypertension with multiple cardiovascular risk factors and cholesterol <250 mg/dL. The ASCOT-LLA study compared atorvastatin with placebo in 10,305 hypertensive Caucasian patients with multiple cardiovascular risk factors and a total nonfasting cholesterol of 250 mg/dL (6.5 mmol/L) or less. Patients were aged 40 to 79 years and had at least 3 other cardiovascular risk factors (left ventricular hypertrophy, abnormal electrocardiogram, type 2 diabetes, peripheral artery disease, stroke or transient ischemic attack, male sex, age >55 years, proteinuria or microalbuminuria, smoking, family history of premature coronary heart disease). The study was stopped early at a median of 3.3 years because atorvastatin significantly reduced cardiac events. Atorvastatin also significantly reduced ischemic strokes when compared with placebo (relative risk [RR]=0.73, 95% confidence interval [CI], 0.56–0.96; P=.024). This study did not differentiate between first or second stroke. The NNT was 155.⁴

Ischemic stroke and coronary disease. The LIPID trial randomized 9014 patients with a history of acute coronary syndromes and total cholesterol of 150 to 270 mg/dL (4 to 7 mmol/L) to either pravastatin or placebo and followed them for 6 years. Among the 350 patients with prior ischemic stroke, there were 388 new ischemic stokes over the course of the study. When adjusted for risk factors (atrial fibrillation, history of cerebrovascular accident, diabetes, hypertension, cigarette smoking, body mass index, and male sex), pravastatin reduced recurrent ischemic stroke by 21% relative to placebo (P=.024). The reduction was not modified by baseline lipid level.⁵

A meta-analysis of 15 randomized placebo-controlled trials using various statins (32,684 participants) assessed the risk of strokes for patients with a history of coronary disease. Among patients who had cerebrovascular disease, statins significantly reduced recurrent ischemic stroke (RR=0.74; 95% CI, 0.64–0.86). One recurrence of ischemic stroke would be prevented for every 110 coronary disease patients treated with a statin. Achieving final total cholesterol <232 mg/dL correlated with reduced risk of recurrent stroke.⁶ Three of the studies evaluated primary prevention of stroke and did not show a significant risk reduction (RR=0.85; P=.4). Statins did not reduce the rate of hemorrhagic stroke or fatal strokes.

Risks of statins. In 1 study involving 35,000 participants and 158,000 person-years of observation, there were 8 cases of rhabdomyolysis in the treatment groups vs 5 in the placebo groups.⁷ Forty-three deaths attributed to statin therapy have been reported to the Food and Drug Administration from 1987 to 2001, or 1 per million person-years of use. The Heart Protection Study found simvastatin and placebo users reported myopathy or muscle pain at the same annual rate of 0.01%.

Recommendations from others

We found no recommendations specifically regarding the use of statins to prevent stroke. However, the Third Report of the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) describes symptomatic carotid artery disease as a coronary heart disease risk equivalent and recommends therapy to reduce the LDL below 100 mg/dL.⁸

Evidence summary

We found no studies evaluating statins for the primary prevention of stroke. An observational study of 433 patients with ischemic stroke found that patients who were taking statins before hospital admission more often had better outcomes (51%) than those who were not taking statins (38%). However, the groups differed in many respects.¹ Many coronary event prevention and treatment trials using statins include the risk of primary and recurrent ischemic stroke as secondary endpoints for patients with high cardiac risk.

Primary prevention of stroke in vascular disease. The Heart Protection Study followed 20,536 patients in the United Kingdom (aged 40–80 years), 3280 with a history of cerebrovascular disease (defined as nondisabling stroke, transient cerebral ischemic attack, or carotid endarterectomy or angioplasty) and 17,256 with other occlusive arterial disease, coronary artery disease, or diabetes. Patients were randomized to receive either simvastatin 40 mg or placebo for an average of 5 years. The endpoint was major vascular events: myocardial infarction, stroke of any type, and revascularization procedure.

