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What’s the most practical way to rule out adrenal insufficiency?
A morning serum cortisol level >13 mcg/dL reliably rules out adrenal insufficiency, and the test is easy and safe to perform. Because of low specificity, patients with a level of ≤13 mcg/dL need further evaluation with the cosyntropin stimulation test (CST) (strength of recommendation [SOR]: A, meta-analysis of diagnostic cohort studies).
The 250 mcg CST requires intravenous (IV) or intramuscular (IM) administration of cosyntropin and multiple blood draws; a normal response reliably rules out primary adrenal insufficiency (SOR: B, meta-analysis of lower-quality diagnostic cohort studies) and moderately decreases the likelihood of secondary adrenal insufficiency (SOR: A, meta-analysis of diagnostic cohort studies). The 1 mcg CST has better diagnostic discrimination, but requires an extra step to dilute the cosyntropin (SOR: A, meta-analysis of diagnostic cohort studies).
Evidence summary
The morning serum cortisol level is the most convenient test for adrenal insufficiency because it requires a single blood draw. The 250 mcg CST involves IV or IM administration of cosyntropin and several blood draws. The 1 mcg CST, introduced to improve detection of partial and secondary adrenal insufficiency, requires dilution of the cosyntropin before administration because the smallest available dose is 250 mcg.
The insulin tolerance test is widely considered the gold standard, but requires close observation, is unpleasant for the patient, and carries some risk. Metyrapone and corticotropin-releasing hormone tests are not widely available.1
Negative CST rules out primary insufficiency
Researchers conducting a meta-analysis of the CST in diagnosing both primary and secondary adrenal insufficiency searched MEDLINE for English-language studies from 1966 to 2002 and used summary receiver-operating characteristic (ROC) curves to combine the sensitivities and specificities from individual studies.2 Four studies of primary adrenal insufficiency showed a negative likelihood ratio of 0.026 for the 250 mcg CST. A negative CST would, therefore, significantly decrease the post-test probability of primary adrenal insufficiency and effectively rule out the condition.
However, primary adrenal insufficiency was already established in the 4 studies, and consecutive testing with an accepted gold standard was not done. Thus, the studies likely overestimate the accuracy of the CST test characteristics.
Using CST results for secondary insufficiency
Twenty studies evaluating the 250 mcg CST for diagnosing secondary adrenal insufficiency were of higher quality. They included patients with and without disease and compared the CST with gold-standard tests, either the insulin tolerance test or metyrapone test. The summary ROC curve indicated a negative likelihood ratio of 0.45, which would decrease only moderately the post-test probability of secondary adrenal insufficiency.
The 1 mcg CST: More discriminating than 250 mcg
Using a ROC curve generated from 22 studies, the authors found the test characteristics of the 250 mcg CST and the 1 mcg CST to be similar. Only 7 of these studies included paired data for the standard- and low-dose CST in the same patients, however. In the 7 studies with paired data, the 1 mcg CST had better diagnostic discrimination, based on a larger area under the ROC, than the 250 mcg CST.
13 mcg/dL is the rule-out threshold for morning serum cortisol
A subsequent meta-analysis, based on a PubMed search of English-language studies from 1966 to 2006, compared the performance of morning serum cortisol, the 1 mcg CST, and the 250 mcg CST for diagnosing secondary adrenal insufficiency. This analysis used patient-level data obtained from the original investigators instead of reported study-level results.3 Data from patients described as normal, healthy control subjects were excluded.
Studies included in the meta-analysis used an accepted gold-standard test, such as the insulin tolerance test or metyrapone test. Studies that were performed in a critical care setting or used older, less reliable cortisol assays were excluded, as were studies for which patient-level data couldn’t be obtained. Three new studies were included, and 12 of the previously used studies were excluded.
Instead of using the reported cortisol cutoff levels, the authors defined a negative test as the mean cortisol level (the “rule-out threshold”) above which the negative likelihood ratio of adrenal insufficiency is <0.15. The rule-out thresholds for morning serum cortisol, 1 mcg CST, and 250 mcg CST were 13, 22, and 30 mcg/dL, respectively.
An optimal testing strategy for secondary insufficiency
The authors proposed an optimal testing strategy for secondary adrenal insufficiency (assuming a low or moderate pretest probability) that starts with a morning serum cortisol measurement:
- A serum cortisol level >13 mcg/dL can effectively rule out adrenal insufficiency.
- If the morning serum cortisol is <13 mcg/dL, a 1 mcg CST >22 mcg/dL can rule out adrenal insufficiency.
- Patients would need an insulin tolerance test or metyrapone test only if the low-dose CST is <22 mcg/dL.
Recommendations
Williams Textbook of Endocrinology states that a basal cortisol level higher than 14.5 mcg/dL invariably indicates an intact hypothalamic-pituitary-adrenal axis. However, to confirm the diagnosis of adrenal insufficiency, all patients, except those with a recent pituitary insult, should undergo a CST. An insulin tolerance test should be done only if the patient has a subnormal response to cosyntropin (to rule out a false-positive CST) or has had a recent pituitary insult.4
1. Salvatori R. Adrenal insufficiency. JAMA. 2005;294:2481-2488.
2. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003;139:194-204.
3. Kazlauskaite R, Evans A, Villabona C, et al. Corticotropin tests for hypothalamic-pituitary adrenal insufficiency: a meta-analysis. J Clin Endocrin Metab. August 12, 2008. Available at: http://jcem.endojournals.org/cgi/content/abstract/jc.2008-0710v1. Accessed August 12, 2008.
4. Stewart PM. The adrenal cortex. In: Kronenberg HM, Melmed S, Polonsky KS, et al, eds. Williams Textbook of Endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008:445-503.
