Clinical Inquiries

Evidence summary

The American Academy of Otolargynology-Head and Neck Surgery defines chronic rhinosinusitis as the persistence of 2 major or 1 major and 2 minor criteria lasting at least 12 weeks (Table).¹ The other categories of rhinosinusitis are acute (symptoms lasting <3 weeks) and subacute (symptoms lasting 3-12 weeks).

Two placebo-controlled trials have evaluated antibiotic treatment of chronic rhinosinusitis in children. In 1 study, 141 children with chronic rhinosinusitis were randomly assigned to 1 of 4 treatment arms: saline nose drops; xylometazoline (Otrivin) drops with oral amoxicillin 3 times daily; surgical drainage; or surgical drainage, amoxicillin 3 times daily and xylometazoline drops.² Outcomes were resolution of purulent rhinitis, no purulent drainage on exam, and no abnormalities of maxillary sinus on x-ray. The absence of all 3 findings constituted cure. At 6 weeks there was a non-statistically significant higher resolution in the fourth group, but by 26 weeks the groups were indistinguishable. At 6 weeks, 53%, 50%, 55%, and 79% of each group, respectively, were cured. These results increased to 69%, 74%, 69%, and 64% at 26 weeks.

Another study randomized 79 children with chronic sinusitis to treatment with cefaclor vs placebo following antral washout.³ Measured outcomes were similar to those in the prior study. At 6 weeks, 12.3% more patients in the antibiotic group achieved cure than the placebo group (64.8% vs 52.5%), but this difference was not statistically significant (P=.28). At 12 weeks, no differences in improvement were seen between the 2 groups (89% vs 89.5%)

No studies (since 1966) have evaluated antibiotic use compared with placebo in adults. We did not review the numerous studies comparing different antibiotics without placebo.

Recommendations from others

The American Academy of Otolaryngology-Head and Neck Surgery, in conjunction with the American Academy of Rhinology and the American

Academy of Otolaryngic Allergy, state that the use of antibiotics active against beta-lactamase producing organisms might be beneficial in some cases.³ A consensus statement from a panel convened in Belgium in 1996 stated antibiotics should be given for 5 to 7 days with repeat treatments if the child does not respond initially.⁵

TABLE 2
Diagnostic criteria for rhinosinusitis

Evidence summary

The American Academy of Otolargynology-Head and Neck Surgery defines chronic rhinosinusitis as the persistence of 2 major or 1 major and 2 minor criteria lasting at least 12 weeks (Table).¹ The other categories of rhinosinusitis are acute (symptoms lasting <3 weeks) and subacute (symptoms lasting 3-12 weeks).

Two placebo-controlled trials have evaluated antibiotic treatment of chronic rhinosinusitis in children. In 1 study, 141 children with chronic rhinosinusitis were randomly assigned to 1 of 4 treatment arms: saline nose drops; xylometazoline (Otrivin) drops with oral amoxicillin 3 times daily; surgical drainage; or surgical drainage, amoxicillin 3 times daily and xylometazoline drops.² Outcomes were resolution of purulent rhinitis, no purulent drainage on exam, and no abnormalities of maxillary sinus on x-ray. The absence of all 3 findings constituted cure. At 6 weeks there was a non-statistically significant higher resolution in the fourth group, but by 26 weeks the groups were indistinguishable. At 6 weeks, 53%, 50%, 55%, and 79% of each group, respectively, were cured. These results increased to 69%, 74%, 69%, and 64% at 26 weeks.

Another study randomized 79 children with chronic sinusitis to treatment with cefaclor vs placebo following antral washout.³ Measured outcomes were similar to those in the prior study. At 6 weeks, 12.3% more patients in the antibiotic group achieved cure than the placebo group (64.8% vs 52.5%), but this difference was not statistically significant (P=.28). At 12 weeks, no differences in improvement were seen between the 2 groups (89% vs 89.5%)

No studies (since 1966) have evaluated antibiotic use compared with placebo in adults. We did not review the numerous studies comparing different antibiotics without placebo.

Recommendations from others

The American Academy of Otolaryngology-Head and Neck Surgery, in conjunction with the American Academy of Rhinology and the American

Academy of Otolaryngic Allergy, state that the use of antibiotics active against beta-lactamase producing organisms might be beneficial in some cases.³ A consensus statement from a panel convened in Belgium in 1996 stated antibiotics should be given for 5 to 7 days with repeat treatments if the child does not respond initially.⁵

TABLE 2
Diagnostic criteria for rhinosinusitis

Evidence summary

The American Academy of Otolargynology-Head and Neck Surgery defines chronic rhinosinusitis as the persistence of 2 major or 1 major and 2 minor criteria lasting at least 12 weeks (Table).¹ The other categories of rhinosinusitis are acute (symptoms lasting <3 weeks) and subacute (symptoms lasting 3-12 weeks).

Two placebo-controlled trials have evaluated antibiotic treatment of chronic rhinosinusitis in children. In 1 study, 141 children with chronic rhinosinusitis were randomly assigned to 1 of 4 treatment arms: saline nose drops; xylometazoline (Otrivin) drops with oral amoxicillin 3 times daily; surgical drainage; or surgical drainage, amoxicillin 3 times daily and xylometazoline drops.² Outcomes were resolution of purulent rhinitis, no purulent drainage on exam, and no abnormalities of maxillary sinus on x-ray. The absence of all 3 findings constituted cure. At 6 weeks there was a non-statistically significant higher resolution in the fourth group, but by 26 weeks the groups were indistinguishable. At 6 weeks, 53%, 50%, 55%, and 79% of each group, respectively, were cured. These results increased to 69%, 74%, 69%, and 64% at 26 weeks.

Another study randomized 79 children with chronic sinusitis to treatment with cefaclor vs placebo following antral washout.³ Measured outcomes were similar to those in the prior study. At 6 weeks, 12.3% more patients in the antibiotic group achieved cure than the placebo group (64.8% vs 52.5%), but this difference was not statistically significant (P=.28). At 12 weeks, no differences in improvement were seen between the 2 groups (89% vs 89.5%)

No studies (since 1966) have evaluated antibiotic use compared with placebo in adults. We did not review the numerous studies comparing different antibiotics without placebo.

Recommendations from others

The American Academy of Otolaryngology-Head and Neck Surgery, in conjunction with the American Academy of Rhinology and the American

Academy of Otolaryngic Allergy, state that the use of antibiotics active against beta-lactamase producing organisms might be beneficial in some cases.³ A consensus statement from a panel convened in Belgium in 1996 stated antibiotics should be given for 5 to 7 days with repeat treatments if the child does not respond initially.⁵

TABLE 2
Diagnostic criteria for rhinosinusitis

Evidence summary

Warfarin, at both low and conventional doses, has been shown to be effective in preventing recurrence of DVT. A large, 4-year placebo-controlled randomized controlled trial showed that long-term low-dose warfarin (international normalized ratio [INR], 1.5-1.9) was more effective than placebo for prevention of DVT (hazard ratio=0.36; 95% confidence interval [CI], 0.19-0.67).¹

A double-blind randomized controlled trial of 738 patients demonstrated that conventional-intensity warfarin therapy (INR=2.0-3.0) was more effective than low-intensity therapy (INR=1.5-1.9) in prevention of recurrent DVT. There were 1.9 vs 0.7 DVTs per 100 person-years in the low-intensity vs conventional-intensity therapy groups (hazard ratio=2.8; 95% CI, 1.1-7.0; number needed to treat [NNT]=37). No significant difference was seen in the frequency of bleeding complications between the groups.² This and other studies suggest that low-intensity warfarin therapy reduces the relative risk of thrombosis by about 75%, and conventional-intensity therapy reduces this risk by over 90%.²

Several studies have examined the duration of warfarin therapy. A meta-analysis found treatment with warfarin for 12 to 24 weeks decreased DVT recurrence compared with 2- to 6-week regimens (relative risk [RR]=0.60; 95% CI, 0.45-0.79; NNT=21).³ A multicenter randomized controlled trial found extending warfarin treatment for 12 months vs 3 months resulted in a 95% relative risk reduction (RRR) in risk of DVT recurrence (95% CI, 63-99; NNT=5).⁴ A multicenter randomized trial showed similar results, but risk for recurrence was the same after treatment was stopped, regardless of the length of treatment.⁵

In patients with cancer, warfarin was shown to be more effective than placebo in prevention of DVT. In a trial of 311 breast cancer patients receiving chemotherapy, treatment with very-low-dose warfarin (INR=1.3-1.9) decreased thrombotic events compared with placebo, with no increase in bleeding complications (RRR=85%; P=.031; NNT=27).⁶ A later cost analysis showed that very-low-dose warfarin can be used in prevention of DVT in breast cancer patients on chemotherapy without an increase in health care costs.⁷

Although immobilized patients are at high risk for DVT, no randomized controlled trials exist for the use of warfarin in these patients. A few small studies suggest that warfarin reduces DVT rates in spinal-cord-injured patients.⁸ A small trial randomized stroke patients undergoing rehabilitation to placebo or fixed 1- or 2-mg doses of warfarin. This underpowered study showed a nonsignificant decrease in the risk of development of DVT (RR=0.39; 95% CI, 0.13-1.37).⁸

Recommendations from others

The 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy makes these recommendations:⁹

Prior DVT: Oral anticoagulation therapy (INR=2.0-3.0) is indicated for at least 3 months for patients with proximal DVT or for at least 6 months in those with idiopathic proximal vein thrombosis or recurrent venous thrombosis. Indefinite anticoagulation is indicated for patients with more than 1 episode of idiopathic proximal vein thrombosis or pulmonary embolus.