Simvastatin reduced the combined risk of non-fatal or fatal ischemic stroke for patients with no history of cerebrovascular disease (3.2% for simvastatin vs 4.8% with placebo; relative risk reduction=33%, number needed to treat [NNT]=63; P=.0001).² As noted in other well-done studies, the Heart Protection Study showed no difference in the number of hemorrhagic strokes between treatment and placebo groups. There were 3500 subjects with pretreatment low-density lipoprotein (LDL) cholesterol <100 mg/dL; lowering LDL to 65 mg/dL reduced major vascular event risk by about 25%.³

Hypertension with multiple cardiovascular risk factors and cholesterol <250 mg/dL. The ASCOT-LLA study compared atorvastatin with placebo in 10,305 hypertensive Caucasian patients with multiple cardiovascular risk factors and a total nonfasting cholesterol of 250 mg/dL (6.5 mmol/L) or less. Patients were aged 40 to 79 years and had at least 3 other cardiovascular risk factors (left ventricular hypertrophy, abnormal electrocardiogram, type 2 diabetes, peripheral artery disease, stroke or transient ischemic attack, male sex, age >55 years, proteinuria or microalbuminuria, smoking, family history of premature coronary heart disease). The study was stopped early at a median of 3.3 years because atorvastatin significantly reduced cardiac events. Atorvastatin also significantly reduced ischemic strokes when compared with placebo (relative risk [RR]=0.73, 95% confidence interval [CI], 0.56–0.96; P=.024). This study did not differentiate between first or second stroke. The NNT was 155.⁴

Ischemic stroke and coronary disease. The LIPID trial randomized 9014 patients with a history of acute coronary syndromes and total cholesterol of 150 to 270 mg/dL (4 to 7 mmol/L) to either pravastatin or placebo and followed them for 6 years. Among the 350 patients with prior ischemic stroke, there were 388 new ischemic stokes over the course of the study. When adjusted for risk factors (atrial fibrillation, history of cerebrovascular accident, diabetes, hypertension, cigarette smoking, body mass index, and male sex), pravastatin reduced recurrent ischemic stroke by 21% relative to placebo (P=.024). The reduction was not modified by baseline lipid level.⁵

A meta-analysis of 15 randomized placebo-controlled trials using various statins (32,684 participants) assessed the risk of strokes for patients with a history of coronary disease. Among patients who had cerebrovascular disease, statins significantly reduced recurrent ischemic stroke (RR=0.74; 95% CI, 0.64–0.86). One recurrence of ischemic stroke would be prevented for every 110 coronary disease patients treated with a statin. Achieving final total cholesterol <232 mg/dL correlated with reduced risk of recurrent stroke.⁶ Three of the studies evaluated primary prevention of stroke and did not show a significant risk reduction (RR=0.85; P=.4). Statins did not reduce the rate of hemorrhagic stroke or fatal strokes.

Risks of statins. In 1 study involving 35,000 participants and 158,000 person-years of observation, there were 8 cases of rhabdomyolysis in the treatment groups vs 5 in the placebo groups.⁷ Forty-three deaths attributed to statin therapy have been reported to the Food and Drug Administration from 1987 to 2001, or 1 per million person-years of use. The Heart Protection Study found simvastatin and placebo users reported myopathy or muscle pain at the same annual rate of 0.01%.

Recommendations from others

We found no recommendations specifically regarding the use of statins to prevent stroke. However, the Third Report of the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) describes symptomatic carotid artery disease as a coronary heart disease risk equivalent and recommends therapy to reduce the LDL below 100 mg/dL.⁸

Evidence summary

We found no studies evaluating statins for the primary prevention of stroke. An observational study of 433 patients with ischemic stroke found that patients who were taking statins before hospital admission more often had better outcomes (51%) than those who were not taking statins (38%). However, the groups differed in many respects.¹ Many coronary event prevention and treatment trials using statins include the risk of primary and recurrent ischemic stroke as secondary endpoints for patients with high cardiac risk.

Primary prevention of stroke in vascular disease. The Heart Protection Study followed 20,536 patients in the United Kingdom (aged 40–80 years), 3280 with a history of cerebrovascular disease (defined as nondisabling stroke, transient cerebral ischemic attack, or carotid endarterectomy or angioplasty) and 17,256 with other occlusive arterial disease, coronary artery disease, or diabetes. Patients were randomized to receive either simvastatin 40 mg or placebo for an average of 5 years. The endpoint was major vascular events: myocardial infarction, stroke of any type, and revascularization procedure.