A morning serum cortisol level >13 mcg/dL reliably rules out adrenal insufficiency, and the test is easy and safe to perform. Because of low specificity, patients with a level of ≤13 mcg/dL need further evaluation with the cosyntropin stimulation test (CST) (strength of recommendation [SOR]: A, meta-analysis of diagnostic cohort studies).
The 250 mcg CST requires intravenous (IV) or intramuscular (IM) administration of cosyntropin and multiple blood draws; a normal response reliably rules out primary adrenal insufficiency (SOR: B, meta-analysis of lower-quality diagnostic cohort studies) and moderately decreases the likelihood of secondary adrenal insufficiency (SOR: A, meta-analysis of diagnostic cohort studies). The 1 mcg CST has better diagnostic discrimination, but requires an extra step to dilute the cosyntropin (SOR: A, meta-analysis of diagnostic cohort studies).
Evidence summary
The morning serum cortisol level is the most convenient test for adrenal insufficiency because it requires a single blood draw. The 250 mcg CST involves IV or IM administration of cosyntropin and several blood draws. The 1 mcg CST, introduced to improve detection of partial and secondary adrenal insufficiency, requires dilution of the cosyntropin before administration because the smallest available dose is 250 mcg.
The insulin tolerance test is widely considered the gold standard, but requires close observation, is unpleasant for the patient, and carries some risk. Metyrapone and corticotropin-releasing hormone tests are not widely available.1
Negative CST rules out primary insufficiency
Researchers conducting a meta-analysis of the CST in diagnosing both primary and secondary adrenal insufficiency searched MEDLINE for English-language studies from 1966 to 2002 and used summary receiver-operating characteristic (ROC) curves to combine the sensitivities and specificities from individual studies.2 Four studies of primary adrenal insufficiency showed a negative likelihood ratio of 0.026 for the 250 mcg CST. A negative CST would, therefore, significantly decrease the post-test probability of primary adrenal insufficiency and effectively rule out the condition.
However, primary adrenal insufficiency was already established in the 4 studies, and consecutive testing with an accepted gold standard was not done. Thus, the studies likely overestimate the accuracy of the CST test characteristics.
Using CST results for secondary insufficiency
Twenty studies evaluating the 250 mcg CST for diagnosing secondary adrenal insufficiency were of higher quality. They included patients with and without disease and compared the CST with gold-standard tests, either the insulin tolerance test or metyrapone test. The summary ROC curve indicated a negative likelihood ratio of 0.45, which would decrease only moderately the post-test probability of secondary adrenal insufficiency.
The 1 mcg CST: More discriminating than 250 mcg
Using a ROC curve generated from 22 studies, the authors found the test characteristics of the 250 mcg CST and the 1 mcg CST to be similar. Only 7 of these studies included paired data for the standard- and low-dose CST in the same patients, however. In the 7 studies with paired data, the 1 mcg CST had better diagnostic discrimination, based on a larger area under the ROC, than the 250 mcg CST.
13 mcg/dL is the rule-out threshold for morning serum cortisol
A subsequent meta-analysis, based on a PubMed search of English-language studies from 1966 to 2006, compared the performance of morning serum cortisol, the 1 mcg CST, and the 250 mcg CST for diagnosing secondary adrenal insufficiency. This analysis used patient-level data obtained from the original investigators instead of reported study-level results.3 Data from patients described as normal, healthy control subjects were excluded.
Studies included in the meta-analysis used an accepted gold-standard test, such as the insulin tolerance test or metyrapone test. Studies that were performed in a critical care setting or used older, less reliable cortisol assays were excluded, as were studies for which patient-level data couldn’t be obtained. Three new studies were included, and 12 of the previously used studies were excluded.
Instead of using the reported cortisol cutoff levels, the authors defined a negative test as the mean cortisol level (the “rule-out threshold”) above which the negative likelihood ratio of adrenal insufficiency is <0.15. The rule-out thresholds for morning serum cortisol, 1 mcg CST, and 250 mcg CST were 13, 22, and 30 mcg/dL, respectively.
An optimal testing strategy for secondary insufficiency
The authors proposed an optimal testing strategy for secondary adrenal insufficiency (assuming a low or moderate pretest probability) that starts with a morning serum cortisol measurement:
- A serum cortisol level >13 mcg/dL can effectively rule out adrenal insufficiency.
- If the morning serum cortisol is <13 mcg/dL, a 1 mcg CST >22 mcg/dL can rule out adrenal insufficiency.
- Patients would need an insulin tolerance test or metyrapone test only if the low-dose CST is <22 mcg/dL.
Recommendations
Williams Textbook of Endocrinology states that a basal cortisol level higher than 14.5 mcg/dL invariably indicates an intact hypothalamic-pituitary-adrenal axis. However, to confirm the diagnosis of adrenal insufficiency, all patients, except those with a recent pituitary insult, should undergo a CST. An insulin tolerance test should be done only if the patient has a subnormal response to cosyntropin (to rule out a false-positive CST) or has had a recent pituitary insult.4
A morning serum cortisol level >13 mcg/dL reliably rules out adrenal insufficiency, and the test is easy and safe to perform. Because of low specificity, patients with a level of ≤13 mcg/dL need further evaluation with the cosyntropin stimulation test (CST) (strength of recommendation [SOR]: A, meta-analysis of diagnostic cohort studies).
The 250 mcg CST requires intravenous (IV) or intramuscular (IM) administration of cosyntropin and multiple blood draws; a normal response reliably rules out primary adrenal insufficiency (SOR: B, meta-analysis of lower-quality diagnostic cohort studies) and moderately decreases the likelihood of secondary adrenal insufficiency (SOR: A, meta-analysis of diagnostic cohort studies). The 1 mcg CST has better diagnostic discrimination, but requires an extra step to dilute the cosyntropin (SOR: A, meta-analysis of diagnostic cohort studies).