Malignancy: Indefinite anticoagulation (INR= 2.0-3.0) is indicated for patients with thrombosis complicating malignancy. Prophylaxis with low-intensity warfarin in ambulatory patients with cancer to prevent initial DVT warrants further study.

Acute spinal cord injuries: Low-molecular-weight heparin or switch to full-dose oral anti-coagulation (INR=2.0-3.0) for the duration of the rehabilitation phase.

Evidence summary

Warfarin, at both low and conventional doses, has been shown to be effective in preventing recurrence of DVT. A large, 4-year placebo-controlled randomized controlled trial showed that long-term low-dose warfarin (international normalized ratio [INR], 1.5-1.9) was more effective than placebo for prevention of DVT (hazard ratio=0.36; 95% confidence interval [CI], 0.19-0.67).¹

A double-blind randomized controlled trial of 738 patients demonstrated that conventional-intensity warfarin therapy (INR=2.0-3.0) was more effective than low-intensity therapy (INR=1.5-1.9) in prevention of recurrent DVT. There were 1.9 vs 0.7 DVTs per 100 person-years in the low-intensity vs conventional-intensity therapy groups (hazard ratio=2.8; 95% CI, 1.1-7.0; number needed to treat [NNT]=37). No significant difference was seen in the frequency of bleeding complications between the groups.² This and other studies suggest that low-intensity warfarin therapy reduces the relative risk of thrombosis by about 75%, and conventional-intensity therapy reduces this risk by over 90%.²

Several studies have examined the duration of warfarin therapy. A meta-analysis found treatment with warfarin for 12 to 24 weeks decreased DVT recurrence compared with 2- to 6-week regimens (relative risk [RR]=0.60; 95% CI, 0.45-0.79; NNT=21).³ A multicenter randomized controlled trial found extending warfarin treatment for 12 months vs 3 months resulted in a 95% relative risk reduction (RRR) in risk of DVT recurrence (95% CI, 63-99; NNT=5).⁴ A multicenter randomized trial showed similar results, but risk for recurrence was the same after treatment was stopped, regardless of the length of treatment.⁵

In patients with cancer, warfarin was shown to be more effective than placebo in prevention of DVT. In a trial of 311 breast cancer patients receiving chemotherapy, treatment with very-low-dose warfarin (INR=1.3-1.9) decreased thrombotic events compared with placebo, with no increase in bleeding complications (RRR=85%; P=.031; NNT=27).⁶ A later cost analysis showed that very-low-dose warfarin can be used in prevention of DVT in breast cancer patients on chemotherapy without an increase in health care costs.⁷

Although immobilized patients are at high risk for DVT, no randomized controlled trials exist for the use of warfarin in these patients. A few small studies suggest that warfarin reduces DVT rates in spinal-cord-injured patients.⁸ A small trial randomized stroke patients undergoing rehabilitation to placebo or fixed 1- or 2-mg doses of warfarin. This underpowered study showed a nonsignificant decrease in the risk of development of DVT (RR=0.39; 95% CI, 0.13-1.37).⁸

Recommendations from others

The 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy makes these recommendations:⁹

Prior DVT: Oral anticoagulation therapy (INR=2.0-3.0) is indicated for at least 3 months for patients with proximal DVT or for at least 6 months in those with idiopathic proximal vein thrombosis or recurrent venous thrombosis. Indefinite anticoagulation is indicated for patients with more than 1 episode of idiopathic proximal vein thrombosis or pulmonary embolus.

Malignancy: Indefinite anticoagulation (INR= 2.0-3.0) is indicated for patients with thrombosis complicating malignancy. Prophylaxis with low-intensity warfarin in ambulatory patients with cancer to prevent initial DVT warrants further study.

Acute spinal cord injuries: Low-molecular-weight heparin or switch to full-dose oral anti-coagulation (INR=2.0-3.0) for the duration of the rehabilitation phase.

Evidence summary

Warfarin, at both low and conventional doses, has been shown to be effective in preventing recurrence of DVT. A large, 4-year placebo-controlled randomized controlled trial showed that long-term low-dose warfarin (international normalized ratio [INR], 1.5-1.9) was more effective than placebo for prevention of DVT (hazard ratio=0.36; 95% confidence interval [CI], 0.19-0.67).¹

A double-blind randomized controlled trial of 738 patients demonstrated that conventional-intensity warfarin therapy (INR=2.0-3.0) was more effective than low-intensity therapy (INR=1.5-1.9) in prevention of recurrent DVT. There were 1.9 vs 0.7 DVTs per 100 person-years in the low-intensity vs conventional-intensity therapy groups (hazard ratio=2.8; 95% CI, 1.1-7.0; number needed to treat [NNT]=37). No significant difference was seen in the frequency of bleeding complications between the groups.² This and other studies suggest that low-intensity warfarin therapy reduces the relative risk of thrombosis by about 75%, and conventional-intensity therapy reduces this risk by over 90%.²

Several studies have examined the duration of warfarin therapy. A meta-analysis found treatment with warfarin for 12 to 24 weeks decreased DVT recurrence compared with 2- to 6-week regimens (relative risk [RR]=0.60; 95% CI, 0.45-0.79; NNT=21).³ A multicenter randomized controlled trial found extending warfarin treatment for 12 months vs 3 months resulted in a 95% relative risk reduction (RRR) in risk of DVT recurrence (95% CI, 63-99; NNT=5).⁴ A multicenter randomized trial showed similar results, but risk for recurrence was the same after treatment was stopped, regardless of the length of treatment.⁵

In patients with cancer, warfarin was shown to be more effective than placebo in prevention of DVT. In a trial of 311 breast cancer patients receiving chemotherapy, treatment with very-low-dose warfarin (INR=1.3-1.9) decreased thrombotic events compared with placebo, with no increase in bleeding complications (RRR=85%; P=.031; NNT=27).⁶ A later cost analysis showed that very-low-dose warfarin can be used in prevention of DVT in breast cancer patients on chemotherapy without an increase in health care costs.⁷

Although immobilized patients are at high risk for DVT, no randomized controlled trials exist for the use of warfarin in these patients. A few small studies suggest that warfarin reduces DVT rates in spinal-cord-injured patients.⁸ A small trial randomized stroke patients undergoing rehabilitation to placebo or fixed 1- or 2-mg doses of warfarin. This underpowered study showed a nonsignificant decrease in the risk of development of DVT (RR=0.39; 95% CI, 0.13-1.37).⁸

Recommendations from others

The 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy makes these recommendations:⁹

Prior DVT: Oral anticoagulation therapy (INR=2.0-3.0) is indicated for at least 3 months for patients with proximal DVT or for at least 6 months in those with idiopathic proximal vein thrombosis or recurrent venous thrombosis. Indefinite anticoagulation is indicated for patients with more than 1 episode of idiopathic proximal vein thrombosis or pulmonary embolus.

Malignancy: Indefinite anticoagulation (INR= 2.0-3.0) is indicated for patients with thrombosis complicating malignancy. Prophylaxis with low-intensity warfarin in ambulatory patients with cancer to prevent initial DVT warrants further study.

Acute spinal cord injuries: Low-molecular-weight heparin or switch to full-dose oral anti-coagulation (INR=2.0-3.0) for the duration of the rehabilitation phase.

Evidence summary

M pneumoniae and C pneumoniae account for about 30% of community-acquired pneumonia (CAP), making them the most common “atypicals.” Clinically they are indistinguishable from other causes of pneumonia; most studies use cultures to identify cases among populations with CAP.

Azithromycin and erythromycin were compared in 3 studies of children with CAP.^1-3 Together, they identified 69 cases due to M pneumoniae or C pneumoniae. Only 3 patients did not respond to either antibiotic. In the largest of the 3 studies,³ side effects were noted in 10% of CAP patients on azithromycin and 20% on erythromycin (P<.05).