Simvastatin reduced the combined risk of non-fatal or fatal ischemic stroke for patients with no history of cerebrovascular disease (3.2% for simvastatin vs 4.8% with placebo; relative risk reduction=33%, number needed to treat [NNT]=63; P=.0001).² As noted in other well-done studies, the Heart Protection Study showed no difference in the number of hemorrhagic strokes between treatment and placebo groups. There were 3500 subjects with pretreatment low-density lipoprotein (LDL) cholesterol <100 mg/dL; lowering LDL to 65 mg/dL reduced major vascular event risk by about 25%.³

Hypertension with multiple cardiovascular risk factors and cholesterol <250 mg/dL. The ASCOT-LLA study compared atorvastatin with placebo in 10,305 hypertensive Caucasian patients with multiple cardiovascular risk factors and a total nonfasting cholesterol of 250 mg/dL (6.5 mmol/L) or less. Patients were aged 40 to 79 years and had at least 3 other cardiovascular risk factors (left ventricular hypertrophy, abnormal electrocardiogram, type 2 diabetes, peripheral artery disease, stroke or transient ischemic attack, male sex, age >55 years, proteinuria or microalbuminuria, smoking, family history of premature coronary heart disease). The study was stopped early at a median of 3.3 years because atorvastatin significantly reduced cardiac events. Atorvastatin also significantly reduced ischemic strokes when compared with placebo (relative risk [RR]=0.73, 95% confidence interval [CI], 0.56–0.96; P=.024). This study did not differentiate between first or second stroke. The NNT was 155.⁴

Ischemic stroke and coronary disease. The LIPID trial randomized 9014 patients with a history of acute coronary syndromes and total cholesterol of 150 to 270 mg/dL (4 to 7 mmol/L) to either pravastatin or placebo and followed them for 6 years. Among the 350 patients with prior ischemic stroke, there were 388 new ischemic stokes over the course of the study. When adjusted for risk factors (atrial fibrillation, history of cerebrovascular accident, diabetes, hypertension, cigarette smoking, body mass index, and male sex), pravastatin reduced recurrent ischemic stroke by 21% relative to placebo (P=.024). The reduction was not modified by baseline lipid level.⁵

A meta-analysis of 15 randomized placebo-controlled trials using various statins (32,684 participants) assessed the risk of strokes for patients with a history of coronary disease. Among patients who had cerebrovascular disease, statins significantly reduced recurrent ischemic stroke (RR=0.74; 95% CI, 0.64–0.86). One recurrence of ischemic stroke would be prevented for every 110 coronary disease patients treated with a statin. Achieving final total cholesterol <232 mg/dL correlated with reduced risk of recurrent stroke.⁶ Three of the studies evaluated primary prevention of stroke and did not show a significant risk reduction (RR=0.85; P=.4). Statins did not reduce the rate of hemorrhagic stroke or fatal strokes.

Risks of statins. In 1 study involving 35,000 participants and 158,000 person-years of observation, there were 8 cases of rhabdomyolysis in the treatment groups vs 5 in the placebo groups.⁷ Forty-three deaths attributed to statin therapy have been reported to the Food and Drug Administration from 1987 to 2001, or 1 per million person-years of use. The Heart Protection Study found simvastatin and placebo users reported myopathy or muscle pain at the same annual rate of 0.01%.

Recommendations from others

We found no recommendations specifically regarding the use of statins to prevent stroke. However, the Third Report of the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) describes symptomatic carotid artery disease as a coronary heart disease risk equivalent and recommends therapy to reduce the LDL below 100 mg/dL.⁸

Evidence summary

The leading cause of morbidity and mortality in the United States is cardiovascular disease (ischemic CHD, stroke, peripheral vascular disease).¹ A meta-analysis of 5 placebo-controlled randomized controlled trials involving more than 50,000 patients free of CHD and stroke evaluated aspirin for primary prevention of cardiovascular disease. Since 3 of the trials excluded women, only 20% of the participants were female. The mean age of participants was 57 years.

The treatment groups took aspirin 75 to 500 mg/d for 3 to 7 years. The meta-analysis found that compared with placebo, aspirin significantly reduced total CHD events (odds ratio [OR]=0.72; 95% confidence interval [CI], 0.60–0.87).² Aspirin did not reduce coronary disease mortality (OR=0.87; 95% CI, 0.70–1.09); however, results from 1 study did achieve statistical significance (OR=0.64; 95% CI, 0.42–0.99).³ No differences were found between aspirin-treated and control groups for all-cause mortality or ischemic stroke reduction.

