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Do statins delay onset or slow progression of Alzheimer’s dementia?
Statins (coenzyme-A reductase inhibitors) should not be used with the single intent to delay the onset or slow the progression of dementia. Large randomized control trials (RCTs) found that the administration of a statin had no significant effect on preventing or slowing all-cause cognitive decline (strength of recommendation [SOR]: A, based on large RCTs with narrow confidence interval).1,2 Specifically, there is insufficient evidence that statins delay the onset or slow the progression of Alzheimer’s dementia (SOR: B, based on systematic review with heterogeneity).3
While 3 epidemiologic studies4-6 have found a decreased incidence of dementia among those taking statins, these studies have significant methodological shortcomings and do not show a causal relationship (SOR: C, based on poor-quality studies).
Evidence summary
Approximately 4 million people in the United States suffer with Alzheimer’s disease. The prevalence rises with age and is approximately 47% among those aged 85 years and older.7
Amyloid plaques are thought to be responsible for clinical changes associated with Alzheimer’s dementia. Research has indicated that amyloid precursors may be more prevalent in a cholesterol-rich environment. This led to the theory that treating hypercholesterolemia may decrease the prevalence of Alzheimer’s disease.8
The PROSPER trial, which was designed to test the effect of pravastatin (Pravachol) on coronary heart disease and stroke, randomized 5804 study participants into 1 group assigned to take pravastatin and another group assigned to take placebo. An additional study endpoint was pravastatin’s effect on cognitive function as measured by 4 different tests, including the Mini-Mental Status Exam (MMSE). Overall cognitive function declined at the same rate in treatment and placebo groups. There was no significant difference between the 2 groups over 3 years using 4 different methods of assessment. In particular, the MMSE scores differed by only 0.06 points (95% confidence interval [CI], 0.04–0.16; P=.26).
The largest RCT of a statin agent, the Heart Protection Study, enrolled more than 20,000 people and randomized them to simvastatin (Zocor) or placebo. After a median of 5 years of follow-up, there was no difference in cognitive scores or the rate of diagnosis of dementia between the 2 groups.2
A systematic review concluded that no good evidence recommended statins for reducing the risk of Alzheimer’s dementia.3 Notably, the review did find a body of inconclusive evidence that lowering serum cholesterol may retard disease pathogenesis. An observational study of 56,790 charts included in the computer databases of 3 hospitals found that the prevalence of probable Alzheimer’s dementia in the cohort taking statins was 60% to 73% (P<.001) lower than in the total patient population or in patients taking antihypertensive or cardiovascular medications.4
Also included in the review was a nested case-control study of 1364 patients that found an adjusted relative risk for dementia of 0.29 (95% CI, 0.013–0.063; P=.002) among those taking statins.5 This study did not distinguish between Alzheimer’s dementia and other forms of dementia. These studies do not demonstrate a causal relationship between statins and Alzheimer’s dementia.
The best way to determine if there is a true effect of statins on Alzheimer’s dementia is to conduct a clinical trial. Two ongoing clinical trials are designed specifically to determine if the use of statins delay the onset or slow the progression of Alzheimer’s dementia.9,10 To date, these trials have not published interim findings.
Recommendations from others
No organization has issued recommendations for the use of statins to delay the onset or slow the progression of Alzheimer’s dementia.
We are obligated to protect patients from potential risks of unnecessary medications
Seema Modi, MD
East Carolina University, Greenville, NC
Alzheimer’s disease is a difficult and emotionally charged topic. Many patients who have watched a family member suffer from Alzheimer’s disease would go to great lengths to delay or prevent developing Alzheimer’s disease themselves. As a result of direct drug marketing to consumers, plus increased lay media coverage of health issues, our patients are now better informed than ever and make more direct requests for certain medications by name.
Imagine talking with a well-read patient who has learned from a newspaper article or morning news show about 1 of the 3 epidemiological studies that show decreased incidence of dementia among statin users. The patient now stands before you, requesting a prescription for a statin. Though this patient is otherwise healthy and has a desirable cholesterol level, you will still find it difficult to explain to the patient why you will not write the prescription. As physicians, we are obligated to protect our patients from the potential risks of unnecessary medications. We are also obligated to protect our healthcare system from escalation of already high healthcare costs. Evidence from rigorous clinical trials is the tool that can help us provide this protection.
1. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630.
2. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disears or other high-risk conditions. Lancet 2004;363:757-767.
3. Scott HD, Laake K. Statins for the prevention of Alzheimer’s disease. Cochrane Database Syst Rev 2001;(3):CD003160.-
4. Wolozin B, Kellman W, Rousseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439-1443.
5. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000;356:1627-1631.
6. Zamrini E, McGwin G, Roseman JM. Association between statin use and Alzheimer’s disease. Neuroepidemiology 2004;23:94-98.
7. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 1989;262:2551-2556.
8. Selkoe DJ. Physiological production of the beta-amyloid protein and the mechanism of Alzheimers-Disease. Trends Neurosci 1993;16:403-409.
9. Sano M, Thal LJ. Cholesterol Lowering Agent to Slow Progression (CLASP) of Alzheimer’s Disease Study. February 3, 2003 (Last reviewed December, 2004). Available at: www.clinicaltrials.gov/ct/show/NCT00053599?order=4. Accessed on June 8, 2005.
10. Lipitor as a Treatment of Alzheimer’s Disease. September 19, 2001 (Last reviewed November, 2004). Available at: www.clinicaltrials.gov/ct/show/NCT00024531?order=1. Accessed on June 8, 2005.
Statins (coenzyme-A reductase inhibitors) should not be used with the single intent to delay the onset or slow the progression of dementia. Large randomized control trials (RCTs) found that the administration of a statin had no significant effect on preventing or slowing all-cause cognitive decline (strength of recommendation [SOR]: A, based on large RCTs with narrow confidence interval).1,2 Specifically, there is insufficient evidence that statins delay the onset or slow the progression of Alzheimer’s dementia (SOR: B, based on systematic review with heterogeneity).3
While 3 epidemiologic studies4-6 have found a decreased incidence of dementia among those taking statins, these studies have significant methodological shortcomings and do not show a causal relationship (SOR: C, based on poor-quality studies).
Evidence summary
Approximately 4 million people in the United States suffer with Alzheimer’s disease. The prevalence rises with age and is approximately 47% among those aged 85 years and older.7
Amyloid plaques are thought to be responsible for clinical changes associated with Alzheimer’s dementia. Research has indicated that amyloid precursors may be more prevalent in a cholesterol-rich environment. This led to the theory that treating hypercholesterolemia may decrease the prevalence of Alzheimer’s disease.8
The PROSPER trial, which was designed to test the effect of pravastatin (Pravachol) on coronary heart disease and stroke, randomized 5804 study participants into 1 group assigned to take pravastatin and another group assigned to take placebo. An additional study endpoint was pravastatin’s effect on cognitive function as measured by 4 different tests, including the Mini-Mental Status Exam (MMSE). Overall cognitive function declined at the same rate in treatment and placebo groups. There was no significant difference between the 2 groups over 3 years using 4 different methods of assessment. In particular, the MMSE scores differed by only 0.06 points (95% confidence interval [CI], 0.04–0.16; P=.26).
The largest RCT of a statin agent, the Heart Protection Study, enrolled more than 20,000 people and randomized them to simvastatin (Zocor) or placebo. After a median of 5 years of follow-up, there was no difference in cognitive scores or the rate of diagnosis of dementia between the 2 groups.2
A systematic review concluded that no good evidence recommended statins for reducing the risk of Alzheimer’s dementia.3 Notably, the review did find a body of inconclusive evidence that lowering serum cholesterol may retard disease pathogenesis. An observational study of 56,790 charts included in the computer databases of 3 hospitals found that the prevalence of probable Alzheimer’s dementia in the cohort taking statins was 60% to 73% (P<.001) lower than in the total patient population or in patients taking antihypertensive or cardiovascular medications.4
Also included in the review was a nested case-control study of 1364 patients that found an adjusted relative risk for dementia of 0.29 (95% CI, 0.013–0.063; P=.002) among those taking statins.5 This study did not distinguish between Alzheimer’s dementia and other forms of dementia. These studies do not demonstrate a causal relationship between statins and Alzheimer’s dementia.
The best way to determine if there is a true effect of statins on Alzheimer’s dementia is to conduct a clinical trial. Two ongoing clinical trials are designed specifically to determine if the use of statins delay the onset or slow the progression of Alzheimer’s dementia.9,10 To date, these trials have not published interim findings.
Recommendations from others
No organization has issued recommendations for the use of statins to delay the onset or slow the progression of Alzheimer’s dementia.
We are obligated to protect patients from potential risks of unnecessary medications
Seema Modi, MD
East Carolina University, Greenville, NC
Alzheimer’s disease is a difficult and emotionally charged topic. Many patients who have watched a family member suffer from Alzheimer’s disease would go to great lengths to delay or prevent developing Alzheimer’s disease themselves. As a result of direct drug marketing to consumers, plus increased lay media coverage of health issues, our patients are now better informed than ever and make more direct requests for certain medications by name.