Another study looked at patients aged 12 to 80 years with pneumonia due to M pneumoniae (75 cases) or Chlamydophila psittaci (formerly Chlamydia psittaci, 16 cases).⁴ All patients responded to treatment. Clarithromycin and erythromycin were compared in children aged 3 to 12 years with CAP.⁵ M pneumoniae or C pneumoniae was identified in 42 cases. Two of 18 patients did not respond to erythromycin; 3 of 27 patients did not respond to clarithromycin.

Another study compared these antibiotics for patients with CAP aged 12 to 93 years.⁶ Subgroup analysis of those with M pneumoniae or C pneumoniae (n=27) showed similar efficacy. Pooling all 268 patients with CAP, side effects were seen in 31% of patients on clarithromycin and 59% on erythromycin (P<.001).

A comparison study of newer macrolides in 40 adults with CAP identified 13 with M pneumoniae or C pneumoniae (Table).⁷ One patient did not respond of the 8 treated with clarithromycin; none among the 5 treated with azithromycin. There was 1 adverse event (from clarithromycin).

TABLE
Macrolides: comparison studies

Recommendations from others

The Infectious Diseases Society of America⁸ recommends a macrolide for adults with pneumonia caused by M pneumoniae or C pneumoniae, and does not promote one over another. The British Thoracic Society⁹ recommends any of the macrolides for pneumonia caused by these pathogens in children.

Since CAP is often caused by “atypical organisms,” macrolides are sometimes recommended as empiric outpatient therapy. In this setting, the American Thoracic Society¹⁰ discourages using erythromycin, citing a higher side-effect rate and poorer effectiveness against Haemophilus influenza. However, the Canadian Infectious Disease Society¹¹ supports the use of any of the 3 macrolides in mild CAP except for patients with chronic obstructive pulmonary disease, who are more likely to harbor H influenza.

Evidence summary

M pneumoniae and C pneumoniae account for about 30% of community-acquired pneumonia (CAP), making them the most common “atypicals.” Clinically they are indistinguishable from other causes of pneumonia; most studies use cultures to identify cases among populations with CAP.

Azithromycin and erythromycin were compared in 3 studies of children with CAP.^1-3 Together, they identified 69 cases due to M pneumoniae or C pneumoniae. Only 3 patients did not respond to either antibiotic. In the largest of the 3 studies,³ side effects were noted in 10% of CAP patients on azithromycin and 20% on erythromycin (P<.05).

Another study looked at patients aged 12 to 80 years with pneumonia due to M pneumoniae (75 cases) or Chlamydophila psittaci (formerly Chlamydia psittaci, 16 cases).⁴ All patients responded to treatment. Clarithromycin and erythromycin were compared in children aged 3 to 12 years with CAP.⁵ M pneumoniae or C pneumoniae was identified in 42 cases. Two of 18 patients did not respond to erythromycin; 3 of 27 patients did not respond to clarithromycin.

Another study compared these antibiotics for patients with CAP aged 12 to 93 years.⁶ Subgroup analysis of those with M pneumoniae or C pneumoniae (n=27) showed similar efficacy. Pooling all 268 patients with CAP, side effects were seen in 31% of patients on clarithromycin and 59% on erythromycin (P<.001).

A comparison study of newer macrolides in 40 adults with CAP identified 13 with M pneumoniae or C pneumoniae (Table).⁷ One patient did not respond of the 8 treated with clarithromycin; none among the 5 treated with azithromycin. There was 1 adverse event (from clarithromycin).

TABLE
Macrolides: comparison studies

Recommendations from others

The Infectious Diseases Society of America⁸ recommends a macrolide for adults with pneumonia caused by M pneumoniae or C pneumoniae, and does not promote one over another. The British Thoracic Society⁹ recommends any of the macrolides for pneumonia caused by these pathogens in children.

Since CAP is often caused by “atypical organisms,” macrolides are sometimes recommended as empiric outpatient therapy. In this setting, the American Thoracic Society¹⁰ discourages using erythromycin, citing a higher side-effect rate and poorer effectiveness against Haemophilus influenza. However, the Canadian Infectious Disease Society¹¹ supports the use of any of the 3 macrolides in mild CAP except for patients with chronic obstructive pulmonary disease, who are more likely to harbor H influenza.

Evidence summary

M pneumoniae and C pneumoniae account for about 30% of community-acquired pneumonia (CAP), making them the most common “atypicals.” Clinically they are indistinguishable from other causes of pneumonia; most studies use cultures to identify cases among populations with CAP.

Azithromycin and erythromycin were compared in 3 studies of children with CAP.^1-3 Together, they identified 69 cases due to M pneumoniae or C pneumoniae. Only 3 patients did not respond to either antibiotic. In the largest of the 3 studies,³ side effects were noted in 10% of CAP patients on azithromycin and 20% on erythromycin (P<.05).

Another study looked at patients aged 12 to 80 years with pneumonia due to M pneumoniae (75 cases) or Chlamydophila psittaci (formerly Chlamydia psittaci, 16 cases).⁴ All patients responded to treatment. Clarithromycin and erythromycin were compared in children aged 3 to 12 years with CAP.⁵ M pneumoniae or C pneumoniae was identified in 42 cases. Two of 18 patients did not respond to erythromycin; 3 of 27 patients did not respond to clarithromycin.

Another study compared these antibiotics for patients with CAP aged 12 to 93 years.⁶ Subgroup analysis of those with M pneumoniae or C pneumoniae (n=27) showed similar efficacy. Pooling all 268 patients with CAP, side effects were seen in 31% of patients on clarithromycin and 59% on erythromycin (P<.001).

A comparison study of newer macrolides in 40 adults with CAP identified 13 with M pneumoniae or C pneumoniae (Table).⁷ One patient did not respond of the 8 treated with clarithromycin; none among the 5 treated with azithromycin. There was 1 adverse event (from clarithromycin).

TABLE
Macrolides: comparison studies

Recommendations from others

The Infectious Diseases Society of America⁸ recommends a macrolide for adults with pneumonia caused by M pneumoniae or C pneumoniae, and does not promote one over another. The British Thoracic Society⁹ recommends any of the macrolides for pneumonia caused by these pathogens in children.

Since CAP is often caused by “atypical organisms,” macrolides are sometimes recommended as empiric outpatient therapy. In this setting, the American Thoracic Society¹⁰ discourages using erythromycin, citing a higher side-effect rate and poorer effectiveness against Haemophilus influenza. However, the Canadian Infectious Disease Society¹¹ supports the use of any of the 3 macrolides in mild CAP except for patients with chronic obstructive pulmonary disease, who are more likely to harbor H influenza.

FIGURE 1 Mitral valve prolapse

Evidence summary

Only disease-oriented evidence and expert opinion address prevention for endocarditis. A randomized trial would require an estimated 6000 patients to demonstrate benefit.²

Endocarditis occurs in MVP at a rate of 0.1 cases/100 patient-years.³ However, MVP is the most common predisposing/precipitating cause of native valve endocarditis.^4,5 In animal models, antibiotics prevent endocarditis following experimental bacteremia. The antibiotic can be administered either just before or up to 2 hours after the bacteremic event.² It is worth noting that most bacteremia is not associated with medical procedures. Since endocarditis is often fatal, recommendations have been developed based on these animal models. Estimates of effectiveness of prophylaxis from case-control studies in humans (not limited to patients with MVP) estimate effectiveness from 49% to 91%.²

For patients with MVP who do not have evidence of mitral regurgitation on physical examination or echocardiography, the risk of morbidity may be greater from antibiotic therapy than the risk of endocarditis. Prophylaxis for these patients is not recommended. Patients with MVP associated with regurgitation are at moderate risk and may benefit from antibiotic prophylaxis.

Recommendations from others

The American Heart Association has published recommendations in 1985,⁶ 1990,⁷ and 1997.¹ The 1997 recommendations are summarized in Figure 2 . The Swiss Working Group for Endocarditis Prophylaxis published similar recommendations in 2000.⁸ Recommended prophylactic regimens appear in Table 1. Table 2 shows a modified list of procedures for which prophylaxis is recommended.

