G. L. Morris 3rd, MD

In Children with Epilepsy, Is Using Adjunctive Vagus Nerve Stimulation (VNS) Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 14 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction (responder rate). In the pooled analysis of 481 children, the responder rate was 55% (95% confidence interval [CI] 51%–59%), but there was significant heterogeneity in the data. Two of the 16 studies were not included in the analysis because either they did not provide information about responder rate or they included a significant number (>20%) of adults in their population. The pooled seizure freedom rate was 7% (95% CI 5%–10%).

Recommendation

VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy (Level C).

Clinical Context

VNS may be considered a possibly effective option after a child with medication-resistant epilepsy has been declared a poor surgical candidate or has had unsuccessful surgery.

In Patients with Lennox-Gastaut Syndrome (LGS), Is Using Adjunctive VNS Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS Therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 4 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction in patients with LGS. The pooled analysis of 113 patients with LGS (including data from articles with multiple seizure types where LGS data were parsed out) yielded a 55% (95% CI 46%–64%) responder rate.

Recommendation

VNS may be considered in patients with LGS (Level C).

Clinical Context

The responder rate for patients with LGS does not appear to differ from that of the general population of patients with medication-resistant epilepsy.

In Patients with Epilepsy, Is Using VNS Associated with Mood Improvement?

Conclusion

Based on data from 2 Class III studies, VNS is possibly effective for mood improvement in adults with epilepsy.

Recommendation

In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C).

Clinical Context

Depression is a common comorbidity for people with epilepsy. VNS may provide an additional benefit by improving mood in some patients; however, the potential for mood improvement should be considered a secondary rather than a primary reason for VNS implantation. The evidence does not clearly support an independent effect on mood in this complex population.

In Patients with Epilepsy, Is VNS Use Associated with Reduced Seizure Frequency Over Time?

Conclusion

Based on data from 2 Class III studies, VNS is possibly associated with an increase in ≥50% seizure frequency reduction rates of 7% from 1 to 5 years postimplantation.

Recommendation

VNS may be considered progressively effective in patients over multiple years of exposure (Level C).

Clinical Context

The loss of medication efficacy over time is a challenging aspect of epilepsy management. The evidence of maintained efficacy in the long term and the trend toward improvement over time make VNS an option.

In Patients Undergoing VNS Therapy, Does Rapid Stimulation (Usual VNS Settings Are 7 Seconds "On" and 30 Seconds "Off") Improve Seizure Frequency More Often Than Standard Stimulation Settings (30 Seconds "On" and 300 Seconds "Off")?

Conclusion

These 3 Class III studies were underpowered to detect a difference in efficacy between rapid stimulation (7 seconds "on," 30 seconds "off") used either after standard stimulation (30 seconds "on," 300 seconds "off") was unsuccessful or as an initial treatment setting.

Recommendation

Optimal VNS settings are still unknown, and the evidence is insufficient to support a recommendation for the use of standard stimulation vs. rapid stimulation to reduce seizure occurrence (Level U).

Clinical Context

Rapid cycling increases the duty cycle and hastens the need for battery replacement; therefore, when used, the efficacy of rapid cycling should be carefully assessed.

In Patients Undergoing VNS Therapy, Does Using Additional Magnet-Activated Stimulation Trains for Auras or at Seizure Onset Interrupt Seizures Relative to Not Using Additional Magnet-Induced Stimulation Trains for Auras or at Seizure Onset?

Conclusion

Based on data from 2 Class III studies, seizure abortion with magnet-activated stimulation is possibly associated with overall response to VNS therapy. Based on 3 Class III studies, magnet-activated stimulation may be expected to abort seizures one-fourth to two-thirds of the time when used during seizure auras (one Class III study omitted because it was not generalizable).

Recommendation

Patients may be counseled that VNS magnet activation may be associated with seizure abortion when used at the time of seizure auras (Level C) and that seizure abortion with magnet use may be associated with overall response to VNS treatment (Level C).