Imagine talking with a well-read patient who has learned from a newspaper article or morning news show about 1 of the 3 epidemiological studies that show decreased incidence of dementia among statin users. The patient now stands before you, requesting a prescription for a statin. Though this patient is otherwise healthy and has a desirable cholesterol level, you will still find it difficult to explain to the patient why you will not write the prescription. As physicians, we are obligated to protect our patients from the potential risks of unnecessary medications. We are also obligated to protect our healthcare system from escalation of already high healthcare costs. Evidence from rigorous clinical trials is the tool that can help us provide this protection.
Statins (coenzyme-A reductase inhibitors) should not be used with the single intent to delay the onset or slow the progression of dementia. Large randomized control trials (RCTs) found that the administration of a statin had no significant effect on preventing or slowing all-cause cognitive decline (strength of recommendation [SOR]: A, based on large RCTs with narrow confidence interval).1,2 Specifically, there is insufficient evidence that statins delay the onset or slow the progression of Alzheimer’s dementia (SOR: B, based on systematic review with heterogeneity).3
While 3 epidemiologic studies4-6 have found a decreased incidence of dementia among those taking statins, these studies have significant methodological shortcomings and do not show a causal relationship (SOR: C, based on poor-quality studies).
Evidence summary
Approximately 4 million people in the United States suffer with Alzheimer’s disease. The prevalence rises with age and is approximately 47% among those aged 85 years and older.7
Amyloid plaques are thought to be responsible for clinical changes associated with Alzheimer’s dementia. Research has indicated that amyloid precursors may be more prevalent in a cholesterol-rich environment. This led to the theory that treating hypercholesterolemia may decrease the prevalence of Alzheimer’s disease.8
The PROSPER trial, which was designed to test the effect of pravastatin (Pravachol) on coronary heart disease and stroke, randomized 5804 study participants into 1 group assigned to take pravastatin and another group assigned to take placebo. An additional study endpoint was pravastatin’s effect on cognitive function as measured by 4 different tests, including the Mini-Mental Status Exam (MMSE). Overall cognitive function declined at the same rate in treatment and placebo groups. There was no significant difference between the 2 groups over 3 years using 4 different methods of assessment. In particular, the MMSE scores differed by only 0.06 points (95% confidence interval [CI], 0.04–0.16; P=.26).
The largest RCT of a statin agent, the Heart Protection Study, enrolled more than 20,000 people and randomized them to simvastatin (Zocor) or placebo. After a median of 5 years of follow-up, there was no difference in cognitive scores or the rate of diagnosis of dementia between the 2 groups.2
A systematic review concluded that no good evidence recommended statins for reducing the risk of Alzheimer’s dementia.3 Notably, the review did find a body of inconclusive evidence that lowering serum cholesterol may retard disease pathogenesis. An observational study of 56,790 charts included in the computer databases of 3 hospitals found that the prevalence of probable Alzheimer’s dementia in the cohort taking statins was 60% to 73% (P<.001) lower than in the total patient population or in patients taking antihypertensive or cardiovascular medications.4
Also included in the review was a nested case-control study of 1364 patients that found an adjusted relative risk for dementia of 0.29 (95% CI, 0.013–0.063; P=.002) among those taking statins.5 This study did not distinguish between Alzheimer’s dementia and other forms of dementia. These studies do not demonstrate a causal relationship between statins and Alzheimer’s dementia.
The best way to determine if there is a true effect of statins on Alzheimer’s dementia is to conduct a clinical trial. Two ongoing clinical trials are designed specifically to determine if the use of statins delay the onset or slow the progression of Alzheimer’s dementia.9,10 To date, these trials have not published interim findings.
Recommendations from others
No organization has issued recommendations for the use of statins to delay the onset or slow the progression of Alzheimer’s dementia.
We are obligated to protect patients from potential risks of unnecessary medications
Seema Modi, MD
East Carolina University, Greenville, NC
Alzheimer’s disease is a difficult and emotionally charged topic. Many patients who have watched a family member suffer from Alzheimer’s disease would go to great lengths to delay or prevent developing Alzheimer’s disease themselves. As a result of direct drug marketing to consumers, plus increased lay media coverage of health issues, our patients are now better informed than ever and make more direct requests for certain medications by name.
Imagine talking with a well-read patient who has learned from a newspaper article or morning news show about 1 of the 3 epidemiological studies that show decreased incidence of dementia among statin users. The patient now stands before you, requesting a prescription for a statin. Though this patient is otherwise healthy and has a desirable cholesterol level, you will still find it difficult to explain to the patient why you will not write the prescription. As physicians, we are obligated to protect our patients from the potential risks of unnecessary medications. We are also obligated to protect our healthcare system from escalation of already high healthcare costs. Evidence from rigorous clinical trials is the tool that can help us provide this protection.
1. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630.
2. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disears or other high-risk conditions. Lancet 2004;363:757-767.
3. Scott HD, Laake K. Statins for the prevention of Alzheimer’s disease. Cochrane Database Syst Rev 2001;(3):CD003160.-
4. Wolozin B, Kellman W, Rousseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439-1443.
5. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000;356:1627-1631.
6. Zamrini E, McGwin G, Roseman JM. Association between statin use and Alzheimer’s disease. Neuroepidemiology 2004;23:94-98.
7. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 1989;262:2551-2556.
8. Selkoe DJ. Physiological production of the beta-amyloid protein and the mechanism of Alzheimers-Disease. Trends Neurosci 1993;16:403-409.
9. Sano M, Thal LJ. Cholesterol Lowering Agent to Slow Progression (CLASP) of Alzheimer’s Disease Study. February 3, 2003 (Last reviewed December, 2004). Available at: www.clinicaltrials.gov/ct/show/NCT00053599?order=4. Accessed on June 8, 2005.
10. Lipitor as a Treatment of Alzheimer’s Disease. September 19, 2001 (Last reviewed November, 2004). Available at: www.clinicaltrials.gov/ct/show/NCT00024531?order=1. Accessed on June 8, 2005.
1. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630.
2. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disears or other high-risk conditions. Lancet 2004;363:757-767.
3. Scott HD, Laake K. Statins for the prevention of Alzheimer’s disease. Cochrane Database Syst Rev 2001;(3):CD003160.-
4. Wolozin B, Kellman W, Rousseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439-1443.
5. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000;356:1627-1631.
6. Zamrini E, McGwin G, Roseman JM. Association between statin use and Alzheimer’s disease. Neuroepidemiology 2004;23:94-98.
7. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 1989;262:2551-2556.
8. Selkoe DJ. Physiological production of the beta-amyloid protein and the mechanism of Alzheimers-Disease. Trends Neurosci 1993;16:403-409.
9. Sano M, Thal LJ. Cholesterol Lowering Agent to Slow Progression (CLASP) of Alzheimer’s Disease Study. February 3, 2003 (Last reviewed December, 2004). Available at: www.clinicaltrials.gov/ct/show/NCT00053599?order=4. Accessed on June 8, 2005.
10. Lipitor as a Treatment of Alzheimer’s Disease. September 19, 2001 (Last reviewed November, 2004). Available at: www.clinicaltrials.gov/ct/show/NCT00024531?order=1. Accessed on June 8, 2005.
Evidence-based answers from the Family Physicians Inquiries Network
How useful is high-sensitivity CRP as a risk factor for coronary artery disease?
Little evidence supports the use of the high-sensitivity C-reactive protein assay (hs-CRP) as a screening test for cardiovascular disease (CVD) in the healthy adult population. There is significant debate about its use in populations at moderate risk for cardiovascular disease, with some evidence suggesting its use if the results of the test will alter treatment recommendations1 (strength of recommendation [SOR]: C, based on extrapolation of consistent level 2 studies). Research to date is inadequate to determine the role of hs-CRP in risk-stratification of patients when considered in light of other standard risk factors (Table).
TABLE
Evidence-based use of C-reactive protein in cardiovascular disease
| Known CV disease | Framingham risk score | Screen with CRP for risk assessment? | Follow CRP along with lipids if treated with statins? |
|---|---|---|---|
| No | Low risk (1%–5%) | No | No |
| No | Moderate or high risk (6% or higher) | Little evidence to support screening | Only if trying to decide whether to use aggressive (high-dose) statin therapy. In this situation, if moderate-dose therapy does not lower CRP, consider this as a possible reason to move to higher doses.10,11 (strength of recommendation: B, based on 2 very recent level 2 studies) |
| Yes | Any score | No—disease is established, screening is not appropriate |
Evidence summary
C-reactive protein is a nonspecific serum marker of inflammatory response. While it is elevated in a variety of conditions, a link has been suggested between CRP and pathogenesis of clinical cardiovascular disease.1
Several retrospective studies have reported risk ratios for developing cardiovascular disease, ranging from 2.3 to 4.4 when comparing subjects with the highest levels of hs-CRP with those who have the lowest levels.2-9 Though systematic bias in retrospective study design limits the interpretation of these findings, the findings are of some benefit to answering this question when large, prospective, randomized studies are not available.