FIGURE 2
Determining the need for antibiotic prophylaxis for patients with mitral valve prolapse

TABLE 1
Recommended prophylactic regimens for mitral valve prolaspe

TABLE 2
Procedures for which endocarditis prophylaxis is, or is not, recommended

FIGURE 1 Mitral valve prolapse

Evidence summary

Only disease-oriented evidence and expert opinion address prevention for endocarditis. A randomized trial would require an estimated 6000 patients to demonstrate benefit.²

Endocarditis occurs in MVP at a rate of 0.1 cases/100 patient-years.³ However, MVP is the most common predisposing/precipitating cause of native valve endocarditis.^4,5 In animal models, antibiotics prevent endocarditis following experimental bacteremia. The antibiotic can be administered either just before or up to 2 hours after the bacteremic event.² It is worth noting that most bacteremia is not associated with medical procedures. Since endocarditis is often fatal, recommendations have been developed based on these animal models. Estimates of effectiveness of prophylaxis from case-control studies in humans (not limited to patients with MVP) estimate effectiveness from 49% to 91%.²

For patients with MVP who do not have evidence of mitral regurgitation on physical examination or echocardiography, the risk of morbidity may be greater from antibiotic therapy than the risk of endocarditis. Prophylaxis for these patients is not recommended. Patients with MVP associated with regurgitation are at moderate risk and may benefit from antibiotic prophylaxis.

Recommendations from others

The American Heart Association has published recommendations in 1985,⁶ 1990,⁷ and 1997.¹ The 1997 recommendations are summarized in Figure 2 . The Swiss Working Group for Endocarditis Prophylaxis published similar recommendations in 2000.⁸ Recommended prophylactic regimens appear in Table 1. Table 2 shows a modified list of procedures for which prophylaxis is recommended.

FIGURE 2
Determining the need for antibiotic prophylaxis for patients with mitral valve prolapse

TABLE 1
Recommended prophylactic regimens for mitral valve prolaspe

TABLE 2
Procedures for which endocarditis prophylaxis is, or is not, recommended

FIGURE 1 Mitral valve prolapse

Evidence summary

Only disease-oriented evidence and expert opinion address prevention for endocarditis. A randomized trial would require an estimated 6000 patients to demonstrate benefit.²

Endocarditis occurs in MVP at a rate of 0.1 cases/100 patient-years.³ However, MVP is the most common predisposing/precipitating cause of native valve endocarditis.^4,5 In animal models, antibiotics prevent endocarditis following experimental bacteremia. The antibiotic can be administered either just before or up to 2 hours after the bacteremic event.² It is worth noting that most bacteremia is not associated with medical procedures. Since endocarditis is often fatal, recommendations have been developed based on these animal models. Estimates of effectiveness of prophylaxis from case-control studies in humans (not limited to patients with MVP) estimate effectiveness from 49% to 91%.²

For patients with MVP who do not have evidence of mitral regurgitation on physical examination or echocardiography, the risk of morbidity may be greater from antibiotic therapy than the risk of endocarditis. Prophylaxis for these patients is not recommended. Patients with MVP associated with regurgitation are at moderate risk and may benefit from antibiotic prophylaxis.

Recommendations from others

The American Heart Association has published recommendations in 1985,⁶ 1990,⁷ and 1997.¹ The 1997 recommendations are summarized in Figure 2 . The Swiss Working Group for Endocarditis Prophylaxis published similar recommendations in 2000.⁸ Recommended prophylactic regimens appear in Table 1. Table 2 shows a modified list of procedures for which prophylaxis is recommended.

FIGURE 2
Determining the need for antibiotic prophylaxis for patients with mitral valve prolapse

TABLE 1
Recommended prophylactic regimens for mitral valve prolaspe

TABLE 2
Procedures for which endocarditis prophylaxis is, or is not, recommended

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

No prospective, interventional studies evaluate the treatment of Osgood-Schlatter disease. One case series followed the natural course of the disease in 261 patients (365 symptomatic knees) for 12 to 24 months; 237 (90.8%) patients responded well to restriction of sports activity and nonsteroidal anti-inflammatory agents. The 24 patients who did not improve with conservative measures underwent surgical excision of ossicles, and all returned to normal activities (mean time, 4.5 weeks).¹

In another case series of 118 patients (151 knees), 88% responded to intermittent limitation of activity (weeks to months) or cylinder casting if limiting activity was ineffective. The remaining 14 patients showed no improvement from these measures; all had surgical excision of an ossicle, sometimes combined with a tubercle-thinning procedure. Only 1 of these patients (7%) did not have complete relief and return to full activities at 6 weeks.²

Retrospective analyses also support a conservative approach. One retrospective survey of 68 young athletes with Osgood-Schlatter found they required an average of 3.2 months off all training and 7.3 months of some activity restrictions.³ In another survey, 20 of 22 (91%) adolescent athletes with Osgood-Schlatter were able to manage their symptoms with ice, aspirin, and mild activity modification. Only 2 needed to stop playing all sports for any period of time, and none required surgery.⁴

Another retrospective review analyzed 50 patients with Osgood-Schlatter (69 knees) for an average of 9 years. No treatments or activity restrictions were recommended. At time of follow-up, 36 (76%) had no limitations, but kneeling continued to be uncomfortable in 60%.⁵

No interventional studies have explicitly evaluated commonly recommended conservative treatments such as ice, analgesics, activity restriction, stretching, strengthening, or anti-inflammatory medication. Corticosteroid injections are generally not recommended, due to case reports of complications, primarily related to subcutaneous atrophy.⁶ One small case series demonstrated improvement in Osgood-Schlatter disease pain in 19 of 24 (79%) knees after using an infrapatellar strap for 6 to 8 weeks.⁷

Refractory cases have been treated with a variety of surgical interventions. In 1 case series, 67 patients (70 knees) (mean age 19.6, 77% male) with at least 18 months of symptoms despite conservative treatment underwent resection of an ossicle (62 cases) or excision of prominent tibial tubercle (8 cases). These patients were followed for 2.2 years, with 56 (90%) patients with ossicle-resection able to return to maximal sports activity without pain, tenderness, loss of motion, or atrophy.⁸

Another case series compared 22 patients who1 underwent drilling of the tibial tubercle (with or without the removal of the tibial tubercle) with 22 patients who had excision of loose ossicles or cartilage. Seventeen of the 22 (77%) patients with ossicle excision had complete resolution of symptoms compared with 8 of the 22 (36%) in the patients who underwent tibial tubercle drilling.⁹

One surgical series evaluated excision of tibial tuberosity in 35 patients (42 knees) who did not improve with conservative treatment for an average of 13.25 months. For 37 of 42 knees (88%), patients reported complete relief of pain, and all returned to activity without limitation. The average time to return to sports was 15.2 weeks.¹⁰

Recommendations from others

The American Academy of Orthopaedic Surgeons and the American Academy of Family Practice recommend activity limitation, ice, anti-inflammatories, protective padding, quadriceps/hamstring strengthening, and time in the management of Osgood-Schlatter disease.^11,12

Evidence summary

No prospective, interventional studies evaluate the treatment of Osgood-Schlatter disease. One case series followed the natural course of the disease in 261 patients (365 symptomatic knees) for 12 to 24 months; 237 (90.8%) patients responded well to restriction of sports activity and nonsteroidal anti-inflammatory agents. The 24 patients who did not improve with conservative measures underwent surgical excision of ossicles, and all returned to normal activities (mean time, 4.5 weeks).¹

In another case series of 118 patients (151 knees), 88% responded to intermittent limitation of activity (weeks to months) or cylinder casting if limiting activity was ineffective. The remaining 14 patients showed no improvement from these measures; all had surgical excision of an ossicle, sometimes combined with a tubercle-thinning procedure. Only 1 of these patients (7%) did not have complete relief and return to full activities at 6 weeks.²

Retrospective analyses also support a conservative approach. One retrospective survey of 68 young athletes with Osgood-Schlatter found they required an average of 3.2 months off all training and 7.3 months of some activity restrictions.³ In another survey, 20 of 22 (91%) adolescent athletes with Osgood-Schlatter were able to manage their symptoms with ice, aspirin, and mild activity modification. Only 2 needed to stop playing all sports for any period of time, and none required surgery.⁴

Another retrospective review analyzed 50 patients with Osgood-Schlatter (69 knees) for an average of 9 years. No treatments or activity restrictions were recommended. At time of follow-up, 36 (76%) had no limitations, but kneeling continued to be uncomfortable in 60%.⁵

No interventional studies have explicitly evaluated commonly recommended conservative treatments such as ice, analgesics, activity restriction, stretching, strengthening, or anti-inflammatory medication. Corticosteroid injections are generally not recommended, due to case reports of complications, primarily related to subcutaneous atrophy.⁶ One small case series demonstrated improvement in Osgood-Schlatter disease pain in 19 of 24 (79%) knees after using an infrapatellar strap for 6 to 8 weeks.⁷

Refractory cases have been treated with a variety of surgical interventions. In 1 case series, 67 patients (70 knees) (mean age 19.6, 77% male) with at least 18 months of symptoms despite conservative treatment underwent resection of an ossicle (62 cases) or excision of prominent tibial tubercle (8 cases). These patients were followed for 2.2 years, with 56 (90%) patients with ossicle-resection able to return to maximal sports activity without pain, tenderness, loss of motion, or atrophy.⁸