Evidence summary
The morning serum cortisol level is the most convenient test for adrenal insufficiency because it requires a single blood draw. The 250 mcg CST involves IV or IM administration of cosyntropin and several blood draws. The 1 mcg CST, introduced to improve detection of partial and secondary adrenal insufficiency, requires dilution of the cosyntropin before administration because the smallest available dose is 250 mcg.
The insulin tolerance test is widely considered the gold standard, but requires close observation, is unpleasant for the patient, and carries some risk. Metyrapone and corticotropin-releasing hormone tests are not widely available.1
Negative CST rules out primary insufficiency
Researchers conducting a meta-analysis of the CST in diagnosing both primary and secondary adrenal insufficiency searched MEDLINE for English-language studies from 1966 to 2002 and used summary receiver-operating characteristic (ROC) curves to combine the sensitivities and specificities from individual studies.2 Four studies of primary adrenal insufficiency showed a negative likelihood ratio of 0.026 for the 250 mcg CST. A negative CST would, therefore, significantly decrease the post-test probability of primary adrenal insufficiency and effectively rule out the condition.
However, primary adrenal insufficiency was already established in the 4 studies, and consecutive testing with an accepted gold standard was not done. Thus, the studies likely overestimate the accuracy of the CST test characteristics.
Using CST results for secondary insufficiency
Twenty studies evaluating the 250 mcg CST for diagnosing secondary adrenal insufficiency were of higher quality. They included patients with and without disease and compared the CST with gold-standard tests, either the insulin tolerance test or metyrapone test. The summary ROC curve indicated a negative likelihood ratio of 0.45, which would decrease only moderately the post-test probability of secondary adrenal insufficiency.
The 1 mcg CST: More discriminating than 250 mcg
Using a ROC curve generated from 22 studies, the authors found the test characteristics of the 250 mcg CST and the 1 mcg CST to be similar. Only 7 of these studies included paired data for the standard- and low-dose CST in the same patients, however. In the 7 studies with paired data, the 1 mcg CST had better diagnostic discrimination, based on a larger area under the ROC, than the 250 mcg CST.
13 mcg/dL is the rule-out threshold for morning serum cortisol
A subsequent meta-analysis, based on a PubMed search of English-language studies from 1966 to 2006, compared the performance of morning serum cortisol, the 1 mcg CST, and the 250 mcg CST for diagnosing secondary adrenal insufficiency. This analysis used patient-level data obtained from the original investigators instead of reported study-level results.3 Data from patients described as normal, healthy control subjects were excluded.
Studies included in the meta-analysis used an accepted gold-standard test, such as the insulin tolerance test or metyrapone test. Studies that were performed in a critical care setting or used older, less reliable cortisol assays were excluded, as were studies for which patient-level data couldn’t be obtained. Three new studies were included, and 12 of the previously used studies were excluded.
Instead of using the reported cortisol cutoff levels, the authors defined a negative test as the mean cortisol level (the “rule-out threshold”) above which the negative likelihood ratio of adrenal insufficiency is <0.15. The rule-out thresholds for morning serum cortisol, 1 mcg CST, and 250 mcg CST were 13, 22, and 30 mcg/dL, respectively.
An optimal testing strategy for secondary insufficiency
The authors proposed an optimal testing strategy for secondary adrenal insufficiency (assuming a low or moderate pretest probability) that starts with a morning serum cortisol measurement:
- A serum cortisol level >13 mcg/dL can effectively rule out adrenal insufficiency.
- If the morning serum cortisol is <13 mcg/dL, a 1 mcg CST >22 mcg/dL can rule out adrenal insufficiency.
- Patients would need an insulin tolerance test or metyrapone test only if the low-dose CST is <22 mcg/dL.
Recommendations
Williams Textbook of Endocrinology states that a basal cortisol level higher than 14.5 mcg/dL invariably indicates an intact hypothalamic-pituitary-adrenal axis. However, to confirm the diagnosis of adrenal insufficiency, all patients, except those with a recent pituitary insult, should undergo a CST. An insulin tolerance test should be done only if the patient has a subnormal response to cosyntropin (to rule out a false-positive CST) or has had a recent pituitary insult.4
1. Salvatori R. Adrenal insufficiency. JAMA. 2005;294:2481-2488.
2. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003;139:194-204.
3. Kazlauskaite R, Evans A, Villabona C, et al. Corticotropin tests for hypothalamic-pituitary adrenal insufficiency: a meta-analysis. J Clin Endocrin Metab. August 12, 2008. Available at: http://jcem.endojournals.org/cgi/content/abstract/jc.2008-0710v1. Accessed August 12, 2008.
4. Stewart PM. The adrenal cortex. In: Kronenberg HM, Melmed S, Polonsky KS, et al, eds. Williams Textbook of Endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008:445-503.
1. Salvatori R. Adrenal insufficiency. JAMA. 2005;294:2481-2488.
2. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003;139:194-204.
3. Kazlauskaite R, Evans A, Villabona C, et al. Corticotropin tests for hypothalamic-pituitary adrenal insufficiency: a meta-analysis. J Clin Endocrin Metab. August 12, 2008. Available at: http://jcem.endojournals.org/cgi/content/abstract/jc.2008-0710v1. Accessed August 12, 2008.
4. Stewart PM. The adrenal cortex. In: Kronenberg HM, Melmed S, Polonsky KS, et al, eds. Williams Textbook of Endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008:445-503.
Evidence-based answers from the Family Physicians Inquiries Network
Who should receive vertebroplasty?
Percutaneous vertebroplasty has been used to treat aggressive vertebral hemangiomas, osteoporotic vertebral compression fractures, and vertebral lesions from metastatic disease or myeloma. Consider it for patients with severe acute or chronic pain related to one of these lesions who have failed a reasonable course of medical therapy (strength of recommendation [SOR]: B, based on structured reviews of observational studies). Contraindications include an uncorrectable coagulation disorder, infection in the area, spinal cord compression, destruction of the posterior wall of the vertebral body, and severe degrees of vertebral body collapse (SOR: B, based on structured reviews of observational studies). Pain relief from vertebroplasty for osteoporotic vertebral fractures may be less for older fractures (SOR: C).