One of the largest and most recent of these studies reports adjusted odds for development of coronary artery disease of 1.45 (95% confidence interval [CI], 1.25–1.68) for subjects in the top third of hs-CRP levels compared with those in the bottom third.9 Odds ratios (OR) for other predictors of coronary artery disease are higher than this, in particular total cholesterol (OR=2.35; 95% CI, 2.03–2.74), cigarette smoking (OR=1.87; 95% CI, 1.62–2.22), and elevated systolic blood pressure (OR=1.50; 95% CI, 1.30–1.73). This shows that hs-CRP does not contribute as much as these factors to the established risk profile for coronary heart disease.
These same authors go on to provide a systematic review of 22 prospective studies of hs-CRP involving 7068 patients, which showed that an elevated hs-CRP was associated with higher odds of developing coronary artery disease (OR=1.58; 95% CI, 1.48–1.68). They also examined the largest 4 studies in their review (which included 4107 cases) and found a slightly lower OR of 1.49 (95% CI, 1.37–1.62). This meta-analysis included only studies published since 2000 because earlier studies, which had yielded higher odds for hs-CRP, suggested a pattern consistent with publication bias.
Two very recent studies evaluating statin therapy for CVD suggest that CRP may be monitored as an independent factor for predicting CVD outcomes for patients undergoing aggressive lipid therapy.10,11 These randomized, masked trials suggest that CRP is directly predictive of recurrent events among patients with known CVD. Its usefulness may be greatest when trying to decide whether to pursue aggressive (high-dose) statin therapy for these patients.
It is not clear whether hs-CRP is a direct, causative marker for atherosclerosis or whether it is simply a proxy marker elevated in conjunction with other known risk factors. This issue, combined with the fact that its elevation does not contribute as significantly as other risk factors, makes hs-CRP an inappropriate screening test for cardiovascular disease in the healthy adult population. If results continue to accrue supporting the relationship between statin therapy and reduction of CVD outcomes attributable to CRP, we may find that monitoring CRP levels becomes appropriate in the management of patients with known moderate or severe risk or known disease.
Recommendations from others
A consensus statement from the American Heart Association and the Centers for Disease Control and Prevention discourages use of hs-CRP for screening in the healthy adult population. It offers support for using hs-CRP for assessment of patients at medium risk levels for whom the test will alter treatment decisions.1 Guidelines from the Institute for Clinical Systems Improvement for lipid management in adults state that, “non-traditional risk factors (C-reactive protein [CRP] and total homocysteine) have been shown to have some predictive values in screening vascular disease. The value of screening for these risk factors is not yet known.”12
hs-CRP may be useful as a risk marker in some moderately high-risk patients
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
Elevated hs-CRP is not a standard cardiovascular risk factor, but may be useful for patients with Framingham Risk scores of 10% to 20%. The updated National Cholesterol Education Panel Adult Treatment Panel III guidelines list elevated hs-CRP (>3 mg/L) as an influencing factor in deciding whether to use an LDL-lowering drug for moderately high-risk patients with LDL-cholesterol values <130 mg/dL.13 However, no prospective studies prove that elevated hs-CRP should guide therapy. The JUPITER trial is a prospective, placebo-controlled trial evaluating cardiovascular events with statin therapy in primary prevention patients with LDL values <130 mg/dL and hs-CRP values >2 mg/L.14 When this study is completed, the definitive clinical utility of hs-CRP will be known. Until then, hs-CRP is a risk marker that may be useful for some moderately high-risk patients.
1. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.
2. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997;17:1121-1127.
3. Speidl WS, Graf S, Hornykewycz S, et al. High-sensitivity C-reactive protein in the prediction of coronary events in patients with premature coronary artery disease. Am Heart J 2002;144:449-455.
4. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565.
5. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.
6. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237-242.
7. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J 2002;144:233-238.
8. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000;321:199-204.
9. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387-1397.
10. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29-38.
11. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-28.
12. Institute for Clinical Systems Improvement. Lipid Management in Adults. Available at: www.guideline.gov. Accessed on February 7, 2005.
13. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239.
14. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292-2297.
Little evidence supports the use of the high-sensitivity C-reactive protein assay (hs-CRP) as a screening test for cardiovascular disease (CVD) in the healthy adult population. There is significant debate about its use in populations at moderate risk for cardiovascular disease, with some evidence suggesting its use if the results of the test will alter treatment recommendations1 (strength of recommendation [SOR]: C, based on extrapolation of consistent level 2 studies). Research to date is inadequate to determine the role of hs-CRP in risk-stratification of patients when considered in light of other standard risk factors (Table).
TABLE
Evidence-based use of C-reactive protein in cardiovascular disease
| Known CV disease | Framingham risk score | Screen with CRP for risk assessment? | Follow CRP along with lipids if treated with statins? |
|---|---|---|---|
| No | Low risk (1%–5%) | No | No |
| No | Moderate or high risk (6% or higher) | Little evidence to support screening | Only if trying to decide whether to use aggressive (high-dose) statin therapy. In this situation, if moderate-dose therapy does not lower CRP, consider this as a possible reason to move to higher doses.10,11 (strength of recommendation: B, based on 2 very recent level 2 studies) |
| Yes | Any score | No—disease is established, screening is not appropriate |
Evidence summary
C-reactive protein is a nonspecific serum marker of inflammatory response. While it is elevated in a variety of conditions, a link has been suggested between CRP and pathogenesis of clinical cardiovascular disease.1
Several retrospective studies have reported risk ratios for developing cardiovascular disease, ranging from 2.3 to 4.4 when comparing subjects with the highest levels of hs-CRP with those who have the lowest levels.2-9 Though systematic bias in retrospective study design limits the interpretation of these findings, the findings are of some benefit to answering this question when large, prospective, randomized studies are not available.
One of the largest and most recent of these studies reports adjusted odds for development of coronary artery disease of 1.45 (95% confidence interval [CI], 1.25–1.68) for subjects in the top third of hs-CRP levels compared with those in the bottom third.9 Odds ratios (OR) for other predictors of coronary artery disease are higher than this, in particular total cholesterol (OR=2.35; 95% CI, 2.03–2.74), cigarette smoking (OR=1.87; 95% CI, 1.62–2.22), and elevated systolic blood pressure (OR=1.50; 95% CI, 1.30–1.73). This shows that hs-CRP does not contribute as much as these factors to the established risk profile for coronary heart disease.
These same authors go on to provide a systematic review of 22 prospective studies of hs-CRP involving 7068 patients, which showed that an elevated hs-CRP was associated with higher odds of developing coronary artery disease (OR=1.58; 95% CI, 1.48–1.68). They also examined the largest 4 studies in their review (which included 4107 cases) and found a slightly lower OR of 1.49 (95% CI, 1.37–1.62). This meta-analysis included only studies published since 2000 because earlier studies, which had yielded higher odds for hs-CRP, suggested a pattern consistent with publication bias.
Two very recent studies evaluating statin therapy for CVD suggest that CRP may be monitored as an independent factor for predicting CVD outcomes for patients undergoing aggressive lipid therapy.10,11 These randomized, masked trials suggest that CRP is directly predictive of recurrent events among patients with known CVD. Its usefulness may be greatest when trying to decide whether to pursue aggressive (high-dose) statin therapy for these patients.
It is not clear whether hs-CRP is a direct, causative marker for atherosclerosis or whether it is simply a proxy marker elevated in conjunction with other known risk factors. This issue, combined with the fact that its elevation does not contribute as significantly as other risk factors, makes hs-CRP an inappropriate screening test for cardiovascular disease in the healthy adult population. If results continue to accrue supporting the relationship between statin therapy and reduction of CVD outcomes attributable to CRP, we may find that monitoring CRP levels becomes appropriate in the management of patients with known moderate or severe risk or known disease.
Recommendations from others
A consensus statement from the American Heart Association and the Centers for Disease Control and Prevention discourages use of hs-CRP for screening in the healthy adult population. It offers support for using hs-CRP for assessment of patients at medium risk levels for whom the test will alter treatment decisions.1 Guidelines from the Institute for Clinical Systems Improvement for lipid management in adults state that, “non-traditional risk factors (C-reactive protein [CRP] and total homocysteine) have been shown to have some predictive values in screening vascular disease. The value of screening for these risk factors is not yet known.”12
hs-CRP may be useful as a risk marker in some moderately high-risk patients
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
Elevated hs-CRP is not a standard cardiovascular risk factor, but may be useful for patients with Framingham Risk scores of 10% to 20%. The updated National Cholesterol Education Panel Adult Treatment Panel III guidelines list elevated hs-CRP (>3 mg/L) as an influencing factor in deciding whether to use an LDL-lowering drug for moderately high-risk patients with LDL-cholesterol values <130 mg/dL.13 However, no prospective studies prove that elevated hs-CRP should guide therapy. The JUPITER trial is a prospective, placebo-controlled trial evaluating cardiovascular events with statin therapy in primary prevention patients with LDL values <130 mg/dL and hs-CRP values >2 mg/L.14 When this study is completed, the definitive clinical utility of hs-CRP will be known. Until then, hs-CRP is a risk marker that may be useful for some moderately high-risk patients.