Another case series compared 22 patients who1 underwent drilling of the tibial tubercle (with or without the removal of the tibial tubercle) with 22 patients who had excision of loose ossicles or cartilage. Seventeen of the 22 (77%) patients with ossicle excision had complete resolution of symptoms compared with 8 of the 22 (36%) in the patients who underwent tibial tubercle drilling.⁹

One surgical series evaluated excision of tibial tuberosity in 35 patients (42 knees) who did not improve with conservative treatment for an average of 13.25 months. For 37 of 42 knees (88%), patients reported complete relief of pain, and all returned to activity without limitation. The average time to return to sports was 15.2 weeks.¹⁰

Recommendations from others

The American Academy of Orthopaedic Surgeons and the American Academy of Family Practice recommend activity limitation, ice, anti-inflammatories, protective padding, quadriceps/hamstring strengthening, and time in the management of Osgood-Schlatter disease.^11,12

Evidence summary

No prospective, interventional studies evaluate the treatment of Osgood-Schlatter disease. One case series followed the natural course of the disease in 261 patients (365 symptomatic knees) for 12 to 24 months; 237 (90.8%) patients responded well to restriction of sports activity and nonsteroidal anti-inflammatory agents. The 24 patients who did not improve with conservative measures underwent surgical excision of ossicles, and all returned to normal activities (mean time, 4.5 weeks).¹

In another case series of 118 patients (151 knees), 88% responded to intermittent limitation of activity (weeks to months) or cylinder casting if limiting activity was ineffective. The remaining 14 patients showed no improvement from these measures; all had surgical excision of an ossicle, sometimes combined with a tubercle-thinning procedure. Only 1 of these patients (7%) did not have complete relief and return to full activities at 6 weeks.²

Retrospective analyses also support a conservative approach. One retrospective survey of 68 young athletes with Osgood-Schlatter found they required an average of 3.2 months off all training and 7.3 months of some activity restrictions.³ In another survey, 20 of 22 (91%) adolescent athletes with Osgood-Schlatter were able to manage their symptoms with ice, aspirin, and mild activity modification. Only 2 needed to stop playing all sports for any period of time, and none required surgery.⁴

Another retrospective review analyzed 50 patients with Osgood-Schlatter (69 knees) for an average of 9 years. No treatments or activity restrictions were recommended. At time of follow-up, 36 (76%) had no limitations, but kneeling continued to be uncomfortable in 60%.⁵

No interventional studies have explicitly evaluated commonly recommended conservative treatments such as ice, analgesics, activity restriction, stretching, strengthening, or anti-inflammatory medication. Corticosteroid injections are generally not recommended, due to case reports of complications, primarily related to subcutaneous atrophy.⁶ One small case series demonstrated improvement in Osgood-Schlatter disease pain in 19 of 24 (79%) knees after using an infrapatellar strap for 6 to 8 weeks.⁷

Refractory cases have been treated with a variety of surgical interventions. In 1 case series, 67 patients (70 knees) (mean age 19.6, 77% male) with at least 18 months of symptoms despite conservative treatment underwent resection of an ossicle (62 cases) or excision of prominent tibial tubercle (8 cases). These patients were followed for 2.2 years, with 56 (90%) patients with ossicle-resection able to return to maximal sports activity without pain, tenderness, loss of motion, or atrophy.⁸

Another case series compared 22 patients who1 underwent drilling of the tibial tubercle (with or without the removal of the tibial tubercle) with 22 patients who had excision of loose ossicles or cartilage. Seventeen of the 22 (77%) patients with ossicle excision had complete resolution of symptoms compared with 8 of the 22 (36%) in the patients who underwent tibial tubercle drilling.⁹

One surgical series evaluated excision of tibial tuberosity in 35 patients (42 knees) who did not improve with conservative treatment for an average of 13.25 months. For 37 of 42 knees (88%), patients reported complete relief of pain, and all returned to activity without limitation. The average time to return to sports was 15.2 weeks.¹⁰

Recommendations from others

The American Academy of Orthopaedic Surgeons and the American Academy of Family Practice recommend activity limitation, ice, anti-inflammatories, protective padding, quadriceps/hamstring strengthening, and time in the management of Osgood-Schlatter disease.^11,12

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

Evidence summary

The concept of a continuous graded relationship between DBP and cardiovascular risk is supported by a meta-analysis of 14 randomized clinical trials showing that lowering DBP by 6 mm Hg reduced the risk of coronary heart disease by 14% (95% confidence interval [CI], 4%–22%; P<.01; NNT=200).¹ Throughout the range of DBP in study subjects, 70–115 mm Hg, a lower DBP was associated with a lower risk of coronary heart disease.

However, there is concern that lowering DBP too much may actually increase cardiovascular risk. A 10-year observational study showed that in patients with a history of ischemic heart disease, the incidence of fatal MI was lowest when DBP was between 85 to 90 mm Hg and increased with DBP <85 mm Hg, thus demonstrating a J-shaped curve.²

Farnett et al³ derived a summary curve from 13 studies that stratified cardiovascular outcomes by level of achieved blood pressure; the nadir of the curve for ischemic heart disease events occurred at 86 to 89 mm Hg DBP. The risk was independent of type of drug therapy, and more pronounced in study subjects with known cardiovascular disease.

A meta-analysis of 7 randomized controlled trials involving 40,233 hypertensive patients used statistical modeling to determine the shape of the “mortality curve” over a range of DBP categories, defined in 10-mm Hg increments from 65 to 106. The subjects received mainly beta-blockers or thiazide diuretics; controls received placebo or no treatment.⁴ Both groups demonstrated increased risk for cardiovascular and all-cause death at the lowest DBP levels. Among treated patients, overall death rate was lowest with a DBP in the range of 76 to 85 mm Hg; among controls the nadir was 86 to 95 mm Hg.

The Hypertension Optimal Treatment (HOT) trial⁵ was specifically designed to determine the optimal target blood pressure for hypertensive patients: 18,790 men and women with DBP 100 to 115 mm Hg were randomly assigned to target DBP groups of <90, <85, or <80 mm Hg. All were treated with felodipine and other agents in a stepped-care protocol; average follow-up was 3.8 years. The lowest incidence of cardiovascular events occurred at a mean DBP of 82.6 mm Hg and fewest cardiovascular deaths at 86.5 mm Hg. Further reductions in DBP neither lowered nor increased cardiovascular risk.

A French cohort study⁶ followed over 4700 hyper-tensive men for an average of 14 years. These men had their hypertension treated in usual fashion by their own physicians. In this group, SBP was much more accurate than DBP in classifying severity of hypertension and in predicting cardiovascular risk.

Recommendations from others

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)⁷ and the World Health Organization–International Society of Hyper-tension Guidelines⁸ state that the relationship between cardiovascular risk and blood pressure is continuous, without a lower threshold. Target blood pressure goals are <140/90 mm Hg in uncomplicated hypertension and <130/80 mm Hg for individuals with diabetes or kidney disease. The National High Blood Pressure Education Program stressed that SBP, not DBP, should become the major criterion for diagnosis and treatment of hypertension.⁹

Evidence summary

The concept of a continuous graded relationship between DBP and cardiovascular risk is supported by a meta-analysis of 14 randomized clinical trials showing that lowering DBP by 6 mm Hg reduced the risk of coronary heart disease by 14% (95% confidence interval [CI], 4%–22%; P<.01; NNT=200).¹ Throughout the range of DBP in study subjects, 70–115 mm Hg, a lower DBP was associated with a lower risk of coronary heart disease.

However, there is concern that lowering DBP too much may actually increase cardiovascular risk. A 10-year observational study showed that in patients with a history of ischemic heart disease, the incidence of fatal MI was lowest when DBP was between 85 to 90 mm Hg and increased with DBP <85 mm Hg, thus demonstrating a J-shaped curve.²

Farnett et al³ derived a summary curve from 13 studies that stratified cardiovascular outcomes by level of achieved blood pressure; the nadir of the curve for ischemic heart disease events occurred at 86 to 89 mm Hg DBP. The risk was independent of type of drug therapy, and more pronounced in study subjects with known cardiovascular disease.

A meta-analysis of 7 randomized controlled trials involving 40,233 hypertensive patients used statistical modeling to determine the shape of the “mortality curve” over a range of DBP categories, defined in 10-mm Hg increments from 65 to 106. The subjects received mainly beta-blockers or thiazide diuretics; controls received placebo or no treatment.⁴ Both groups demonstrated increased risk for cardiovascular and all-cause death at the lowest DBP levels. Among treated patients, overall death rate was lowest with a DBP in the range of 76 to 85 mm Hg; among controls the nadir was 86 to 95 mm Hg.