In Patients Undergoing VNS Therapy, Have New Safety Concerns Emerged Since the Last Assessment?

Clinical Context

Current physician attention to intraoperative rhythm disturbances from VNS use need not be changed. The paroxysmal nature of epilepsy poses a challenge for identifying a cardiac rhythm disturbance as device-related rather than as an additional seizure manifestation. Video electroencephalogram (EEG) and electrocardiogram (ECG) monitoring of new-onset events that might be cardiac-related would be warranted to exclude this possibility in what is likely to be a small number of patients. Reduced sudden unexpected death in epilepsy (SUDEP) rates over time is an important finding associated with VNS therapy; in a cohort of 1,819 individuals followed 3,176.3 person-years from VNS implantation, the SUDEP rate was 5.5 per 1,000 over the first 2 years but only 1.7 per 1,000 thereafter. The clinical importance of the effect of VNS on sleep apnea and treatment is unclear, but caution regarding VNS use in this setting is suggested.

In Children Undergoing VNS Therapy, Do Adverse Events (AEs) Differ from Those in Adults?

Clinical Context

Children may have greater risk for wound infection than adults due to behaviors more common in children. Extra vigilance in monitoring for occurrence of site infection in children should be undertaken.

Definitions:

Classification of Evidence for Therapeutic Intervention

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

In Children with Epilepsy, Is Using Adjunctive Vagus Nerve Stimulation (VNS) Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 14 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction (responder rate). In the pooled analysis of 481 children, the responder rate was 55% (95% confidence interval [CI] 51%–59%), but there was significant heterogeneity in the data. Two of the 16 studies were not included in the analysis because either they did not provide information about responder rate or they included a significant number (>20%) of adults in their population. The pooled seizure freedom rate was 7% (95% CI 5%–10%).

Recommendation

VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy (Level C).

Clinical Context

VNS may be considered a possibly effective option after a child with medication-resistant epilepsy has been declared a poor surgical candidate or has had unsuccessful surgery.

In Patients with Lennox-Gastaut Syndrome (LGS), Is Using Adjunctive VNS Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS Therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 4 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction in patients with LGS. The pooled analysis of 113 patients with LGS (including data from articles with multiple seizure types where LGS data were parsed out) yielded a 55% (95% CI 46%–64%) responder rate.

Recommendation

VNS may be considered in patients with LGS (Level C).

Clinical Context

The responder rate for patients with LGS does not appear to differ from that of the general population of patients with medication-resistant epilepsy.

In Patients with Epilepsy, Is Using VNS Associated with Mood Improvement?

Conclusion

Based on data from 2 Class III studies, VNS is possibly effective for mood improvement in adults with epilepsy.

Recommendation

In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C).

Clinical Context

Depression is a common comorbidity for people with epilepsy. VNS may provide an additional benefit by improving mood in some patients; however, the potential for mood improvement should be considered a secondary rather than a primary reason for VNS implantation. The evidence does not clearly support an independent effect on mood in this complex population.

In Patients with Epilepsy, Is VNS Use Associated with Reduced Seizure Frequency Over Time?

Conclusion

Based on data from 2 Class III studies, VNS is possibly associated with an increase in ≥50% seizure frequency reduction rates of 7% from 1 to 5 years postimplantation.

Recommendation

VNS may be considered progressively effective in patients over multiple years of exposure (Level C).

Clinical Context

The loss of medication efficacy over time is a challenging aspect of epilepsy management. The evidence of maintained efficacy in the long term and the trend toward improvement over time make VNS an option.

In Patients Undergoing VNS Therapy, Does Rapid Stimulation (Usual VNS Settings Are 7 Seconds "On" and 30 Seconds "Off") Improve Seizure Frequency More Often Than Standard Stimulation Settings (30 Seconds "On" and 300 Seconds "Off")?