Little evidence supports the use of the high-sensitivity C-reactive protein assay (hs-CRP) as a screening test for cardiovascular disease (CVD) in the healthy adult population. There is significant debate about its use in populations at moderate risk for cardiovascular disease, with some evidence suggesting its use if the results of the test will alter treatment recommendations1 (strength of recommendation [SOR]: C, based on extrapolation of consistent level 2 studies). Research to date is inadequate to determine the role of hs-CRP in risk-stratification of patients when considered in light of other standard risk factors (Table).
TABLE
Evidence-based use of C-reactive protein in cardiovascular disease
| Known CV disease | Framingham risk score | Screen with CRP for risk assessment? | Follow CRP along with lipids if treated with statins? |
|---|---|---|---|
| No | Low risk (1%–5%) | No | No |
| No | Moderate or high risk (6% or higher) | Little evidence to support screening | Only if trying to decide whether to use aggressive (high-dose) statin therapy. In this situation, if moderate-dose therapy does not lower CRP, consider this as a possible reason to move to higher doses.10,11 (strength of recommendation: B, based on 2 very recent level 2 studies) |
| Yes | Any score | No—disease is established, screening is not appropriate |
Evidence summary
C-reactive protein is a nonspecific serum marker of inflammatory response. While it is elevated in a variety of conditions, a link has been suggested between CRP and pathogenesis of clinical cardiovascular disease.1
Several retrospective studies have reported risk ratios for developing cardiovascular disease, ranging from 2.3 to 4.4 when comparing subjects with the highest levels of hs-CRP with those who have the lowest levels.2-9 Though systematic bias in retrospective study design limits the interpretation of these findings, the findings are of some benefit to answering this question when large, prospective, randomized studies are not available.
One of the largest and most recent of these studies reports adjusted odds for development of coronary artery disease of 1.45 (95% confidence interval [CI], 1.25–1.68) for subjects in the top third of hs-CRP levels compared with those in the bottom third.9 Odds ratios (OR) for other predictors of coronary artery disease are higher than this, in particular total cholesterol (OR=2.35; 95% CI, 2.03–2.74), cigarette smoking (OR=1.87; 95% CI, 1.62–2.22), and elevated systolic blood pressure (OR=1.50; 95% CI, 1.30–1.73). This shows that hs-CRP does not contribute as much as these factors to the established risk profile for coronary heart disease.
These same authors go on to provide a systematic review of 22 prospective studies of hs-CRP involving 7068 patients, which showed that an elevated hs-CRP was associated with higher odds of developing coronary artery disease (OR=1.58; 95% CI, 1.48–1.68). They also examined the largest 4 studies in their review (which included 4107 cases) and found a slightly lower OR of 1.49 (95% CI, 1.37–1.62). This meta-analysis included only studies published since 2000 because earlier studies, which had yielded higher odds for hs-CRP, suggested a pattern consistent with publication bias.
Two very recent studies evaluating statin therapy for CVD suggest that CRP may be monitored as an independent factor for predicting CVD outcomes for patients undergoing aggressive lipid therapy.10,11 These randomized, masked trials suggest that CRP is directly predictive of recurrent events among patients with known CVD. Its usefulness may be greatest when trying to decide whether to pursue aggressive (high-dose) statin therapy for these patients.
It is not clear whether hs-CRP is a direct, causative marker for atherosclerosis or whether it is simply a proxy marker elevated in conjunction with other known risk factors. This issue, combined with the fact that its elevation does not contribute as significantly as other risk factors, makes hs-CRP an inappropriate screening test for cardiovascular disease in the healthy adult population. If results continue to accrue supporting the relationship between statin therapy and reduction of CVD outcomes attributable to CRP, we may find that monitoring CRP levels becomes appropriate in the management of patients with known moderate or severe risk or known disease.
Recommendations from others
A consensus statement from the American Heart Association and the Centers for Disease Control and Prevention discourages use of hs-CRP for screening in the healthy adult population. It offers support for using hs-CRP for assessment of patients at medium risk levels for whom the test will alter treatment decisions.1 Guidelines from the Institute for Clinical Systems Improvement for lipid management in adults state that, “non-traditional risk factors (C-reactive protein [CRP] and total homocysteine) have been shown to have some predictive values in screening vascular disease. The value of screening for these risk factors is not yet known.”12
hs-CRP may be useful as a risk marker in some moderately high-risk patients
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
Elevated hs-CRP is not a standard cardiovascular risk factor, but may be useful for patients with Framingham Risk scores of 10% to 20%. The updated National Cholesterol Education Panel Adult Treatment Panel III guidelines list elevated hs-CRP (>3 mg/L) as an influencing factor in deciding whether to use an LDL-lowering drug for moderately high-risk patients with LDL-cholesterol values <130 mg/dL.13 However, no prospective studies prove that elevated hs-CRP should guide therapy. The JUPITER trial is a prospective, placebo-controlled trial evaluating cardiovascular events with statin therapy in primary prevention patients with LDL values <130 mg/dL and hs-CRP values >2 mg/L.14 When this study is completed, the definitive clinical utility of hs-CRP will be known. Until then, hs-CRP is a risk marker that may be useful for some moderately high-risk patients.
1. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.
2. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997;17:1121-1127.
3. Speidl WS, Graf S, Hornykewycz S, et al. High-sensitivity C-reactive protein in the prediction of coronary events in patients with premature coronary artery disease. Am Heart J 2002;144:449-455.
4. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565.
5. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.
6. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237-242.
7. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J 2002;144:233-238.
8. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000;321:199-204.
9. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387-1397.
10. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29-38.
11. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-28.
12. Institute for Clinical Systems Improvement. Lipid Management in Adults. Available at: www.guideline.gov. Accessed on February 7, 2005.
13. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239.
14. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292-2297.
1. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.
2. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997;17:1121-1127.
3. Speidl WS, Graf S, Hornykewycz S, et al. High-sensitivity C-reactive protein in the prediction of coronary events in patients with premature coronary artery disease. Am Heart J 2002;144:449-455.
4. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565.
5. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.
6. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237-242.
7. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J 2002;144:233-238.
8. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000;321:199-204.
9. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387-1397.
10. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29-38.
11. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-28.
12. Institute for Clinical Systems Improvement. Lipid Management in Adults. Available at: www.guideline.gov. Accessed on February 7, 2005.
13. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239.
14. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292-2297.
Evidence-based answers from the Family Physicians Inquiries Network
How should thyroid replacement be initiated?
Levothyroxine (LT4) should be used alone as initial replacement for patients with hypothyroidism (strength of recommendation [SOR]: A). The optimal initial dose is 1.6 μg/kg/d for healthy people aged 60 years or younger (SOR: B). Patients aged more than 60 years may require less levothyroxine to achieve therapeutic serum thyroid hormone replacement, so initial replacement should be decreased to 25 to 50 μg daily (SOR: C).
Since patients with known heart disease may develop dysrhythmias, angina, and myocardial infarctions when started on full replacement doses, experts recommend starting 12.5 to 25 μg daily for this population (SOR: C). Brand-name (Synthroid, Levoxyl, etc) and generic LT4 are bioequivalent (SOR: B), although the US Food and Drug Administration (FDA) does not consider these products to be interchangeable until proven therapeutically equivalent.