The Hypertension Optimal Treatment (HOT) trial⁵ was specifically designed to determine the optimal target blood pressure for hypertensive patients: 18,790 men and women with DBP 100 to 115 mm Hg were randomly assigned to target DBP groups of <90, <85, or <80 mm Hg. All were treated with felodipine and other agents in a stepped-care protocol; average follow-up was 3.8 years. The lowest incidence of cardiovascular events occurred at a mean DBP of 82.6 mm Hg and fewest cardiovascular deaths at 86.5 mm Hg. Further reductions in DBP neither lowered nor increased cardiovascular risk.

A French cohort study⁶ followed over 4700 hyper-tensive men for an average of 14 years. These men had their hypertension treated in usual fashion by their own physicians. In this group, SBP was much more accurate than DBP in classifying severity of hypertension and in predicting cardiovascular risk.

Recommendations from others

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)⁷ and the World Health Organization–International Society of Hyper-tension Guidelines⁸ state that the relationship between cardiovascular risk and blood pressure is continuous, without a lower threshold. Target blood pressure goals are <140/90 mm Hg in uncomplicated hypertension and <130/80 mm Hg for individuals with diabetes or kidney disease. The National High Blood Pressure Education Program stressed that SBP, not DBP, should become the major criterion for diagnosis and treatment of hypertension.⁹

Evidence summary

The concept of a continuous graded relationship between DBP and cardiovascular risk is supported by a meta-analysis of 14 randomized clinical trials showing that lowering DBP by 6 mm Hg reduced the risk of coronary heart disease by 14% (95% confidence interval [CI], 4%–22%; P<.01; NNT=200).¹ Throughout the range of DBP in study subjects, 70–115 mm Hg, a lower DBP was associated with a lower risk of coronary heart disease.

However, there is concern that lowering DBP too much may actually increase cardiovascular risk. A 10-year observational study showed that in patients with a history of ischemic heart disease, the incidence of fatal MI was lowest when DBP was between 85 to 90 mm Hg and increased with DBP <85 mm Hg, thus demonstrating a J-shaped curve.²

Farnett et al³ derived a summary curve from 13 studies that stratified cardiovascular outcomes by level of achieved blood pressure; the nadir of the curve for ischemic heart disease events occurred at 86 to 89 mm Hg DBP. The risk was independent of type of drug therapy, and more pronounced in study subjects with known cardiovascular disease.

A meta-analysis of 7 randomized controlled trials involving 40,233 hypertensive patients used statistical modeling to determine the shape of the “mortality curve” over a range of DBP categories, defined in 10-mm Hg increments from 65 to 106. The subjects received mainly beta-blockers or thiazide diuretics; controls received placebo or no treatment.⁴ Both groups demonstrated increased risk for cardiovascular and all-cause death at the lowest DBP levels. Among treated patients, overall death rate was lowest with a DBP in the range of 76 to 85 mm Hg; among controls the nadir was 86 to 95 mm Hg.

The Hypertension Optimal Treatment (HOT) trial⁵ was specifically designed to determine the optimal target blood pressure for hypertensive patients: 18,790 men and women with DBP 100 to 115 mm Hg were randomly assigned to target DBP groups of <90, <85, or <80 mm Hg. All were treated with felodipine and other agents in a stepped-care protocol; average follow-up was 3.8 years. The lowest incidence of cardiovascular events occurred at a mean DBP of 82.6 mm Hg and fewest cardiovascular deaths at 86.5 mm Hg. Further reductions in DBP neither lowered nor increased cardiovascular risk.

A French cohort study⁶ followed over 4700 hyper-tensive men for an average of 14 years. These men had their hypertension treated in usual fashion by their own physicians. In this group, SBP was much more accurate than DBP in classifying severity of hypertension and in predicting cardiovascular risk.

Recommendations from others

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)⁷ and the World Health Organization–International Society of Hyper-tension Guidelines⁸ state that the relationship between cardiovascular risk and blood pressure is continuous, without a lower threshold. Target blood pressure goals are <140/90 mm Hg in uncomplicated hypertension and <130/80 mm Hg for individuals with diabetes or kidney disease. The National High Blood Pressure Education Program stressed that SBP, not DBP, should become the major criterion for diagnosis and treatment of hypertension.⁹

Evidence summary

ACE inhibitors have been used most commonly for the treatment of congestive heart failure and hypertension and to slow the progression of proteinuria. Their primary mechanism of action is the suppression of angiotensin II by blocking its formation via renin and angiotensin I, thereby reducing the main deleterious effects of angiotensin II, which are mediated through vaso-constriction. Other pathways of angiotensin II formation exist and may escape inhibition of the converting enzyme.¹ ARBs block the action of angiotensin II at the AT1 receptor and may, in theory, provide additive benefit.

The data describing the use of the combination of an ACE inhibitor and an ARB in heart failure are from the Valsartan Heart Failure Trial (ValHeFT),² the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Trial (CHARM),³ and in the Valsartan in Acute Myocardial Infarction Trial (VALIANT).⁴

In ValHeFT, 5010 patients with systolic dysfunction were randomized to the ARB valsartan or placebo in addition to background therapy, which included an ACE inhibitor in 93% of subjects. The primary endpoints were mortality and combined mortality and morbidity. An increase in mortality was found among patients on the triple therapy combination of valsartan, an ACE inhibitor, and a beta-blocker (relative risk [RR]=1.4; 95% confidence interval [CI], 1.1–1.9). Among those not on beta-blockers, adding valsartan to baseline therapy of an ACE inhibitor resulted in a modest improvement in the combined endpoint (RR=0.8; 95% CI, 0.7–0.9), but no change in mortality alone was found.²

In CHARM, candesartan was added to baseline therapy among patients with heart failure. Baseline therapy included diuretics (90%), beta blockers (55%), spironolactone (17%), and other cardiovascular medications as necessary. In this study, those in the treatment arm had a decrease in the combined endpoint of cardiovascular death plus congestive heart failure admission (RR=0.85; 95% CI, 0.75–0.96), but no difference was seen in overall mortality. Of note, no adverse interaction was demonstrated for those on the triple combination of ACE inhibitors, ARBs, and beta-blockers.³

Similarly, VALIANT demonstrated the safety but the lack of incremental efficacy in adding valsartan to ACE inhibitors for patients with left ventricular dysfunction after a myocardial infarction.⁴

Limited evidence is available from randomized controlled trials on the safety or efficacy of combination therapy exclusively for hyperten-sive patients. The available published trials were short-term and assessed blood pressure rather than more clinically significant endpoints such as risk of cardiovascular events and mortality. One trial of 177 patients found no significant difference in 24-hour ambulatory mean diastolic blood pressure with combination therapy vs ACE inhibitor or ARB monotherapy, but did show a decrease in clinic diastolic blood pressure.⁵ Another small trial of 20 patients demonstrated improved ambulatory blood pressure control with combination therapy vs ACE inhibitor monotherapy.⁶

Several trials have investigated the effect of combination therapy on diabetic and nondiabet-ic proteinuria. Conclusions from these trials are limited by their small sample size and by measurement of intermediate outcomes without mortality data. The largest trial, COOPERATE, was conducted in Japan and included 336 patients with nondiabetic renal disease.⁷ The investigators found that significantly fewer patients receiving combination therapy reached the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease compared with patients receiving monotherapy. The CALM study included 199 patients with hypertension, micro-albuminuria, and type 2 diabetes mellitus, and demonstrated significantly greater attenuation of urinary albumin/creatinine ratio and significantly improved blood pressure control with combination therapy compared with either therapy alone.⁸

Another trial, ONTARGET, is being conducted to assess the impact of ACE inhibitor or ARB monotherapy and combination therapy on reducing cardiovascular risk; it includes a combined primary endpoint of morbidity and mortality. The study involves 23,400 high-risk patients and will have a follow-up period of 5.5 years. This trial enrolls patients who have coronary disease, cere-brovascular disease, peripheral vascular disease, or diabetes with end-organ damage (inclusion and exclusion criteria are based upon those used in the HOPE study).

Recommendations from others

We were unable to find to find any recommendations regarding the addition of ARB drugs to ACE inhibitors.

Evidence summary

ACE inhibitors have been used most commonly for the treatment of congestive heart failure and hypertension and to slow the progression of proteinuria. Their primary mechanism of action is the suppression of angiotensin II by blocking its formation via renin and angiotensin I, thereby reducing the main deleterious effects of angiotensin II, which are mediated through vaso-constriction. Other pathways of angiotensin II formation exist and may escape inhibition of the converting enzyme.¹ ARBs block the action of angiotensin II at the AT1 receptor and may, in theory, provide additive benefit.