Long-term sequelae of this procedure are unknown, so proceed with caution
James T. Birch, Jr, MD
Department of Family and Community Medicine, University of Missouri–Columbia
Vertebroplasty appears to be becoming the standard of care for back pain due to compression fractures. It has become the next step, in the absence of contraindications, when conservative measures fail. The long-term sequelae of this relatively new procedure are unknown, so it is prudent to proceed with caution. I am following a few patients who have had this procedure due to osteoporotic vertebral fractures and back pain. All are living remarkably pain-free lives.
Future studies should probably be focused on the best types and the appropriate amount of bone cement to inject for relief of pain symptoms and minimize leakage. Another important study would involve comparing the clinical outcomes and long-term complications for patients who have had vertebroplasty vs kyphoplasty.
Evidence summary
No randomized controlled trials have been published regarding percutaneous vertebroplasty. A 2005 Technology Assessment by the Centers for Medicare and Medicaid Services (CMS) provides the best evidence about indications and efficacy of percutaneous vertebroplasty for vertebral fractures.1 The CMS report is based on a search of Medline and Current Contents through April 2005 for relevant studies, along with hand searches of retrieved articles’ references and of recent pertinent journals. Study inclusion criteria included English language, vertebral fractures due to osteoporosis or malignancy, consecutive patient enrollment, outcomes reported for pain, functional status, and quality of life, and study size ≥20 patients for studies of osteoporosis or ≥10 patients for studies of malignancy. There was no description of a formal study validity assessment or attempts to control bias by use of multiple reviewers.
Fifteen studies were included, representing 1056 patients. Fourteen of the studies were observational and 1 was a nonrandomized controlled trial. The common inclusion requirement was severe pain attributable to vertebral fracture. Nine of the studies further specified failure of analgesics or conservative treatments. The studies showed statistically significant decreases in comparative visual analog pain scale scores in the short term. Four studies showed pain reduction lasting up to 1 year. These results favor the conclusion that percutaneous vertebroplasty provides short- and long-term pain reduction for patients meeting the inclusion criteria. However, the lack of randomized trials cannot control for the placebo effect, the natural history of vertebral fractures, and regression to the mean as possible reasons for the apparent efficacy of percutaneous vertebroplasty.
Two structured, but not systematic, reviews of percutaneous vertebroplasty in vertebral fractures2,3 included 15 small observational studies, of which only 1 was included in the CMS report. These reviews examined outcomes of vertebroplasty performed from less than 1 month to a mean of 7 months after fracture, using similar inclusion criteria to those used in the CMS report. The studies’ common patient exclusion criteria were uncorrectable coagulation disorder, infection in the area, spinal cord compression, destruction of the posterior vertebral wall, and severe degrees of vertebral body collapse (defined as >67% collapse). The 2 reviews found between 67% and 100% of patients reported pain reduction after vertebroplasty in follow-up periods ranging from 24 hours to up to 10 years. Based on this limited evidence, 1 review suggested that the likelihood of alleviation of pain decreases over time and is low for fractures occurring more than 6 months in the past.3 In contradistinction, 3 subsequent observational studies, involving a total of 233 patients with 365 vertebral compression fractures failed to find an association between postprocedural pain and age of fracture (ranging from less than 2 weeks to more than 24 months from injury).4-6
Recommendations from others
In their guideline on rehabilitation of the patient with osteoporosis, the National Osteoporosis Foundation states an experienced practitioner may perform percutaneous vertebroplasty on a patient with unremitting pain for whom conservative medical therapy has not helped.7 They qualify this recommendation by further stating long-term clinical studies are required before vertebroplasty becomes standard of care. The Medicare Coverage Advisory Committee, in its review of the 2005 CMS report, suggested that percutaneous vertebroplasty produces a clinically important net health benefit for patients with vertebral compression fracture compared to conservative care for both acute and chronic fractures.8
1. Percutaneous vertebroplasty for vertebral fractures caused by osteoporosis and malignancy: Technology assessment. Baltimore, Md: Centers for Medicare and Medicaid Services; last updated 2005. Available at: www.cms.hhs.gov/mcd/viewtechassess.asp?where=index&tid=26. Accessed on June 8, 2006.
2. Levine SA, Perin LA, Hayes D, Hayes WS. An evidence-based evaluation of percutaneous vertebroplasty. Manag Care 2000;9:56-60, 63.
3. Watts NB, Harris ST, Genant HK. Treatment of painful osteoporotic vertebral fractures with percutaneous vertebroplasty or kyphoplasty. Osteoporos Int 2001;12:429-437.
4. Kaufmann TJ, Jensen ME, Schweickert PA, Marx WF, Kallmes DF. Age of fracture and clinical outcomes of percutaneous vertebroplasty. AJNR Am J Neuroradiol 2001;22:1860-1863.
5. Brown DB, Gilula LA, Sehgal M, Shimony JS. Treatment of chronic symptomatic vertebral compression fractures with percutaneous vertebroplasty. AJR Am J Roentgenol 2004;182:319-322.
6. Yu SW, Lee PC, Ma CH, Chuang TY, Chen YJ. Vertebroplasty for the treatment of osteoporotic compression spinal fracture: comparison of remedial action at different stages of injury. J Trauma 2004;56:629-632.
7. Bonner FJ, Sinaki M, Grabois M, et al. Health professional’s guide to rehabilitation of the patient with osteoporosis. Osteoporos Int 2003;14(Suppl 2):S1-S22.
8. Treatment for vertebral body compression fracture. Medicare Coverage Advisory Committee Meeting May 5, 2005. Baltimore, Md: Centers for Medicare and Medicaid Services;last updated 2005. Available at: www.cms.hhs.gov/mcd/viewmcac.asp?where=index&mid=29. Accessed on June 8, 2006.