Evidence summary
Initial thyroid replacement with synthetic LT4 is recommended because LT4 is safe, effective, reliably relieves symptoms, and normalizes lab tests for hypothyroid patients.1,2
Two recent randomized trials comparing LT4 alone or LT4 and LT3 together for a total of 86 adult hypothyroid patients found similar outcomes. One study, which enrolled patients with hypothy-roidism and mild depressive symptoms, assessed scores on the Symptom Check-List-90, the Comprehensive Epidemiological Screens for Depression, and the Medical Outcomes Study health status questionnaire at baseline and multiple times over the duration of the study. For these outcomes, no differences were found between the LT4 alone and combination LT4-LT3 treatment groups within 90% confidence intervals.3 A second study assessed changes in body weight, lipid profile, hypothyroid-specific health-related quality-of-life scores, and 13 neuropsychological measures pre- and posttreatment. This study detected no difference in body weight and serum lipids at baseline and after treatment. The hypothyroid-specific health-related quality-of-life scores similarly improved for both treatment groups. Twelve of 13 neuropsychological tests demonstrated no differences between treatment groups; the Grooved Peg Board Test of manual dexterity and fine visual-motor coordination demonstrated a slight improvement for the LT4 alone treatment group.4
The initial dose of LT4 can be based on the age and health status of the patient. The mean replacement dose of LT4 is 1.6 μg/kg/d for healthy patients aged ≤60 years.5 7 Patients aged >60 years should be started on 25 to 50 μg daily. An uncontrolled cohort study of 84 patients found that for patients aged >60 years, 25- to 50-μg doses of LT4 resulted in similar serum thyrotropin (TSH) levels as the higher (1.6 μg/kg/d) doses required for younger patients.7 Based on expert opinion, patients of any age with heart disease should be given lower doses of 12.5 to 25 μg daily as initial treatment.1,2
The choice of the LT4 preparation continues to be debated. In 1997, a bioequivalence study compared 2 generic brands to 2 name brands by having 22 women with hypothyroidism, who were euthyroid on replacement medication, take each preparation for 6 weeks.8 The area under the curve, peak serum concentration, and time to peak concentration for 3 indexes of thyroid function (thyroxine, triiodothyronine, and free T4 index) were not significantly different and met the FDA criterion for relative bioequivalence. However, they did not examine therapeutic equivalence and from a clinical perspective, some researchers and pharmaceutical companies felt that the authors could not comment on whether the products were interchangeable.8,9 The FDA now requires thyroxine bioavailability and bioequivalence studies to evaluate product substitution.10 The FDA lists Levothyroxine Sodium (Mylan) to be therapeutically equivalent and therefore interchangeable with Unithroid.11
Recommendations from others
The American Association of Clinical Endocrinologists Thyroid Task Force recommends the use of a high-quality brand preparation of LT4 rather than desiccated thyroid hormone, combinations of thyroid hormones, or LT3.12 It recommends a mean replacement dosage of LT4 of 1.6 μg/kg of body weight per day with initial dose ranging from 12.5 μg daily to a full replacement dosage based on the age, weight, and cardiac status of the patient.
UpToDate states that although LT4 products are standardized, subtle differences between preparations exist, and products should be interchanged only with sufficient monitoring after the change. In addition, they recommend generally avoiding generics because the pharmacy may interchange products without physicians being aware.1 . The Physicians’ Information and Education Resource from the American College of Physicians states “Name-brand LT4 products provide more consistent potency than generic preparations. The cost of brand-name LT4 products is only slightly more than that of generic preparations.”2
Instruct patients about the timing of levothyroxine and potential interactions
Santhi Penmetsa, MD
Department of Family and Community Medicine, Baylor College of Medicine
The starting dose of levothyroxine for hypothyroid patients is based on age, severity of the disease, duration of the disease, and existing comorbid conditions. For healthy adults 60 years of age or younger, the optimal starting dose is 1.6 μg/kg/d. For patients more than 60 years of age, the initial dose is 25 to 50 μg/d. To avoid cardiac complications among persons with known heart disease, the recommended initial levothyroxine dose is 12.5 μg/d. In my experience, these guidelines work well in initiating treatment for hypothyroidism.
Few of my patients have noted any difference between generic and brand-name thyroid supplements. Knowing what other medications the patient is taking is important, since medications such as estrogen can decrease the bioavailability of levothyroxine by increasing binding proteins. It is also important to instruct patients about the timing of levothyroxine intake, because some medications can affect absorption (eg, cholestyramine, calcium, or iron).
1. Ross DS. Treatment of hypothyroidism. UpToDate. Last update January 9, 2004. Available at: www.uptodate.com. Accessed on March 4, 2004.
2. McDermott MT. Hypothyroidism. ACP’s PIER: Physicians’ Information and Education Resource. Last update March 17, 2004. Available at: http://online.statref.com/document.aspx?fxid=50&docid=1 297. Accessed on May 10, 2004.
3. Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3’-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4551-4555.
4. Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952-2958.
5. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med 1987;316:764-770.
6. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf) 1988;28:325-333.
7. Sawin CT, Herman T, Molitch ME, London MH, Kramer SM. Aging and the thyroid: Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983;75:206-209.
8. Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997;277:1205-1213.
9. Rennie D. Thyroid storm. JAMA 1997;277:1238-1243.
10. Hennessey JV. Precise thyroxine dosing: Clinical requirements. Endocrinologist 2003;13:479-487.
11. FDA Center for Drug Evaluation and Research. Drugs@FDA: Levothyroxine Sodium (Generic Drug). Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on June 3, 2004.
Levothyroxine (LT4) should be used alone as initial replacement for patients with hypothyroidism (strength of recommendation [SOR]: A). The optimal initial dose is 1.6 μg/kg/d for healthy people aged 60 years or younger (SOR: B). Patients aged more than 60 years may require less levothyroxine to achieve therapeutic serum thyroid hormone replacement, so initial replacement should be decreased to 25 to 50 μg daily (SOR: C).
Since patients with known heart disease may develop dysrhythmias, angina, and myocardial infarctions when started on full replacement doses, experts recommend starting 12.5 to 25 μg daily for this population (SOR: C). Brand-name (Synthroid, Levoxyl, etc) and generic LT4 are bioequivalent (SOR: B), although the US Food and Drug Administration (FDA) does not consider these products to be interchangeable until proven therapeutically equivalent.
Evidence summary
Initial thyroid replacement with synthetic LT4 is recommended because LT4 is safe, effective, reliably relieves symptoms, and normalizes lab tests for hypothyroid patients.1,2
Two recent randomized trials comparing LT4 alone or LT4 and LT3 together for a total of 86 adult hypothyroid patients found similar outcomes. One study, which enrolled patients with hypothy-roidism and mild depressive symptoms, assessed scores on the Symptom Check-List-90, the Comprehensive Epidemiological Screens for Depression, and the Medical Outcomes Study health status questionnaire at baseline and multiple times over the duration of the study. For these outcomes, no differences were found between the LT4 alone and combination LT4-LT3 treatment groups within 90% confidence intervals.3 A second study assessed changes in body weight, lipid profile, hypothyroid-specific health-related quality-of-life scores, and 13 neuropsychological measures pre- and posttreatment. This study detected no difference in body weight and serum lipids at baseline and after treatment. The hypothyroid-specific health-related quality-of-life scores similarly improved for both treatment groups. Twelve of 13 neuropsychological tests demonstrated no differences between treatment groups; the Grooved Peg Board Test of manual dexterity and fine visual-motor coordination demonstrated a slight improvement for the LT4 alone treatment group.4
The initial dose of LT4 can be based on the age and health status of the patient. The mean replacement dose of LT4 is 1.6 μg/kg/d for healthy patients aged ≤60 years.5 7 Patients aged >60 years should be started on 25 to 50 μg daily. An uncontrolled cohort study of 84 patients found that for patients aged >60 years, 25- to 50-μg doses of LT4 resulted in similar serum thyrotropin (TSH) levels as the higher (1.6 μg/kg/d) doses required for younger patients.7 Based on expert opinion, patients of any age with heart disease should be given lower doses of 12.5 to 25 μg daily as initial treatment.1,2
The choice of the LT4 preparation continues to be debated. In 1997, a bioequivalence study compared 2 generic brands to 2 name brands by having 22 women with hypothyroidism, who were euthyroid on replacement medication, take each preparation for 6 weeks.8 The area under the curve, peak serum concentration, and time to peak concentration for 3 indexes of thyroid function (thyroxine, triiodothyronine, and free T4 index) were not significantly different and met the FDA criterion for relative bioequivalence. However, they did not examine therapeutic equivalence and from a clinical perspective, some researchers and pharmaceutical companies felt that the authors could not comment on whether the products were interchangeable.8,9 The FDA now requires thyroxine bioavailability and bioequivalence studies to evaluate product substitution.10 The FDA lists Levothyroxine Sodium (Mylan) to be therapeutically equivalent and therefore interchangeable with Unithroid.11
Recommendations from others
The American Association of Clinical Endocrinologists Thyroid Task Force recommends the use of a high-quality brand preparation of LT4 rather than desiccated thyroid hormone, combinations of thyroid hormones, or LT3.12 It recommends a mean replacement dosage of LT4 of 1.6 μg/kg of body weight per day with initial dose ranging from 12.5 μg daily to a full replacement dosage based on the age, weight, and cardiac status of the patient.