The data describing the use of the combination of an ACE inhibitor and an ARB in heart failure are from the Valsartan Heart Failure Trial (ValHeFT),² the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Trial (CHARM),³ and in the Valsartan in Acute Myocardial Infarction Trial (VALIANT).⁴

In ValHeFT, 5010 patients with systolic dysfunction were randomized to the ARB valsartan or placebo in addition to background therapy, which included an ACE inhibitor in 93% of subjects. The primary endpoints were mortality and combined mortality and morbidity. An increase in mortality was found among patients on the triple therapy combination of valsartan, an ACE inhibitor, and a beta-blocker (relative risk [RR]=1.4; 95% confidence interval [CI], 1.1–1.9). Among those not on beta-blockers, adding valsartan to baseline therapy of an ACE inhibitor resulted in a modest improvement in the combined endpoint (RR=0.8; 95% CI, 0.7–0.9), but no change in mortality alone was found.²

In CHARM, candesartan was added to baseline therapy among patients with heart failure. Baseline therapy included diuretics (90%), beta blockers (55%), spironolactone (17%), and other cardiovascular medications as necessary. In this study, those in the treatment arm had a decrease in the combined endpoint of cardiovascular death plus congestive heart failure admission (RR=0.85; 95% CI, 0.75–0.96), but no difference was seen in overall mortality. Of note, no adverse interaction was demonstrated for those on the triple combination of ACE inhibitors, ARBs, and beta-blockers.³

Similarly, VALIANT demonstrated the safety but the lack of incremental efficacy in adding valsartan to ACE inhibitors for patients with left ventricular dysfunction after a myocardial infarction.⁴

Limited evidence is available from randomized controlled trials on the safety or efficacy of combination therapy exclusively for hyperten-sive patients. The available published trials were short-term and assessed blood pressure rather than more clinically significant endpoints such as risk of cardiovascular events and mortality. One trial of 177 patients found no significant difference in 24-hour ambulatory mean diastolic blood pressure with combination therapy vs ACE inhibitor or ARB monotherapy, but did show a decrease in clinic diastolic blood pressure.⁵ Another small trial of 20 patients demonstrated improved ambulatory blood pressure control with combination therapy vs ACE inhibitor monotherapy.⁶

Several trials have investigated the effect of combination therapy on diabetic and nondiabet-ic proteinuria. Conclusions from these trials are limited by their small sample size and by measurement of intermediate outcomes without mortality data. The largest trial, COOPERATE, was conducted in Japan and included 336 patients with nondiabetic renal disease.⁷ The investigators found that significantly fewer patients receiving combination therapy reached the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease compared with patients receiving monotherapy. The CALM study included 199 patients with hypertension, micro-albuminuria, and type 2 diabetes mellitus, and demonstrated significantly greater attenuation of urinary albumin/creatinine ratio and significantly improved blood pressure control with combination therapy compared with either therapy alone.⁸

Another trial, ONTARGET, is being conducted to assess the impact of ACE inhibitor or ARB monotherapy and combination therapy on reducing cardiovascular risk; it includes a combined primary endpoint of morbidity and mortality. The study involves 23,400 high-risk patients and will have a follow-up period of 5.5 years. This trial enrolls patients who have coronary disease, cere-brovascular disease, peripheral vascular disease, or diabetes with end-organ damage (inclusion and exclusion criteria are based upon those used in the HOPE study).

Recommendations from others

We were unable to find to find any recommendations regarding the addition of ARB drugs to ACE inhibitors.

Evidence summary

ACE inhibitors have been used most commonly for the treatment of congestive heart failure and hypertension and to slow the progression of proteinuria. Their primary mechanism of action is the suppression of angiotensin II by blocking its formation via renin and angiotensin I, thereby reducing the main deleterious effects of angiotensin II, which are mediated through vaso-constriction. Other pathways of angiotensin II formation exist and may escape inhibition of the converting enzyme.¹ ARBs block the action of angiotensin II at the AT1 receptor and may, in theory, provide additive benefit.

The data describing the use of the combination of an ACE inhibitor and an ARB in heart failure are from the Valsartan Heart Failure Trial (ValHeFT),² the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Trial (CHARM),³ and in the Valsartan in Acute Myocardial Infarction Trial (VALIANT).⁴

In ValHeFT, 5010 patients with systolic dysfunction were randomized to the ARB valsartan or placebo in addition to background therapy, which included an ACE inhibitor in 93% of subjects. The primary endpoints were mortality and combined mortality and morbidity. An increase in mortality was found among patients on the triple therapy combination of valsartan, an ACE inhibitor, and a beta-blocker (relative risk [RR]=1.4; 95% confidence interval [CI], 1.1–1.9). Among those not on beta-blockers, adding valsartan to baseline therapy of an ACE inhibitor resulted in a modest improvement in the combined endpoint (RR=0.8; 95% CI, 0.7–0.9), but no change in mortality alone was found.²

In CHARM, candesartan was added to baseline therapy among patients with heart failure. Baseline therapy included diuretics (90%), beta blockers (55%), spironolactone (17%), and other cardiovascular medications as necessary. In this study, those in the treatment arm had a decrease in the combined endpoint of cardiovascular death plus congestive heart failure admission (RR=0.85; 95% CI, 0.75–0.96), but no difference was seen in overall mortality. Of note, no adverse interaction was demonstrated for those on the triple combination of ACE inhibitors, ARBs, and beta-blockers.³

Similarly, VALIANT demonstrated the safety but the lack of incremental efficacy in adding valsartan to ACE inhibitors for patients with left ventricular dysfunction after a myocardial infarction.⁴

Limited evidence is available from randomized controlled trials on the safety or efficacy of combination therapy exclusively for hyperten-sive patients. The available published trials were short-term and assessed blood pressure rather than more clinically significant endpoints such as risk of cardiovascular events and mortality. One trial of 177 patients found no significant difference in 24-hour ambulatory mean diastolic blood pressure with combination therapy vs ACE inhibitor or ARB monotherapy, but did show a decrease in clinic diastolic blood pressure.⁵ Another small trial of 20 patients demonstrated improved ambulatory blood pressure control with combination therapy vs ACE inhibitor monotherapy.⁶

Several trials have investigated the effect of combination therapy on diabetic and nondiabet-ic proteinuria. Conclusions from these trials are limited by their small sample size and by measurement of intermediate outcomes without mortality data. The largest trial, COOPERATE, was conducted in Japan and included 336 patients with nondiabetic renal disease.⁷ The investigators found that significantly fewer patients receiving combination therapy reached the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease compared with patients receiving monotherapy. The CALM study included 199 patients with hypertension, micro-albuminuria, and type 2 diabetes mellitus, and demonstrated significantly greater attenuation of urinary albumin/creatinine ratio and significantly improved blood pressure control with combination therapy compared with either therapy alone.⁸

Another trial, ONTARGET, is being conducted to assess the impact of ACE inhibitor or ARB monotherapy and combination therapy on reducing cardiovascular risk; it includes a combined primary endpoint of morbidity and mortality. The study involves 23,400 high-risk patients and will have a follow-up period of 5.5 years. This trial enrolls patients who have coronary disease, cere-brovascular disease, peripheral vascular disease, or diabetes with end-organ damage (inclusion and exclusion criteria are based upon those used in the HOPE study).

Recommendations from others

We were unable to find to find any recommendations regarding the addition of ARB drugs to ACE inhibitors.

Evidence summary

Truly isolated hypertriglyceridemia is rare. To date, no good trials directly address the effect of reducing truly isolated hypertriglyceridemia on cardiovascular morbidity or mortality. High triglycerides are usually accompanied by other features of the “metabolic syndrome” (low HDL, high LDL, insulin resistance, diabetes, hypertension, and obesity), making it almost impossible to look at these in isolation or attribute risk to a specific component.¹

Whether high triglyceride levels pose risk in the true absence of these other metabolic factors is controversial. One meta-analysis of 17 population-based prospective studies of triglycerides and cardiovascular disease (including 57,000 patients) showed high triglyceride levels to be predictive of cardiac events, even when adjusted for HDL and other risk factors (age, total and LDL cholesterol, smoking, body mass index, and blood pressure).² After adjusting for these other risk factors, the authors found an increased risk for all cardiac endpoints (myocardial infarction, death, etc) of 14% for men and 32% for women (Men: relative risk [RR]=1.14; 95% confidence interval [CI], 1.05–1.28; Women: RR=1.37; 95% CI, 1.13–1.66).