Percutaneous vertebroplasty has been used to treat aggressive vertebral hemangiomas, osteoporotic vertebral compression fractures, and vertebral lesions from metastatic disease or myeloma. Consider it for patients with severe acute or chronic pain related to one of these lesions who have failed a reasonable course of medical therapy (strength of recommendation [SOR]: B, based on structured reviews of observational studies). Contraindications include an uncorrectable coagulation disorder, infection in the area, spinal cord compression, destruction of the posterior wall of the vertebral body, and severe degrees of vertebral body collapse (SOR: B, based on structured reviews of observational studies). Pain relief from vertebroplasty for osteoporotic vertebral fractures may be less for older fractures (SOR: C).
Long-term sequelae of this procedure are unknown, so proceed with caution
James T. Birch, Jr, MD
Department of Family and Community Medicine, University of Missouri–Columbia
Vertebroplasty appears to be becoming the standard of care for back pain due to compression fractures. It has become the next step, in the absence of contraindications, when conservative measures fail. The long-term sequelae of this relatively new procedure are unknown, so it is prudent to proceed with caution. I am following a few patients who have had this procedure due to osteoporotic vertebral fractures and back pain. All are living remarkably pain-free lives.
Future studies should probably be focused on the best types and the appropriate amount of bone cement to inject for relief of pain symptoms and minimize leakage. Another important study would involve comparing the clinical outcomes and long-term complications for patients who have had vertebroplasty vs kyphoplasty.
Evidence summary
No randomized controlled trials have been published regarding percutaneous vertebroplasty. A 2005 Technology Assessment by the Centers for Medicare and Medicaid Services (CMS) provides the best evidence about indications and efficacy of percutaneous vertebroplasty for vertebral fractures.1 The CMS report is based on a search of Medline and Current Contents through April 2005 for relevant studies, along with hand searches of retrieved articles’ references and of recent pertinent journals. Study inclusion criteria included English language, vertebral fractures due to osteoporosis or malignancy, consecutive patient enrollment, outcomes reported for pain, functional status, and quality of life, and study size ≥20 patients for studies of osteoporosis or ≥10 patients for studies of malignancy. There was no description of a formal study validity assessment or attempts to control bias by use of multiple reviewers.
Fifteen studies were included, representing 1056 patients. Fourteen of the studies were observational and 1 was a nonrandomized controlled trial. The common inclusion requirement was severe pain attributable to vertebral fracture. Nine of the studies further specified failure of analgesics or conservative treatments. The studies showed statistically significant decreases in comparative visual analog pain scale scores in the short term. Four studies showed pain reduction lasting up to 1 year. These results favor the conclusion that percutaneous vertebroplasty provides short- and long-term pain reduction for patients meeting the inclusion criteria. However, the lack of randomized trials cannot control for the placebo effect, the natural history of vertebral fractures, and regression to the mean as possible reasons for the apparent efficacy of percutaneous vertebroplasty.
Two structured, but not systematic, reviews of percutaneous vertebroplasty in vertebral fractures2,3 included 15 small observational studies, of which only 1 was included in the CMS report. These reviews examined outcomes of vertebroplasty performed from less than 1 month to a mean of 7 months after fracture, using similar inclusion criteria to those used in the CMS report. The studies’ common patient exclusion criteria were uncorrectable coagulation disorder, infection in the area, spinal cord compression, destruction of the posterior vertebral wall, and severe degrees of vertebral body collapse (defined as >67% collapse). The 2 reviews found between 67% and 100% of patients reported pain reduction after vertebroplasty in follow-up periods ranging from 24 hours to up to 10 years. Based on this limited evidence, 1 review suggested that the likelihood of alleviation of pain decreases over time and is low for fractures occurring more than 6 months in the past.3 In contradistinction, 3 subsequent observational studies, involving a total of 233 patients with 365 vertebral compression fractures failed to find an association between postprocedural pain and age of fracture (ranging from less than 2 weeks to more than 24 months from injury).4-6
Recommendations from others
In their guideline on rehabilitation of the patient with osteoporosis, the National Osteoporosis Foundation states an experienced practitioner may perform percutaneous vertebroplasty on a patient with unremitting pain for whom conservative medical therapy has not helped.7 They qualify this recommendation by further stating long-term clinical studies are required before vertebroplasty becomes standard of care. The Medicare Coverage Advisory Committee, in its review of the 2005 CMS report, suggested that percutaneous vertebroplasty produces a clinically important net health benefit for patients with vertebral compression fracture compared to conservative care for both acute and chronic fractures.8
Percutaneous vertebroplasty has been used to treat aggressive vertebral hemangiomas, osteoporotic vertebral compression fractures, and vertebral lesions from metastatic disease or myeloma. Consider it for patients with severe acute or chronic pain related to one of these lesions who have failed a reasonable course of medical therapy (strength of recommendation [SOR]: B, based on structured reviews of observational studies). Contraindications include an uncorrectable coagulation disorder, infection in the area, spinal cord compression, destruction of the posterior wall of the vertebral body, and severe degrees of vertebral body collapse (SOR: B, based on structured reviews of observational studies). Pain relief from vertebroplasty for osteoporotic vertebral fractures may be less for older fractures (SOR: C).
Long-term sequelae of this procedure are unknown, so proceed with caution
James T. Birch, Jr, MD
Department of Family and Community Medicine, University of Missouri–Columbia
Vertebroplasty appears to be becoming the standard of care for back pain due to compression fractures. It has become the next step, in the absence of contraindications, when conservative measures fail. The long-term sequelae of this relatively new procedure are unknown, so it is prudent to proceed with caution. I am following a few patients who have had this procedure due to osteoporotic vertebral fractures and back pain. All are living remarkably pain-free lives.