UpToDate states that although LT4 products are standardized, subtle differences between preparations exist, and products should be interchanged only with sufficient monitoring after the change. In addition, they recommend generally avoiding generics because the pharmacy may interchange products without physicians being aware.1 . The Physicians’ Information and Education Resource from the American College of Physicians states “Name-brand LT4 products provide more consistent potency than generic preparations. The cost of brand-name LT4 products is only slightly more than that of generic preparations.”2
Instruct patients about the timing of levothyroxine and potential interactions
Santhi Penmetsa, MD
Department of Family and Community Medicine, Baylor College of Medicine
The starting dose of levothyroxine for hypothyroid patients is based on age, severity of the disease, duration of the disease, and existing comorbid conditions. For healthy adults 60 years of age or younger, the optimal starting dose is 1.6 μg/kg/d. For patients more than 60 years of age, the initial dose is 25 to 50 μg/d. To avoid cardiac complications among persons with known heart disease, the recommended initial levothyroxine dose is 12.5 μg/d. In my experience, these guidelines work well in initiating treatment for hypothyroidism.
Few of my patients have noted any difference between generic and brand-name thyroid supplements. Knowing what other medications the patient is taking is important, since medications such as estrogen can decrease the bioavailability of levothyroxine by increasing binding proteins. It is also important to instruct patients about the timing of levothyroxine intake, because some medications can affect absorption (eg, cholestyramine, calcium, or iron).
Levothyroxine (LT4) should be used alone as initial replacement for patients with hypothyroidism (strength of recommendation [SOR]: A). The optimal initial dose is 1.6 μg/kg/d for healthy people aged 60 years or younger (SOR: B). Patients aged more than 60 years may require less levothyroxine to achieve therapeutic serum thyroid hormone replacement, so initial replacement should be decreased to 25 to 50 μg daily (SOR: C).
Since patients with known heart disease may develop dysrhythmias, angina, and myocardial infarctions when started on full replacement doses, experts recommend starting 12.5 to 25 μg daily for this population (SOR: C). Brand-name (Synthroid, Levoxyl, etc) and generic LT4 are bioequivalent (SOR: B), although the US Food and Drug Administration (FDA) does not consider these products to be interchangeable until proven therapeutically equivalent.
Evidence summary
Initial thyroid replacement with synthetic LT4 is recommended because LT4 is safe, effective, reliably relieves symptoms, and normalizes lab tests for hypothyroid patients.1,2
Two recent randomized trials comparing LT4 alone or LT4 and LT3 together for a total of 86 adult hypothyroid patients found similar outcomes. One study, which enrolled patients with hypothy-roidism and mild depressive symptoms, assessed scores on the Symptom Check-List-90, the Comprehensive Epidemiological Screens for Depression, and the Medical Outcomes Study health status questionnaire at baseline and multiple times over the duration of the study. For these outcomes, no differences were found between the LT4 alone and combination LT4-LT3 treatment groups within 90% confidence intervals.3 A second study assessed changes in body weight, lipid profile, hypothyroid-specific health-related quality-of-life scores, and 13 neuropsychological measures pre- and posttreatment. This study detected no difference in body weight and serum lipids at baseline and after treatment. The hypothyroid-specific health-related quality-of-life scores similarly improved for both treatment groups. Twelve of 13 neuropsychological tests demonstrated no differences between treatment groups; the Grooved Peg Board Test of manual dexterity and fine visual-motor coordination demonstrated a slight improvement for the LT4 alone treatment group.4
The initial dose of LT4 can be based on the age and health status of the patient. The mean replacement dose of LT4 is 1.6 μg/kg/d for healthy patients aged ≤60 years.5 7 Patients aged >60 years should be started on 25 to 50 μg daily. An uncontrolled cohort study of 84 patients found that for patients aged >60 years, 25- to 50-μg doses of LT4 resulted in similar serum thyrotropin (TSH) levels as the higher (1.6 μg/kg/d) doses required for younger patients.7 Based on expert opinion, patients of any age with heart disease should be given lower doses of 12.5 to 25 μg daily as initial treatment.1,2
The choice of the LT4 preparation continues to be debated. In 1997, a bioequivalence study compared 2 generic brands to 2 name brands by having 22 women with hypothyroidism, who were euthyroid on replacement medication, take each preparation for 6 weeks.8 The area under the curve, peak serum concentration, and time to peak concentration for 3 indexes of thyroid function (thyroxine, triiodothyronine, and free T4 index) were not significantly different and met the FDA criterion for relative bioequivalence. However, they did not examine therapeutic equivalence and from a clinical perspective, some researchers and pharmaceutical companies felt that the authors could not comment on whether the products were interchangeable.8,9 The FDA now requires thyroxine bioavailability and bioequivalence studies to evaluate product substitution.10 The FDA lists Levothyroxine Sodium (Mylan) to be therapeutically equivalent and therefore interchangeable with Unithroid.11
Recommendations from others
The American Association of Clinical Endocrinologists Thyroid Task Force recommends the use of a high-quality brand preparation of LT4 rather than desiccated thyroid hormone, combinations of thyroid hormones, or LT3.12 It recommends a mean replacement dosage of LT4 of 1.6 μg/kg of body weight per day with initial dose ranging from 12.5 μg daily to a full replacement dosage based on the age, weight, and cardiac status of the patient.
UpToDate states that although LT4 products are standardized, subtle differences between preparations exist, and products should be interchanged only with sufficient monitoring after the change. In addition, they recommend generally avoiding generics because the pharmacy may interchange products without physicians being aware.1 . The Physicians’ Information and Education Resource from the American College of Physicians states “Name-brand LT4 products provide more consistent potency than generic preparations. The cost of brand-name LT4 products is only slightly more than that of generic preparations.”2
Instruct patients about the timing of levothyroxine and potential interactions
Santhi Penmetsa, MD
Department of Family and Community Medicine, Baylor College of Medicine
The starting dose of levothyroxine for hypothyroid patients is based on age, severity of the disease, duration of the disease, and existing comorbid conditions. For healthy adults 60 years of age or younger, the optimal starting dose is 1.6 μg/kg/d. For patients more than 60 years of age, the initial dose is 25 to 50 μg/d. To avoid cardiac complications among persons with known heart disease, the recommended initial levothyroxine dose is 12.5 μg/d. In my experience, these guidelines work well in initiating treatment for hypothyroidism.
Few of my patients have noted any difference between generic and brand-name thyroid supplements. Knowing what other medications the patient is taking is important, since medications such as estrogen can decrease the bioavailability of levothyroxine by increasing binding proteins. It is also important to instruct patients about the timing of levothyroxine intake, because some medications can affect absorption (eg, cholestyramine, calcium, or iron).
1. Ross DS. Treatment of hypothyroidism. UpToDate. Last update January 9, 2004. Available at: www.uptodate.com. Accessed on March 4, 2004.
2. McDermott MT. Hypothyroidism. ACP’s PIER: Physicians’ Information and Education Resource. Last update March 17, 2004. Available at: http://online.statref.com/document.aspx?fxid=50&docid=1 297. Accessed on May 10, 2004.
3. Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3’-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4551-4555.
4. Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952-2958.
5. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med 1987;316:764-770.
6. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf) 1988;28:325-333.
7. Sawin CT, Herman T, Molitch ME, London MH, Kramer SM. Aging and the thyroid: Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983;75:206-209.
8. Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997;277:1205-1213.
9. Rennie D. Thyroid storm. JAMA 1997;277:1238-1243.
10. Hennessey JV. Precise thyroxine dosing: Clinical requirements. Endocrinologist 2003;13:479-487.
11. FDA Center for Drug Evaluation and Research. Drugs@FDA: Levothyroxine Sodium (Generic Drug). Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on June 3, 2004.
1. Ross DS. Treatment of hypothyroidism. UpToDate. Last update January 9, 2004. Available at: www.uptodate.com. Accessed on March 4, 2004.
2. McDermott MT. Hypothyroidism. ACP’s PIER: Physicians’ Information and Education Resource. Last update March 17, 2004. Available at: http://online.statref.com/document.aspx?fxid=50&docid=1 297. Accessed on May 10, 2004.
3. Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3’-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4551-4555.
4. Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952-2958.
5. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med 1987;316:764-770.
6. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf) 1988;28:325-333.
7. Sawin CT, Herman T, Molitch ME, London MH, Kramer SM. Aging and the thyroid: Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983;75:206-209.
8. Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997;277:1205-1213.
9. Rennie D. Thyroid storm. JAMA 1997;277:1238-1243.
10. Hennessey JV. Precise thyroxine dosing: Clinical requirements. Endocrinologist 2003;13:479-487.
11. FDA Center for Drug Evaluation and Research. Drugs@FDA: Levothyroxine Sodium (Generic Drug). Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on June 3, 2004.
Evidence-based answers from the Family Physicians Inquiries Network
Is screening for lead poisoning justified?
Evidence is insufficient to recommend for or against universal screening of young children for lead poisoning in high-prevalence communities (strength of recommendation [SOR]: C). In low-prevalence communities, evidence is insufficient to recommend for or against a targeted screening approach, employing locale-specific demographic risk factors and personal risk questionnaires to inform screening decisions (SOR: C).
Although evidence does not suggest that treatment of individuals with elevated blood lead levels improves individual outcomes, public health strategies aimed at decreasing lead in the environment appear to have resulted in a significant decline in the number of children with elevated blood lead levels in recent decades. One could thus argue that screening may identify communities with high rates of lead poisoning, where environmental strategies could be targeted.