Another meta-analysis of 3 prospective intervention trials with 15,880 enrolled subjects found that triglyceride levels did not provide any clinically meaningful information about risk beyond that provided by other cholesterol subfractions.³

In treatment trials, the most impressive risk reductions come from the groups who fit the lipid triad of low HDL, high LDL, and high triglycerides. Low levels of HDL appear to interact with hypertriglyceridemia to increase coronary risk, and all studies showing improved outcomes have simultaneously increased HDL while lowering triglycerides.^4-6 In 3 large-scale prospective, placebo-controlled trials (the Helsinki Heart Study, a primary prevention study, and the VA-HIT and Bezafibrate Infarction Prevention trials, both secondary prevention studies), lowering triglycerides and raising HDL concurrently improved outcomes.⁵ Successful dietary and medical interventions, especially with statins and fibrates, improved overall lipid profiles—not just triglyceride levels.

Accordingly, elevated triglycerides should prompt providers to rigorously identify these other risk factors for cardiovascular morbidity and mortality, which may not be immediately obvious. In the absence of such other factors, no evidence exists to guide therapy. Expert opinion^7,8 supported by epidemiologic evidence⁹ suggests that patients with triglyceride levels of 500 to 1000 mg/dL may have an increased risk of pancreatitis. Accordingly, providers should consider therapy to lower triglycerides to less than 500 in these patients, regardless of accompanying risk factors.

Recommendations from others

The American College of Physicians, the European Society of Cardiology, and the US Preventive Services Task Force do not recommend screening for hypertriglyceridemia. Clinical guidelines of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III), American Heart Association/American College of Cardiology, and the American Diabetes Association all support LDL lowering as the primary target of therapy based on the patients risk profile.¹⁰ NCEP/ATP III has identified triglyceride levels of <150 as normal, 150–199 as borderline high, 200–499 as high, and 500 as very high.7

A patient with high triglycerides should prompt a search for components of the “meta-bolic syndrome” and secondary causes, including high dietary fat, high alcohol intake, drugs (steroids, beta-blockers, high-estrogen oral contraceptives), medical conditions (hypothyroidism, nephrosis, renal failure, liver disease, Cushing disease, and lupus), and rare familial dyslipidemias.^7,10,11

Evidence summary

Truly isolated hypertriglyceridemia is rare. To date, no good trials directly address the effect of reducing truly isolated hypertriglyceridemia on cardiovascular morbidity or mortality. High triglycerides are usually accompanied by other features of the “metabolic syndrome” (low HDL, high LDL, insulin resistance, diabetes, hypertension, and obesity), making it almost impossible to look at these in isolation or attribute risk to a specific component.¹

Whether high triglyceride levels pose risk in the true absence of these other metabolic factors is controversial. One meta-analysis of 17 population-based prospective studies of triglycerides and cardiovascular disease (including 57,000 patients) showed high triglyceride levels to be predictive of cardiac events, even when adjusted for HDL and other risk factors (age, total and LDL cholesterol, smoking, body mass index, and blood pressure).² After adjusting for these other risk factors, the authors found an increased risk for all cardiac endpoints (myocardial infarction, death, etc) of 14% for men and 32% for women (Men: relative risk [RR]=1.14; 95% confidence interval [CI], 1.05–1.28; Women: RR=1.37; 95% CI, 1.13–1.66).

Another meta-analysis of 3 prospective intervention trials with 15,880 enrolled subjects found that triglyceride levels did not provide any clinically meaningful information about risk beyond that provided by other cholesterol subfractions.³

In treatment trials, the most impressive risk reductions come from the groups who fit the lipid triad of low HDL, high LDL, and high triglycerides. Low levels of HDL appear to interact with hypertriglyceridemia to increase coronary risk, and all studies showing improved outcomes have simultaneously increased HDL while lowering triglycerides.^4-6 In 3 large-scale prospective, placebo-controlled trials (the Helsinki Heart Study, a primary prevention study, and the VA-HIT and Bezafibrate Infarction Prevention trials, both secondary prevention studies), lowering triglycerides and raising HDL concurrently improved outcomes.⁵ Successful dietary and medical interventions, especially with statins and fibrates, improved overall lipid profiles—not just triglyceride levels.

Accordingly, elevated triglycerides should prompt providers to rigorously identify these other risk factors for cardiovascular morbidity and mortality, which may not be immediately obvious. In the absence of such other factors, no evidence exists to guide therapy. Expert opinion^7,8 supported by epidemiologic evidence⁹ suggests that patients with triglyceride levels of 500 to 1000 mg/dL may have an increased risk of pancreatitis. Accordingly, providers should consider therapy to lower triglycerides to less than 500 in these patients, regardless of accompanying risk factors.

Recommendations from others

The American College of Physicians, the European Society of Cardiology, and the US Preventive Services Task Force do not recommend screening for hypertriglyceridemia. Clinical guidelines of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III), American Heart Association/American College of Cardiology, and the American Diabetes Association all support LDL lowering as the primary target of therapy based on the patients risk profile.¹⁰ NCEP/ATP III has identified triglyceride levels of <150 as normal, 150–199 as borderline high, 200–499 as high, and 500 as very high.7

A patient with high triglycerides should prompt a search for components of the “meta-bolic syndrome” and secondary causes, including high dietary fat, high alcohol intake, drugs (steroids, beta-blockers, high-estrogen oral contraceptives), medical conditions (hypothyroidism, nephrosis, renal failure, liver disease, Cushing disease, and lupus), and rare familial dyslipidemias.^7,10,11

Evidence summary

Truly isolated hypertriglyceridemia is rare. To date, no good trials directly address the effect of reducing truly isolated hypertriglyceridemia on cardiovascular morbidity or mortality. High triglycerides are usually accompanied by other features of the “metabolic syndrome” (low HDL, high LDL, insulin resistance, diabetes, hypertension, and obesity), making it almost impossible to look at these in isolation or attribute risk to a specific component.¹

Whether high triglyceride levels pose risk in the true absence of these other metabolic factors is controversial. One meta-analysis of 17 population-based prospective studies of triglycerides and cardiovascular disease (including 57,000 patients) showed high triglyceride levels to be predictive of cardiac events, even when adjusted for HDL and other risk factors (age, total and LDL cholesterol, smoking, body mass index, and blood pressure).² After adjusting for these other risk factors, the authors found an increased risk for all cardiac endpoints (myocardial infarction, death, etc) of 14% for men and 32% for women (Men: relative risk [RR]=1.14; 95% confidence interval [CI], 1.05–1.28; Women: RR=1.37; 95% CI, 1.13–1.66).

Another meta-analysis of 3 prospective intervention trials with 15,880 enrolled subjects found that triglyceride levels did not provide any clinically meaningful information about risk beyond that provided by other cholesterol subfractions.³

In treatment trials, the most impressive risk reductions come from the groups who fit the lipid triad of low HDL, high LDL, and high triglycerides. Low levels of HDL appear to interact with hypertriglyceridemia to increase coronary risk, and all studies showing improved outcomes have simultaneously increased HDL while lowering triglycerides.^4-6 In 3 large-scale prospective, placebo-controlled trials (the Helsinki Heart Study, a primary prevention study, and the VA-HIT and Bezafibrate Infarction Prevention trials, both secondary prevention studies), lowering triglycerides and raising HDL concurrently improved outcomes.⁵ Successful dietary and medical interventions, especially with statins and fibrates, improved overall lipid profiles—not just triglyceride levels.

Accordingly, elevated triglycerides should prompt providers to rigorously identify these other risk factors for cardiovascular morbidity and mortality, which may not be immediately obvious. In the absence of such other factors, no evidence exists to guide therapy. Expert opinion^7,8 supported by epidemiologic evidence⁹ suggests that patients with triglyceride levels of 500 to 1000 mg/dL may have an increased risk of pancreatitis. Accordingly, providers should consider therapy to lower triglycerides to less than 500 in these patients, regardless of accompanying risk factors.

Recommendations from others

The American College of Physicians, the European Society of Cardiology, and the US Preventive Services Task Force do not recommend screening for hypertriglyceridemia. Clinical guidelines of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III), American Heart Association/American College of Cardiology, and the American Diabetes Association all support LDL lowering as the primary target of therapy based on the patients risk profile.¹⁰ NCEP/ATP III has identified triglyceride levels of <150 as normal, 150–199 as borderline high, 200–499 as high, and 500 as very high.7

A patient with high triglycerides should prompt a search for components of the “meta-bolic syndrome” and secondary causes, including high dietary fat, high alcohol intake, drugs (steroids, beta-blockers, high-estrogen oral contraceptives), medical conditions (hypothyroidism, nephrosis, renal failure, liver disease, Cushing disease, and lupus), and rare familial dyslipidemias.^7,10,11