Future studies should probably be focused on the best types and the appropriate amount of bone cement to inject for relief of pain symptoms and minimize leakage. Another important study would involve comparing the clinical outcomes and long-term complications for patients who have had vertebroplasty vs kyphoplasty.
Evidence summary
No randomized controlled trials have been published regarding percutaneous vertebroplasty. A 2005 Technology Assessment by the Centers for Medicare and Medicaid Services (CMS) provides the best evidence about indications and efficacy of percutaneous vertebroplasty for vertebral fractures.1 The CMS report is based on a search of Medline and Current Contents through April 2005 for relevant studies, along with hand searches of retrieved articles’ references and of recent pertinent journals. Study inclusion criteria included English language, vertebral fractures due to osteoporosis or malignancy, consecutive patient enrollment, outcomes reported for pain, functional status, and quality of life, and study size ≥20 patients for studies of osteoporosis or ≥10 patients for studies of malignancy. There was no description of a formal study validity assessment or attempts to control bias by use of multiple reviewers.
Fifteen studies were included, representing 1056 patients. Fourteen of the studies were observational and 1 was a nonrandomized controlled trial. The common inclusion requirement was severe pain attributable to vertebral fracture. Nine of the studies further specified failure of analgesics or conservative treatments. The studies showed statistically significant decreases in comparative visual analog pain scale scores in the short term. Four studies showed pain reduction lasting up to 1 year. These results favor the conclusion that percutaneous vertebroplasty provides short- and long-term pain reduction for patients meeting the inclusion criteria. However, the lack of randomized trials cannot control for the placebo effect, the natural history of vertebral fractures, and regression to the mean as possible reasons for the apparent efficacy of percutaneous vertebroplasty.
Two structured, but not systematic, reviews of percutaneous vertebroplasty in vertebral fractures2,3 included 15 small observational studies, of which only 1 was included in the CMS report. These reviews examined outcomes of vertebroplasty performed from less than 1 month to a mean of 7 months after fracture, using similar inclusion criteria to those used in the CMS report. The studies’ common patient exclusion criteria were uncorrectable coagulation disorder, infection in the area, spinal cord compression, destruction of the posterior vertebral wall, and severe degrees of vertebral body collapse (defined as >67% collapse). The 2 reviews found between 67% and 100% of patients reported pain reduction after vertebroplasty in follow-up periods ranging from 24 hours to up to 10 years. Based on this limited evidence, 1 review suggested that the likelihood of alleviation of pain decreases over time and is low for fractures occurring more than 6 months in the past.3 In contradistinction, 3 subsequent observational studies, involving a total of 233 patients with 365 vertebral compression fractures failed to find an association between postprocedural pain and age of fracture (ranging from less than 2 weeks to more than 24 months from injury).4-6
Recommendations from others
In their guideline on rehabilitation of the patient with osteoporosis, the National Osteoporosis Foundation states an experienced practitioner may perform percutaneous vertebroplasty on a patient with unremitting pain for whom conservative medical therapy has not helped.7 They qualify this recommendation by further stating long-term clinical studies are required before vertebroplasty becomes standard of care. The Medicare Coverage Advisory Committee, in its review of the 2005 CMS report, suggested that percutaneous vertebroplasty produces a clinically important net health benefit for patients with vertebral compression fracture compared to conservative care for both acute and chronic fractures.8
1. Percutaneous vertebroplasty for vertebral fractures caused by osteoporosis and malignancy: Technology assessment. Baltimore, Md: Centers for Medicare and Medicaid Services; last updated 2005. Available at: www.cms.hhs.gov/mcd/viewtechassess.asp?where=index&tid=26. Accessed on June 8, 2006.
2. Levine SA, Perin LA, Hayes D, Hayes WS. An evidence-based evaluation of percutaneous vertebroplasty. Manag Care 2000;9:56-60, 63.
3. Watts NB, Harris ST, Genant HK. Treatment of painful osteoporotic vertebral fractures with percutaneous vertebroplasty or kyphoplasty. Osteoporos Int 2001;12:429-437.
4. Kaufmann TJ, Jensen ME, Schweickert PA, Marx WF, Kallmes DF. Age of fracture and clinical outcomes of percutaneous vertebroplasty. AJNR Am J Neuroradiol 2001;22:1860-1863.
5. Brown DB, Gilula LA, Sehgal M, Shimony JS. Treatment of chronic symptomatic vertebral compression fractures with percutaneous vertebroplasty. AJR Am J Roentgenol 2004;182:319-322.
6. Yu SW, Lee PC, Ma CH, Chuang TY, Chen YJ. Vertebroplasty for the treatment of osteoporotic compression spinal fracture: comparison of remedial action at different stages of injury. J Trauma 2004;56:629-632.
7. Bonner FJ, Sinaki M, Grabois M, et al. Health professional’s guide to rehabilitation of the patient with osteoporosis. Osteoporos Int 2003;14(Suppl 2):S1-S22.
8. Treatment for vertebral body compression fracture. Medicare Coverage Advisory Committee Meeting May 5, 2005. Baltimore, Md: Centers for Medicare and Medicaid Services;last updated 2005. Available at: www.cms.hhs.gov/mcd/viewmcac.asp?where=index&mid=29. Accessed on June 8, 2006.
1. Percutaneous vertebroplasty for vertebral fractures caused by osteoporosis and malignancy: Technology assessment. Baltimore, Md: Centers for Medicare and Medicaid Services; last updated 2005. Available at: www.cms.hhs.gov/mcd/viewtechassess.asp?where=index&tid=26. Accessed on June 8, 2006.
2. Levine SA, Perin LA, Hayes D, Hayes WS. An evidence-based evaluation of percutaneous vertebroplasty. Manag Care 2000;9:56-60, 63.