Aspirin increased the risk of major gastrointestinal bleeding events by almost twofold (OR=1.70; 95% CI, 1.4–2.1). Three of the 5 trials showed no significant increase of intracranial hemorrhage event rates (OR=1.4; 95% CI, 0.9–2.0). Based on combined primary and secondary prevention trials, the risk of intracranial bleeding with aspirin is estimated at 0 to 2 events per 1000 patients per year.²

Although the ideal aspirin dosage is uncertain, lower dosages (75–81 mg/d) have been shown to be as beneficial as higher dosages, and may have fewer bleeding complications. Buffered and entericcoated formulations are no more protective than plain aspirin.⁴

In patients with no known cardiovascular disease, aspirin chemoprevention has been shown to decrease the risk of nonfatal MI and fatal CHD by 28%. At a 5-year CHD risk of 3%, the benefits of prophylaxis outweigh the harms (see Table ) by 2 to 1—assuming the events of stroke, MI, and bleeding are considered roughly equivalent in severity. (A different threshold may be appropriate for patients that perceive 1 of these events as significantly more serious than the others.) Typical patients at a 3% or greater risk for cardiovascular disease include men aged >40 years, post-menopausal women, and younger persons with risk factors for CHD. Physicians determine cardiovascular risk from the presence and severity of risk factors: gender, age, blood pressure, lipid status, diabetes, and smoking status.

Simple risk-assessment tools based on Framingham data are available for computers and palmtop devices (eg, Heart to Heart CV Risk Assessment Calculator, www.meddecisions.com; National Institutes of Health, www.nhlbi.nih.gov/health/prof/heart/). Because only 2 trials included women, it is less clear whether both sexes benefit equally from aspirin prophylaxis.¹

TABLE
Net benefits and harms of aspirin prophylaxis, per 1000 patients

Recommendations from others

The US Preventive Services Task Force recommends that clinicians discuss aspirin prophylaxis with adults at increased risk for CHD (defined as a 5-year risk of 3% or more). Discussion should include the potential benefits and harms of aspirin therapy.⁵

The American Heart Association recommends low-dose aspirin in people at higher risk of coronary heart disease (especially those with a 10-year CHD risk of 10% or greater).⁶ The European Society of Cardiology says there is evidence that low-dose aspirin can reduce the risk of cardiovascular events in asymptomatic high-risk people, such as those with diabetes or well-controlled hypertension, and in men at high multifactorial risk of cardiovascular disease.⁷

Evidence summary

The leading cause of morbidity and mortality in the United States is cardiovascular disease (ischemic CHD, stroke, peripheral vascular disease).¹ A meta-analysis of 5 placebo-controlled randomized controlled trials involving more than 50,000 patients free of CHD and stroke evaluated aspirin for primary prevention of cardiovascular disease. Since 3 of the trials excluded women, only 20% of the participants were female. The mean age of participants was 57 years.

The treatment groups took aspirin 75 to 500 mg/d for 3 to 7 years. The meta-analysis found that compared with placebo, aspirin significantly reduced total CHD events (odds ratio [OR]=0.72; 95% confidence interval [CI], 0.60–0.87).² Aspirin did not reduce coronary disease mortality (OR=0.87; 95% CI, 0.70–1.09); however, results from 1 study did achieve statistical significance (OR=0.64; 95% CI, 0.42–0.99).³ No differences were found between aspirin-treated and control groups for all-cause mortality or ischemic stroke reduction.

Aspirin increased the risk of major gastrointestinal bleeding events by almost twofold (OR=1.70; 95% CI, 1.4–2.1). Three of the 5 trials showed no significant increase of intracranial hemorrhage event rates (OR=1.4; 95% CI, 0.9–2.0). Based on combined primary and secondary prevention trials, the risk of intracranial bleeding with aspirin is estimated at 0 to 2 events per 1000 patients per year.²

Although the ideal aspirin dosage is uncertain, lower dosages (75–81 mg/d) have been shown to be as beneficial as higher dosages, and may have fewer bleeding complications. Buffered and entericcoated formulations are no more protective than plain aspirin.⁴

In patients with no known cardiovascular disease, aspirin chemoprevention has been shown to decrease the risk of nonfatal MI and fatal CHD by 28%. At a 5-year CHD risk of 3%, the benefits of prophylaxis outweigh the harms (see Table ) by 2 to 1—assuming the events of stroke, MI, and bleeding are considered roughly equivalent in severity. (A different threshold may be appropriate for patients that perceive 1 of these events as significantly more serious than the others.) Typical patients at a 3% or greater risk for cardiovascular disease include men aged >40 years, post-menopausal women, and younger persons with risk factors for CHD. Physicians determine cardiovascular risk from the presence and severity of risk factors: gender, age, blood pressure, lipid status, diabetes, and smoking status.