Conclusion

These 3 Class III studies were underpowered to detect a difference in efficacy between rapid stimulation (7 seconds "on," 30 seconds "off") used either after standard stimulation (30 seconds "on," 300 seconds "off") was unsuccessful or as an initial treatment setting.

Recommendation

Optimal VNS settings are still unknown, and the evidence is insufficient to support a recommendation for the use of standard stimulation vs. rapid stimulation to reduce seizure occurrence (Level U).

Clinical Context

Rapid cycling increases the duty cycle and hastens the need for battery replacement; therefore, when used, the efficacy of rapid cycling should be carefully assessed.

In Patients Undergoing VNS Therapy, Does Using Additional Magnet-Activated Stimulation Trains for Auras or at Seizure Onset Interrupt Seizures Relative to Not Using Additional Magnet-Induced Stimulation Trains for Auras or at Seizure Onset?

Conclusion

Based on data from 2 Class III studies, seizure abortion with magnet-activated stimulation is possibly associated with overall response to VNS therapy. Based on 3 Class III studies, magnet-activated stimulation may be expected to abort seizures one-fourth to two-thirds of the time when used during seizure auras (one Class III study omitted because it was not generalizable).

Recommendation

Patients may be counseled that VNS magnet activation may be associated with seizure abortion when used at the time of seizure auras (Level C) and that seizure abortion with magnet use may be associated with overall response to VNS treatment (Level C).

In Patients Undergoing VNS Therapy, Have New Safety Concerns Emerged Since the Last Assessment?

Clinical Context

Current physician attention to intraoperative rhythm disturbances from VNS use need not be changed. The paroxysmal nature of epilepsy poses a challenge for identifying a cardiac rhythm disturbance as device-related rather than as an additional seizure manifestation. Video electroencephalogram (EEG) and electrocardiogram (ECG) monitoring of new-onset events that might be cardiac-related would be warranted to exclude this possibility in what is likely to be a small number of patients. Reduced sudden unexpected death in epilepsy (SUDEP) rates over time is an important finding associated with VNS therapy; in a cohort of 1,819 individuals followed 3,176.3 person-years from VNS implantation, the SUDEP rate was 5.5 per 1,000 over the first 2 years but only 1.7 per 1,000 thereafter. The clinical importance of the effect of VNS on sleep apnea and treatment is unclear, but caution regarding VNS use in this setting is suggested.

In Children Undergoing VNS Therapy, Do Adverse Events (AEs) Differ from Those in Adults?

Clinical Context

Children may have greater risk for wound infection than adults due to behaviors more common in children. Extra vigilance in monitoring for occurrence of site infection in children should be undertaken.

Definitions:

Classification of Evidence for Therapeutic Intervention

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

In Children with Epilepsy, Is Using Adjunctive Vagus Nerve Stimulation (VNS) Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 14 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction (responder rate). In the pooled analysis of 481 children, the responder rate was 55% (95% confidence interval [CI] 51%–59%), but there was significant heterogeneity in the data. Two of the 16 studies were not included in the analysis because either they did not provide information about responder rate or they included a significant number (>20%) of adults in their population. The pooled seizure freedom rate was 7% (95% CI 5%–10%).

Recommendation

VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy (Level C).

Clinical Context

VNS may be considered a possibly effective option after a child with medication-resistant epilepsy has been declared a poor surgical candidate or has had unsuccessful surgery.

In Patients with Lennox-Gastaut Syndrome (LGS), Is Using Adjunctive VNS Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS Therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 4 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction in patients with LGS. The pooled analysis of 113 patients with LGS (including data from articles with multiple seizure types where LGS data were parsed out) yielded a 55% (95% CI 46%–64%) responder rate.

Recommendation

VNS may be considered in patients with LGS (Level C).

Clinical Context

The responder rate for patients with LGS does not appear to differ from that of the general population of patients with medication-resistant epilepsy.

In Patients with Epilepsy, Is Using VNS Associated with Mood Improvement?