3. Watts NB, Harris ST, Genant HK. Treatment of painful osteoporotic vertebral fractures with percutaneous vertebroplasty or kyphoplasty. Osteoporos Int 2001;12:429-437.
4. Kaufmann TJ, Jensen ME, Schweickert PA, Marx WF, Kallmes DF. Age of fracture and clinical outcomes of percutaneous vertebroplasty. AJNR Am J Neuroradiol 2001;22:1860-1863.
5. Brown DB, Gilula LA, Sehgal M, Shimony JS. Treatment of chronic symptomatic vertebral compression fractures with percutaneous vertebroplasty. AJR Am J Roentgenol 2004;182:319-322.
6. Yu SW, Lee PC, Ma CH, Chuang TY, Chen YJ. Vertebroplasty for the treatment of osteoporotic compression spinal fracture: comparison of remedial action at different stages of injury. J Trauma 2004;56:629-632.
7. Bonner FJ, Sinaki M, Grabois M, et al. Health professional’s guide to rehabilitation of the patient with osteoporosis. Osteoporos Int 2003;14(Suppl 2):S1-S22.
8. Treatment for vertebral body compression fracture. Medicare Coverage Advisory Committee Meeting May 5, 2005. Baltimore, Md: Centers for Medicare and Medicaid Services;last updated 2005. Available at: www.cms.hhs.gov/mcd/viewmcac.asp?where=index&mid=29. Accessed on June 8, 2006.
Evidence-based answers from the Family Physicians Inquiries Network
Inhaled fluticasone superior to montelukast in persistent asthma
ABSTRACT
BACKGROUND: Asthma management guidelines recommend patients with persistent asthma use asthma controller therapy in addition to as-needed short-acting beta-agonist therapy to improve symptom control, maintain pulmonary function, and decrease exacerbations. This study compared 2 asthma controllers, inhaled fluticasone and oral montelukast, with respect to clinical efficacy, patient preference, asthma-specific quality of life, and safety.
POPULATION STUDIED: The patients in this study were men and women aged 15 years and older with asthma recruited from multiple centers across the United States. Nonsmoking patients were included with a forced expiratory volume in 1 second (FEV 1 ) of 50% to 80% of predicted that reversed by at least 15% with bronchodilator use. Patients were then eligible for randomization if, after an 8- to 14-day run-in period, their FEV 1 remained within 15% of initial values, they used albuterol at least 6 of the last 7 days, and they had asthma symptom scores of 2 (on a 0 to 5 scale) for at least 4 of the last 7 days.
STUDY DESIGN AND VALIDITY: This study was a double-blinded, randomized trial sponsored by the makers of fluticasone. Patients meeting initial inclusion criteria underwent an 8- to 14-day run-in period in which only short-acting beta-agonist use was allowed. Patients were then randomized to 1 of 2 treatment groups if they met the secondary inclusion criteria. Personal communication with the lead author confirmed that allocation assignment was concealed. Patients received either fluticasone 88 μg twice daily via metered dose inhaler (MDI) and montelukast placebo, or montelukast 10 mg daily with a placebo MDI. Patients kept daily records and had clinical evaluations at regular intervals for 24 weeks. Seventy-six percent of the patients completed the study.
OUTCOMES MEASURED: The primary outcome was percent change in FEV 1 . Other outcomes included peak flow rate, symptom-free days, daily albuterol use, asthma symptom scores, asthma quality-of-life scores, and patient-rated satisfaction with treatment. Safety was also assessed by reports of clinical adverse events and number of asthma exacerbations.
RESULTS: Using an intent-to-treat analysis, the fluticasone group had a significantly greater sustained change in FEV 1 (22% vs 14%; P < .001). Significant differences were noted after just 2 weeks of treatment. Significant differences favoring fluticasone were also found in all secondary outcomes including the patient-oriented outcomes of change in asthma symptom scores (–0.91 vs –0.57; P < .001), asthma quality-of-life scores (1.3 vs 1.0; P = .004), and patient-rated satisfaction with treatment (83% of fluticasone patients satisfied vs 66% of montelukast patients satisfied; P < .001). No differences were noted in overall incidence of adverse events between treatment groups, but significantly more fluticasone-treated patients reported hoarseness (9 vs 0; P = .002) and oral pharyngeal candidiasis (8 vs 0; P = .008). The incidence of asthma exacerbations was similar (19 fluticasone-treated patients vs 21 montelukast-treated patients).
This study confirms earlier studies indicating that inhaled steroids should be first-line treatment for moderate-to-severe persistent asthma. When compared with montelukast, inhaled fluticasone showed greater improvements in clinical measures of asthma, as well as patient-oriented measures such as symptom scores, quality-of-life scores, and patientrated satisfaction. However, moderate-to-severe persistent asthma appears to require more therapeutic measures than just low-dose fluticasone. Despite treatment, patients still used albuterol on more than half of the days, only one third of days were symptom-free, and symptom scores improved by less than 1 point on a 6-point scale.
ABSTRACT
BACKGROUND: Asthma management guidelines recommend patients with persistent asthma use asthma controller therapy in addition to as-needed short-acting beta-agonist therapy to improve symptom control, maintain pulmonary function, and decrease exacerbations. This study compared 2 asthma controllers, inhaled fluticasone and oral montelukast, with respect to clinical efficacy, patient preference, asthma-specific quality of life, and safety.
POPULATION STUDIED: The patients in this study were men and women aged 15 years and older with asthma recruited from multiple centers across the United States. Nonsmoking patients were included with a forced expiratory volume in 1 second (FEV 1 ) of 50% to 80% of predicted that reversed by at least 15% with bronchodilator use. Patients were then eligible for randomization if, after an 8- to 14-day run-in period, their FEV 1 remained within 15% of initial values, they used albuterol at least 6 of the last 7 days, and they had asthma symptom scores of 2 (on a 0 to 5 scale) for at least 4 of the last 7 days.