Simple risk-assessment tools based on Framingham data are available for computers and palmtop devices (eg, Heart to Heart CV Risk Assessment Calculator, www.meddecisions.com; National Institutes of Health, www.nhlbi.nih.gov/health/prof/heart/). Because only 2 trials included women, it is less clear whether both sexes benefit equally from aspirin prophylaxis.¹

TABLE
Net benefits and harms of aspirin prophylaxis, per 1000 patients

Recommendations from others

The US Preventive Services Task Force recommends that clinicians discuss aspirin prophylaxis with adults at increased risk for CHD (defined as a 5-year risk of 3% or more). Discussion should include the potential benefits and harms of aspirin therapy.⁵

The American Heart Association recommends low-dose aspirin in people at higher risk of coronary heart disease (especially those with a 10-year CHD risk of 10% or greater).⁶ The European Society of Cardiology says there is evidence that low-dose aspirin can reduce the risk of cardiovascular events in asymptomatic high-risk people, such as those with diabetes or well-controlled hypertension, and in men at high multifactorial risk of cardiovascular disease.⁷

Evidence summary

The leading cause of morbidity and mortality in the United States is cardiovascular disease (ischemic CHD, stroke, peripheral vascular disease).¹ A meta-analysis of 5 placebo-controlled randomized controlled trials involving more than 50,000 patients free of CHD and stroke evaluated aspirin for primary prevention of cardiovascular disease. Since 3 of the trials excluded women, only 20% of the participants were female. The mean age of participants was 57 years.

The treatment groups took aspirin 75 to 500 mg/d for 3 to 7 years. The meta-analysis found that compared with placebo, aspirin significantly reduced total CHD events (odds ratio [OR]=0.72; 95% confidence interval [CI], 0.60–0.87).² Aspirin did not reduce coronary disease mortality (OR=0.87; 95% CI, 0.70–1.09); however, results from 1 study did achieve statistical significance (OR=0.64; 95% CI, 0.42–0.99).³ No differences were found between aspirin-treated and control groups for all-cause mortality or ischemic stroke reduction.

Aspirin increased the risk of major gastrointestinal bleeding events by almost twofold (OR=1.70; 95% CI, 1.4–2.1). Three of the 5 trials showed no significant increase of intracranial hemorrhage event rates (OR=1.4; 95% CI, 0.9–2.0). Based on combined primary and secondary prevention trials, the risk of intracranial bleeding with aspirin is estimated at 0 to 2 events per 1000 patients per year.²

Although the ideal aspirin dosage is uncertain, lower dosages (75–81 mg/d) have been shown to be as beneficial as higher dosages, and may have fewer bleeding complications. Buffered and entericcoated formulations are no more protective than plain aspirin.⁴

In patients with no known cardiovascular disease, aspirin chemoprevention has been shown to decrease the risk of nonfatal MI and fatal CHD by 28%. At a 5-year CHD risk of 3%, the benefits of prophylaxis outweigh the harms (see Table ) by 2 to 1—assuming the events of stroke, MI, and bleeding are considered roughly equivalent in severity. (A different threshold may be appropriate for patients that perceive 1 of these events as significantly more serious than the others.) Typical patients at a 3% or greater risk for cardiovascular disease include men aged >40 years, post-menopausal women, and younger persons with risk factors for CHD. Physicians determine cardiovascular risk from the presence and severity of risk factors: gender, age, blood pressure, lipid status, diabetes, and smoking status.

Simple risk-assessment tools based on Framingham data are available for computers and palmtop devices (eg, Heart to Heart CV Risk Assessment Calculator, www.meddecisions.com; National Institutes of Health, www.nhlbi.nih.gov/health/prof/heart/). Because only 2 trials included women, it is less clear whether both sexes benefit equally from aspirin prophylaxis.¹

TABLE
Net benefits and harms of aspirin prophylaxis, per 1000 patients

Recommendations from others

The US Preventive Services Task Force recommends that clinicians discuss aspirin prophylaxis with adults at increased risk for CHD (defined as a 5-year risk of 3% or more). Discussion should include the potential benefits and harms of aspirin therapy.⁵

The American Heart Association recommends low-dose aspirin in people at higher risk of coronary heart disease (especially those with a 10-year CHD risk of 10% or greater).⁶ The European Society of Cardiology says there is evidence that low-dose aspirin can reduce the risk of cardiovascular events in asymptomatic high-risk people, such as those with diabetes or well-controlled hypertension, and in men at high multifactorial risk of cardiovascular disease.⁷

Evidence summary

Asymptomatic microhematuria is common in adult primary care populations, with a prevalence ranging from 2.5% to 4.3% in 3 studies.^1-3 It is variably associated with urologic disease.