Conclusion

Based on data from 2 Class III studies, VNS is possibly effective for mood improvement in adults with epilepsy.

Recommendation

In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C).

Clinical Context

Depression is a common comorbidity for people with epilepsy. VNS may provide an additional benefit by improving mood in some patients; however, the potential for mood improvement should be considered a secondary rather than a primary reason for VNS implantation. The evidence does not clearly support an independent effect on mood in this complex population.

In Patients with Epilepsy, Is VNS Use Associated with Reduced Seizure Frequency Over Time?

Conclusion

Based on data from 2 Class III studies, VNS is possibly associated with an increase in ≥50% seizure frequency reduction rates of 7% from 1 to 5 years postimplantation.

Recommendation

VNS may be considered progressively effective in patients over multiple years of exposure (Level C).

Clinical Context

The loss of medication efficacy over time is a challenging aspect of epilepsy management. The evidence of maintained efficacy in the long term and the trend toward improvement over time make VNS an option.

In Patients Undergoing VNS Therapy, Does Rapid Stimulation (Usual VNS Settings Are 7 Seconds "On" and 30 Seconds "Off") Improve Seizure Frequency More Often Than Standard Stimulation Settings (30 Seconds "On" and 300 Seconds "Off")?

Conclusion

These 3 Class III studies were underpowered to detect a difference in efficacy between rapid stimulation (7 seconds "on," 30 seconds "off") used either after standard stimulation (30 seconds "on," 300 seconds "off") was unsuccessful or as an initial treatment setting.

Recommendation

Optimal VNS settings are still unknown, and the evidence is insufficient to support a recommendation for the use of standard stimulation vs. rapid stimulation to reduce seizure occurrence (Level U).

Clinical Context

Rapid cycling increases the duty cycle and hastens the need for battery replacement; therefore, when used, the efficacy of rapid cycling should be carefully assessed.

In Patients Undergoing VNS Therapy, Does Using Additional Magnet-Activated Stimulation Trains for Auras or at Seizure Onset Interrupt Seizures Relative to Not Using Additional Magnet-Induced Stimulation Trains for Auras or at Seizure Onset?

Conclusion

Based on data from 2 Class III studies, seizure abortion with magnet-activated stimulation is possibly associated with overall response to VNS therapy. Based on 3 Class III studies, magnet-activated stimulation may be expected to abort seizures one-fourth to two-thirds of the time when used during seizure auras (one Class III study omitted because it was not generalizable).

Recommendation

Patients may be counseled that VNS magnet activation may be associated with seizure abortion when used at the time of seizure auras (Level C) and that seizure abortion with magnet use may be associated with overall response to VNS treatment (Level C).

In Patients Undergoing VNS Therapy, Have New Safety Concerns Emerged Since the Last Assessment?

Clinical Context

Current physician attention to intraoperative rhythm disturbances from VNS use need not be changed. The paroxysmal nature of epilepsy poses a challenge for identifying a cardiac rhythm disturbance as device-related rather than as an additional seizure manifestation. Video electroencephalogram (EEG) and electrocardiogram (ECG) monitoring of new-onset events that might be cardiac-related would be warranted to exclude this possibility in what is likely to be a small number of patients. Reduced sudden unexpected death in epilepsy (SUDEP) rates over time is an important finding associated with VNS therapy; in a cohort of 1,819 individuals followed 3,176.3 person-years from VNS implantation, the SUDEP rate was 5.5 per 1,000 over the first 2 years but only 1.7 per 1,000 thereafter. The clinical importance of the effect of VNS on sleep apnea and treatment is unclear, but caution regarding VNS use in this setting is suggested.

In Children Undergoing VNS Therapy, Do Adverse Events (AEs) Differ from Those in Adults?

Clinical Context

Children may have greater risk for wound infection than adults due to behaviors more common in children. Extra vigilance in monitoring for occurrence of site infection in children should be undertaken.

Definitions:

Classification of Evidence for Therapeutic Intervention

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).