Because the epidemiology of lead poisoning continues to change, local and state health authorities must continuously update information on which to base decisions about screening.
Evidence summary
The prevalence of elevated blood lead levels varies widely among different demographic groups and geographic regions, and it has decreased dramatically in the last several decades. Racial and ethnic minorities and children of families with low incomes, who live in the Northeast or Midwest, or who live in older houses continue to be at increased risk.1 Children with blood lead levels 10 μg/dL have been shown to have poorer cognitive and behavioral functioning.2
No studies have demonstrated that screening for lead poisoning improves outcomes. To justify screening, one must therefore extrapolate from indirect evidence, demonstrating that screening tests are accurate and that treatment of children detected by screening is effective. Capillary blood samples are comparable with venous samples for detecting elevated blood lead levels. The sensitivity of capillary samples ranges from 86% to 96% compared with venous samples.3
In low-prevalence areas, questionnaires may inform screening decisions. A questionnaire inquiring about age of housing, presence of peeling paint, ongoing renovations, siblings or playmates with elevated blood lead levels, adults in the home with occupational exposures to lead, and proximity to industrial sources of lead has a sensitivity for detecting blood lead levels 10 μg/dL ranging from 32% to 87%. Sensitivity varies depending on the population and geographic location in which the questionnaire is tested. Accuracy is improved by tailoring the questionnaire based on locally important risk factors.4
Proposed treatments for elevated blood lead levels include chelation therapy, education about hygiene and nutrition, household dust control measures, and soil lead abatement. No good-quality trials have demonstrated that lowering slightly to moderately elevated blood lead levels (10–55 μg/dL) improves patient-oriented outcomes such as cognitive and behavioral functioning. Although 1 observational study of chelation therapy linked lowering blood lead levels with improved cognitive function,3 a randomized controlled trial showed that chelation had no effect on cognitive or behavioral outcomes.5
All other trials evaluating treatment for lead poisoning looked at the intermediate outcome of blood lead levels. A systematic review of randomized controlled trials showed that home dust control interventions reduced the proportion of children with elevated blood lead levels (15 μg/dL) from 14% to 6%.6 A randomized controlled trial of high-efficiency particulate air (HEPA) filtration vacuuming showed no effect.7 More intensive interventions such as soil lead abatement and paint remediation have not proven effective in good-quality randomized controlled trials.
Increasing dietary calcium and iron and decreasing dietary fat are also commonly recommended for children with elevated blood lead levels, based on animal models and cross-sectional studies. The only randomized controlled trial that investigated calcium supplementation showed no effect on blood lead levels.8 Our search revealed no good-quality studies on the effect of iron or fat intake on lead poisoning.
In summary, because the prevalence of lead poisoning varies between communities and continues to change, standard recommendations are not possible. Clinicians must rely on local epidemiologic data to make screening decisions. Although questionnaires are accurate in predicting elevated blood lead levels in some settings, no specific set of questions can be recommended for all populations.
No treatment options for those with mild to moderate elevations in blood lead levels have been shown to improve clinically important outcomes, although some interventions may decrease blood lead levels.
Recommendations from others
The Centers for Disease Control and Prevention (CDC) recommends
- that individual states develop screening plans based on local data
- universal screening at 12 and 24 months of age:
Otherwise screening should be targeted based on a questionnaire on age of housing, recent or ongoing remodeling, and having a sibling or playmate diagnosed with lead poisoning, in addition to questions on locally important risk factors.9
The American Academy of Pediatrics endorses the CDC recommendations.2 The US Preventive Services Task Force, the American Academy of Family Physicians, and the American College of Preventive Medicine all recommend screening for lead poisoning at 12 months of age in children with demographic or geographic risk factors.3,10,11
Lead screening: Think locally
Julia Fashner, MD
St. Joseph Regional Medical Center, South Bend, Ind
The local health department can provide information about lead screening in your community, whether based on blood levels or the housing conditions. If your patients need screening, you may want to add a reminder on a flow sheet in the chart to do a questionnaire or a blood draw. Finding and treating severely elevated lead levels can change outcomes, but for less elevated levels, the evidence shows no benefit. You should work with the health department when considering therapy for children with elevated blood lead levels.
1. Kaufmann RB, Clouse TL, Olson DR, Matte TD. Elevated blood lead levels and blood lead screening among US children aged one to five years: 1988–1994. Pediatrics 2000;106:E79.-
2. Screening for elevated blood lead levels. American Academy of Pediatrics Committee on Environmental Health. Pediatrics 1998;101:1072-1078.
3. US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Baltimore, Md: Lippincott Williams & Wilkins; 1996.
4. Binns HJ, LeBailly SA, Fingar AR, Saunders S. Evaluation of risk assessment questions used to target blood lead screening in Illinois. Pediatrics 1999;103:100-106.
5. Rogan WJ, Dietrich KN, Ware JH, et al. The effect of chela-tion therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med 2001;344:1421-1426.
6. Haynes E, Lanphear BP, Tohn E, Farr N, Rhoads GG. The effect of interior lead hazard controls on children’s blood lead concentrations: a systematic evaluation. Environ Health Perspect 2002;110:103-107.
7. Hilts SR, Hertzman C, Marion SA. A controlled trial of the effect of HEPA vacuuming on childhood lead exposure. Can J Public Health 1995;86:345-350.
8. Ballew C, Bowman B. Recommending calcium to reduce lead toxicity in children: a critical review. Nutr Rev 2001;59(3 Pt 1):71-79.
9. Centers for Disease Control and Prevention. Screening Young Children for Lead Poisoning: Guidance for State and Local Public Health Officials. Atlanta, Ga: CDC, 1997.
10. AAFP Policy Recommendations for Periodic Health Examinations 2002. Available at http://www.aafp.org/ exam.xml. Accessed on February 9, 2003.
11. Lane WG, Kemper AR. American College of Preventive Medicine Practice Policy Statement. Screening for elevated blood lead levels in children. Am J Prev Med 2001;20:78-82.
Evidence is insufficient to recommend for or against universal screening of young children for lead poisoning in high-prevalence communities (strength of recommendation [SOR]: C). In low-prevalence communities, evidence is insufficient to recommend for or against a targeted screening approach, employing locale-specific demographic risk factors and personal risk questionnaires to inform screening decisions (SOR: C).
Although evidence does not suggest that treatment of individuals with elevated blood lead levels improves individual outcomes, public health strategies aimed at decreasing lead in the environment appear to have resulted in a significant decline in the number of children with elevated blood lead levels in recent decades. One could thus argue that screening may identify communities with high rates of lead poisoning, where environmental strategies could be targeted.
Because the epidemiology of lead poisoning continues to change, local and state health authorities must continuously update information on which to base decisions about screening.
Evidence summary
The prevalence of elevated blood lead levels varies widely among different demographic groups and geographic regions, and it has decreased dramatically in the last several decades. Racial and ethnic minorities and children of families with low incomes, who live in the Northeast or Midwest, or who live in older houses continue to be at increased risk.1 Children with blood lead levels 10 μg/dL have been shown to have poorer cognitive and behavioral functioning.2
No studies have demonstrated that screening for lead poisoning improves outcomes. To justify screening, one must therefore extrapolate from indirect evidence, demonstrating that screening tests are accurate and that treatment of children detected by screening is effective. Capillary blood samples are comparable with venous samples for detecting elevated blood lead levels. The sensitivity of capillary samples ranges from 86% to 96% compared with venous samples.3
In low-prevalence areas, questionnaires may inform screening decisions. A questionnaire inquiring about age of housing, presence of peeling paint, ongoing renovations, siblings or playmates with elevated blood lead levels, adults in the home with occupational exposures to lead, and proximity to industrial sources of lead has a sensitivity for detecting blood lead levels 10 μg/dL ranging from 32% to 87%. Sensitivity varies depending on the population and geographic location in which the questionnaire is tested. Accuracy is improved by tailoring the questionnaire based on locally important risk factors.4
Proposed treatments for elevated blood lead levels include chelation therapy, education about hygiene and nutrition, household dust control measures, and soil lead abatement. No good-quality trials have demonstrated that lowering slightly to moderately elevated blood lead levels (10–55 μg/dL) improves patient-oriented outcomes such as cognitive and behavioral functioning. Although 1 observational study of chelation therapy linked lowering blood lead levels with improved cognitive function,3 a randomized controlled trial showed that chelation had no effect on cognitive or behavioral outcomes.5
All other trials evaluating treatment for lead poisoning looked at the intermediate outcome of blood lead levels. A systematic review of randomized controlled trials showed that home dust control interventions reduced the proportion of children with elevated blood lead levels (15 μg/dL) from 14% to 6%.6 A randomized controlled trial of high-efficiency particulate air (HEPA) filtration vacuuming showed no effect.7 More intensive interventions such as soil lead abatement and paint remediation have not proven effective in good-quality randomized controlled trials.