A retrospective cohort study of 2005 British men aged >40 years found 85 (4%) with asymptomatic microhematuria. Subsequent evaluation including intravenous pyelogram and cystoscopy found 2 men with infections—1 with bladder cancer and 1 with polycystic kidneys. Benign prostatic hypertrophy, prostatitis, anatomic abnormalities, and stones accounted for the rest.³

A prospective cohort study similarly evaluated 1034 patients with asymptomatic micro-hematuria found through annual health screening of Japanese adults; 471 (45%) had some urologic diagnosis, including 30 (2.9%) with serious disease (urologic malignancies or progressive glomerulopathy), 195 (18.9%) with moderate disease (such as stones, infection, stable glomerulopathy), and the remainder with less serious disease.⁴

However, it is unclear whether asymptomatic microhematuria is a useful marker for detecting urologic disease. Two retrospective cohort studies assessed the prevalence of urologic disease in patients with asymptomatic microhematuria compared with those without. Of 501 male steel-workers—an occupation believed to have a higher risk for urologic malignancy—57 men had urologic disease of any type. Six men with urolog-ic disease had asymptomatic microhematuria, while 51 men with urologic disease did not. The correlation between asymptomatic microhema-turia and the presence of urologic disease was not significant (P>.05). There were 3 cases of urolog-ic cancer in the study, all diagnosed in men without asymptomatic microhematuria.⁵

Among 20,751 California HMO patients who had a periodic health appraisal, screening identified 598 patients with asymptomatic microhematuria (prevalence=2.9%). The medical records for all patients were reviewed for the year prior to screening to find pre-existing urologic disease and then reviewed for new diagnoses over the next 6 years. Three cases of urologic cancer occurred in the group of patients with asymptomatic microhematuria (incidence=0.5%) and 102 cancer cases among the 20,153 patients without asymptomatic microhematuria (incidence=0.5%). Its presence was not significantly associated with either uro-logic cancers or other serious urologic disease.²

No studies demonstrate improved outcomes from screening for asymptomatic microhematuria. Earlier discovery of serious diseases would not often change patient outcome, according to expert opinion.^6,7 Invasive studies, such as intravenous pyelogram and cystoscopy, used to evaluate asymptomatic microhematuria have a rate of serious complications approaching 0.3% (number needed to harm=333).⁷

Recommendations from others

The American Urological Association recommends that all patients with asymptomatic microhematuria be evaluated. However, they do not recommend routine screening for asympto-matic microhematuria to detect urologic malig-nancy.⁸ The US Preventive Services Task Force does not recommend routine screening for bladder cancer by any means, including screening for hematuria.⁹

Evidence summary

Asymptomatic microhematuria is common in adult primary care populations, with a prevalence ranging from 2.5% to 4.3% in 3 studies.^1-3 It is variably associated with urologic disease.

A retrospective cohort study of 2005 British men aged >40 years found 85 (4%) with asymptomatic microhematuria. Subsequent evaluation including intravenous pyelogram and cystoscopy found 2 men with infections—1 with bladder cancer and 1 with polycystic kidneys. Benign prostatic hypertrophy, prostatitis, anatomic abnormalities, and stones accounted for the rest.³

A prospective cohort study similarly evaluated 1034 patients with asymptomatic micro-hematuria found through annual health screening of Japanese adults; 471 (45%) had some urologic diagnosis, including 30 (2.9%) with serious disease (urologic malignancies or progressive glomerulopathy), 195 (18.9%) with moderate disease (such as stones, infection, stable glomerulopathy), and the remainder with less serious disease.⁴