STUDY DESIGN AND VALIDITY: This study was a double-blinded, randomized trial sponsored by the makers of fluticasone. Patients meeting initial inclusion criteria underwent an 8- to 14-day run-in period in which only short-acting beta-agonist use was allowed. Patients were then randomized to 1 of 2 treatment groups if they met the secondary inclusion criteria. Personal communication with the lead author confirmed that allocation assignment was concealed. Patients received either fluticasone 88 μg twice daily via metered dose inhaler (MDI) and montelukast placebo, or montelukast 10 mg daily with a placebo MDI. Patients kept daily records and had clinical evaluations at regular intervals for 24 weeks. Seventy-six percent of the patients completed the study.
OUTCOMES MEASURED: The primary outcome was percent change in FEV 1 . Other outcomes included peak flow rate, symptom-free days, daily albuterol use, asthma symptom scores, asthma quality-of-life scores, and patient-rated satisfaction with treatment. Safety was also assessed by reports of clinical adverse events and number of asthma exacerbations.
RESULTS: Using an intent-to-treat analysis, the fluticasone group had a significantly greater sustained change in FEV 1 (22% vs 14%; P < .001). Significant differences were noted after just 2 weeks of treatment. Significant differences favoring fluticasone were also found in all secondary outcomes including the patient-oriented outcomes of change in asthma symptom scores (–0.91 vs –0.57; P < .001), asthma quality-of-life scores (1.3 vs 1.0; P = .004), and patient-rated satisfaction with treatment (83% of fluticasone patients satisfied vs 66% of montelukast patients satisfied; P < .001). No differences were noted in overall incidence of adverse events between treatment groups, but significantly more fluticasone-treated patients reported hoarseness (9 vs 0; P = .002) and oral pharyngeal candidiasis (8 vs 0; P = .008). The incidence of asthma exacerbations was similar (19 fluticasone-treated patients vs 21 montelukast-treated patients).
This study confirms earlier studies indicating that inhaled steroids should be first-line treatment for moderate-to-severe persistent asthma. When compared with montelukast, inhaled fluticasone showed greater improvements in clinical measures of asthma, as well as patient-oriented measures such as symptom scores, quality-of-life scores, and patientrated satisfaction. However, moderate-to-severe persistent asthma appears to require more therapeutic measures than just low-dose fluticasone. Despite treatment, patients still used albuterol on more than half of the days, only one third of days were symptom-free, and symptom scores improved by less than 1 point on a 6-point scale.
ABSTRACT
BACKGROUND: Asthma management guidelines recommend patients with persistent asthma use asthma controller therapy in addition to as-needed short-acting beta-agonist therapy to improve symptom control, maintain pulmonary function, and decrease exacerbations. This study compared 2 asthma controllers, inhaled fluticasone and oral montelukast, with respect to clinical efficacy, patient preference, asthma-specific quality of life, and safety.
POPULATION STUDIED: The patients in this study were men and women aged 15 years and older with asthma recruited from multiple centers across the United States. Nonsmoking patients were included with a forced expiratory volume in 1 second (FEV 1 ) of 50% to 80% of predicted that reversed by at least 15% with bronchodilator use. Patients were then eligible for randomization if, after an 8- to 14-day run-in period, their FEV 1 remained within 15% of initial values, they used albuterol at least 6 of the last 7 days, and they had asthma symptom scores of 2 (on a 0 to 5 scale) for at least 4 of the last 7 days.
STUDY DESIGN AND VALIDITY: This study was a double-blinded, randomized trial sponsored by the makers of fluticasone. Patients meeting initial inclusion criteria underwent an 8- to 14-day run-in period in which only short-acting beta-agonist use was allowed. Patients were then randomized to 1 of 2 treatment groups if they met the secondary inclusion criteria. Personal communication with the lead author confirmed that allocation assignment was concealed. Patients received either fluticasone 88 μg twice daily via metered dose inhaler (MDI) and montelukast placebo, or montelukast 10 mg daily with a placebo MDI. Patients kept daily records and had clinical evaluations at regular intervals for 24 weeks. Seventy-six percent of the patients completed the study.
OUTCOMES MEASURED: The primary outcome was percent change in FEV 1 . Other outcomes included peak flow rate, symptom-free days, daily albuterol use, asthma symptom scores, asthma quality-of-life scores, and patient-rated satisfaction with treatment. Safety was also assessed by reports of clinical adverse events and number of asthma exacerbations.
RESULTS: Using an intent-to-treat analysis, the fluticasone group had a significantly greater sustained change in FEV 1 (22% vs 14%; P < .001). Significant differences were noted after just 2 weeks of treatment. Significant differences favoring fluticasone were also found in all secondary outcomes including the patient-oriented outcomes of change in asthma symptom scores (–0.91 vs –0.57; P < .001), asthma quality-of-life scores (1.3 vs 1.0; P = .004), and patient-rated satisfaction with treatment (83% of fluticasone patients satisfied vs 66% of montelukast patients satisfied; P < .001). No differences were noted in overall incidence of adverse events between treatment groups, but significantly more fluticasone-treated patients reported hoarseness (9 vs 0; P = .002) and oral pharyngeal candidiasis (8 vs 0; P = .008). The incidence of asthma exacerbations was similar (19 fluticasone-treated patients vs 21 montelukast-treated patients).
This study confirms earlier studies indicating that inhaled steroids should be first-line treatment for moderate-to-severe persistent asthma. When compared with montelukast, inhaled fluticasone showed greater improvements in clinical measures of asthma, as well as patient-oriented measures such as symptom scores, quality-of-life scores, and patientrated satisfaction. However, moderate-to-severe persistent asthma appears to require more therapeutic measures than just low-dose fluticasone. Despite treatment, patients still used albuterol on more than half of the days, only one third of days were symptom-free, and symptom scores improved by less than 1 point on a 6-point scale.