However, it is unclear whether asymptomatic microhematuria is a useful marker for detecting urologic disease. Two retrospective cohort studies assessed the prevalence of urologic disease in patients with asymptomatic microhematuria compared with those without. Of 501 male steel-workers—an occupation believed to have a higher risk for urologic malignancy—57 men had urologic disease of any type. Six men with urolog-ic disease had asymptomatic microhematuria, while 51 men with urologic disease did not. The correlation between asymptomatic microhema-turia and the presence of urologic disease was not significant (P>.05). There were 3 cases of urolog-ic cancer in the study, all diagnosed in men without asymptomatic microhematuria.⁵

Among 20,751 California HMO patients who had a periodic health appraisal, screening identified 598 patients with asymptomatic microhematuria (prevalence=2.9%). The medical records for all patients were reviewed for the year prior to screening to find pre-existing urologic disease and then reviewed for new diagnoses over the next 6 years. Three cases of urologic cancer occurred in the group of patients with asymptomatic microhematuria (incidence=0.5%) and 102 cancer cases among the 20,153 patients without asymptomatic microhematuria (incidence=0.5%). Its presence was not significantly associated with either uro-logic cancers or other serious urologic disease.²

No studies demonstrate improved outcomes from screening for asymptomatic microhematuria. Earlier discovery of serious diseases would not often change patient outcome, according to expert opinion.^6,7 Invasive studies, such as intravenous pyelogram and cystoscopy, used to evaluate asymptomatic microhematuria have a rate of serious complications approaching 0.3% (number needed to harm=333).⁷

Recommendations from others

The American Urological Association recommends that all patients with asymptomatic microhematuria be evaluated. However, they do not recommend routine screening for asympto-matic microhematuria to detect urologic malig-nancy.⁸ The US Preventive Services Task Force does not recommend routine screening for bladder cancer by any means, including screening for hematuria.⁹

Evidence summary

Asymptomatic microhematuria is common in adult primary care populations, with a prevalence ranging from 2.5% to 4.3% in 3 studies.^1-3 It is variably associated with urologic disease.

A retrospective cohort study of 2005 British men aged >40 years found 85 (4%) with asymptomatic microhematuria. Subsequent evaluation including intravenous pyelogram and cystoscopy found 2 men with infections—1 with bladder cancer and 1 with polycystic kidneys. Benign prostatic hypertrophy, prostatitis, anatomic abnormalities, and stones accounted for the rest.³

A prospective cohort study similarly evaluated 1034 patients with asymptomatic micro-hematuria found through annual health screening of Japanese adults; 471 (45%) had some urologic diagnosis, including 30 (2.9%) with serious disease (urologic malignancies or progressive glomerulopathy), 195 (18.9%) with moderate disease (such as stones, infection, stable glomerulopathy), and the remainder with less serious disease.⁴

However, it is unclear whether asymptomatic microhematuria is a useful marker for detecting urologic disease. Two retrospective cohort studies assessed the prevalence of urologic disease in patients with asymptomatic microhematuria compared with those without. Of 501 male steel-workers—an occupation believed to have a higher risk for urologic malignancy—57 men had urologic disease of any type. Six men with urolog-ic disease had asymptomatic microhematuria, while 51 men with urologic disease did not. The correlation between asymptomatic microhema-turia and the presence of urologic disease was not significant (P>.05). There were 3 cases of urolog-ic cancer in the study, all diagnosed in men without asymptomatic microhematuria.⁵

Among 20,751 California HMO patients who had a periodic health appraisal, screening identified 598 patients with asymptomatic microhematuria (prevalence=2.9%). The medical records for all patients were reviewed for the year prior to screening to find pre-existing urologic disease and then reviewed for new diagnoses over the next 6 years. Three cases of urologic cancer occurred in the group of patients with asymptomatic microhematuria (incidence=0.5%) and 102 cancer cases among the 20,153 patients without asymptomatic microhematuria (incidence=0.5%). Its presence was not significantly associated with either uro-logic cancers or other serious urologic disease.²

No studies demonstrate improved outcomes from screening for asymptomatic microhematuria. Earlier discovery of serious diseases would not often change patient outcome, according to expert opinion.^6,7 Invasive studies, such as intravenous pyelogram and cystoscopy, used to evaluate asymptomatic microhematuria have a rate of serious complications approaching 0.3% (number needed to harm=333).⁷

Recommendations from others

The American Urological Association recommends that all patients with asymptomatic microhematuria be evaluated. However, they do not recommend routine screening for asympto-matic microhematuria to detect urologic malig-nancy.⁸ The US Preventive Services Task Force does not recommend routine screening for bladder cancer by any means, including screening for hematuria.⁹