Increasing dietary calcium and iron and decreasing dietary fat are also commonly recommended for children with elevated blood lead levels, based on animal models and cross-sectional studies. The only randomized controlled trial that investigated calcium supplementation showed no effect on blood lead levels.8 Our search revealed no good-quality studies on the effect of iron or fat intake on lead poisoning.
In summary, because the prevalence of lead poisoning varies between communities and continues to change, standard recommendations are not possible. Clinicians must rely on local epidemiologic data to make screening decisions. Although questionnaires are accurate in predicting elevated blood lead levels in some settings, no specific set of questions can be recommended for all populations.
No treatment options for those with mild to moderate elevations in blood lead levels have been shown to improve clinically important outcomes, although some interventions may decrease blood lead levels.
Recommendations from others
The Centers for Disease Control and Prevention (CDC) recommends
- that individual states develop screening plans based on local data
- universal screening at 12 and 24 months of age:
Otherwise screening should be targeted based on a questionnaire on age of housing, recent or ongoing remodeling, and having a sibling or playmate diagnosed with lead poisoning, in addition to questions on locally important risk factors.9
The American Academy of Pediatrics endorses the CDC recommendations.2 The US Preventive Services Task Force, the American Academy of Family Physicians, and the American College of Preventive Medicine all recommend screening for lead poisoning at 12 months of age in children with demographic or geographic risk factors.3,10,11
Lead screening: Think locally
Julia Fashner, MD
St. Joseph Regional Medical Center, South Bend, Ind
The local health department can provide information about lead screening in your community, whether based on blood levels or the housing conditions. If your patients need screening, you may want to add a reminder on a flow sheet in the chart to do a questionnaire or a blood draw. Finding and treating severely elevated lead levels can change outcomes, but for less elevated levels, the evidence shows no benefit. You should work with the health department when considering therapy for children with elevated blood lead levels.
Evidence is insufficient to recommend for or against universal screening of young children for lead poisoning in high-prevalence communities (strength of recommendation [SOR]: C). In low-prevalence communities, evidence is insufficient to recommend for or against a targeted screening approach, employing locale-specific demographic risk factors and personal risk questionnaires to inform screening decisions (SOR: C).
Although evidence does not suggest that treatment of individuals with elevated blood lead levels improves individual outcomes, public health strategies aimed at decreasing lead in the environment appear to have resulted in a significant decline in the number of children with elevated blood lead levels in recent decades. One could thus argue that screening may identify communities with high rates of lead poisoning, where environmental strategies could be targeted.
Because the epidemiology of lead poisoning continues to change, local and state health authorities must continuously update information on which to base decisions about screening.
Evidence summary
The prevalence of elevated blood lead levels varies widely among different demographic groups and geographic regions, and it has decreased dramatically in the last several decades. Racial and ethnic minorities and children of families with low incomes, who live in the Northeast or Midwest, or who live in older houses continue to be at increased risk.1 Children with blood lead levels 10 μg/dL have been shown to have poorer cognitive and behavioral functioning.2
No studies have demonstrated that screening for lead poisoning improves outcomes. To justify screening, one must therefore extrapolate from indirect evidence, demonstrating that screening tests are accurate and that treatment of children detected by screening is effective. Capillary blood samples are comparable with venous samples for detecting elevated blood lead levels. The sensitivity of capillary samples ranges from 86% to 96% compared with venous samples.3
In low-prevalence areas, questionnaires may inform screening decisions. A questionnaire inquiring about age of housing, presence of peeling paint, ongoing renovations, siblings or playmates with elevated blood lead levels, adults in the home with occupational exposures to lead, and proximity to industrial sources of lead has a sensitivity for detecting blood lead levels 10 μg/dL ranging from 32% to 87%. Sensitivity varies depending on the population and geographic location in which the questionnaire is tested. Accuracy is improved by tailoring the questionnaire based on locally important risk factors.4
Proposed treatments for elevated blood lead levels include chelation therapy, education about hygiene and nutrition, household dust control measures, and soil lead abatement. No good-quality trials have demonstrated that lowering slightly to moderately elevated blood lead levels (10–55 μg/dL) improves patient-oriented outcomes such as cognitive and behavioral functioning. Although 1 observational study of chelation therapy linked lowering blood lead levels with improved cognitive function,3 a randomized controlled trial showed that chelation had no effect on cognitive or behavioral outcomes.5
All other trials evaluating treatment for lead poisoning looked at the intermediate outcome of blood lead levels. A systematic review of randomized controlled trials showed that home dust control interventions reduced the proportion of children with elevated blood lead levels (15 μg/dL) from 14% to 6%.6 A randomized controlled trial of high-efficiency particulate air (HEPA) filtration vacuuming showed no effect.7 More intensive interventions such as soil lead abatement and paint remediation have not proven effective in good-quality randomized controlled trials.
Increasing dietary calcium and iron and decreasing dietary fat are also commonly recommended for children with elevated blood lead levels, based on animal models and cross-sectional studies. The only randomized controlled trial that investigated calcium supplementation showed no effect on blood lead levels.8 Our search revealed no good-quality studies on the effect of iron or fat intake on lead poisoning.
In summary, because the prevalence of lead poisoning varies between communities and continues to change, standard recommendations are not possible. Clinicians must rely on local epidemiologic data to make screening decisions. Although questionnaires are accurate in predicting elevated blood lead levels in some settings, no specific set of questions can be recommended for all populations.
No treatment options for those with mild to moderate elevations in blood lead levels have been shown to improve clinically important outcomes, although some interventions may decrease blood lead levels.
Recommendations from others
The Centers for Disease Control and Prevention (CDC) recommends
- that individual states develop screening plans based on local data
- universal screening at 12 and 24 months of age:
Otherwise screening should be targeted based on a questionnaire on age of housing, recent or ongoing remodeling, and having a sibling or playmate diagnosed with lead poisoning, in addition to questions on locally important risk factors.9
The American Academy of Pediatrics endorses the CDC recommendations.2 The US Preventive Services Task Force, the American Academy of Family Physicians, and the American College of Preventive Medicine all recommend screening for lead poisoning at 12 months of age in children with demographic or geographic risk factors.3,10,11
Lead screening: Think locally
Julia Fashner, MD
St. Joseph Regional Medical Center, South Bend, Ind
The local health department can provide information about lead screening in your community, whether based on blood levels or the housing conditions. If your patients need screening, you may want to add a reminder on a flow sheet in the chart to do a questionnaire or a blood draw. Finding and treating severely elevated lead levels can change outcomes, but for less elevated levels, the evidence shows no benefit. You should work with the health department when considering therapy for children with elevated blood lead levels.
1. Kaufmann RB, Clouse TL, Olson DR, Matte TD. Elevated blood lead levels and blood lead screening among US children aged one to five years: 1988–1994. Pediatrics 2000;106:E79.-
2. Screening for elevated blood lead levels. American Academy of Pediatrics Committee on Environmental Health. Pediatrics 1998;101:1072-1078.
3. US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Baltimore, Md: Lippincott Williams & Wilkins; 1996.
4. Binns HJ, LeBailly SA, Fingar AR, Saunders S. Evaluation of risk assessment questions used to target blood lead screening in Illinois. Pediatrics 1999;103:100-106.
5. Rogan WJ, Dietrich KN, Ware JH, et al. The effect of chela-tion therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med 2001;344:1421-1426.
6. Haynes E, Lanphear BP, Tohn E, Farr N, Rhoads GG. The effect of interior lead hazard controls on children’s blood lead concentrations: a systematic evaluation. Environ Health Perspect 2002;110:103-107.
7. Hilts SR, Hertzman C, Marion SA. A controlled trial of the effect of HEPA vacuuming on childhood lead exposure. Can J Public Health 1995;86:345-350.
8. Ballew C, Bowman B. Recommending calcium to reduce lead toxicity in children: a critical review. Nutr Rev 2001;59(3 Pt 1):71-79.
9. Centers for Disease Control and Prevention. Screening Young Children for Lead Poisoning: Guidance for State and Local Public Health Officials. Atlanta, Ga: CDC, 1997.
10. AAFP Policy Recommendations for Periodic Health Examinations 2002. Available at http://www.aafp.org/ exam.xml. Accessed on February 9, 2003.
11. Lane WG, Kemper AR. American College of Preventive Medicine Practice Policy Statement. Screening for elevated blood lead levels in children. Am J Prev Med 2001;20:78-82.
1. Kaufmann RB, Clouse TL, Olson DR, Matte TD. Elevated blood lead levels and blood lead screening among US children aged one to five years: 1988–1994. Pediatrics 2000;106:E79.-
2. Screening for elevated blood lead levels. American Academy of Pediatrics Committee on Environmental Health. Pediatrics 1998;101:1072-1078.
3. US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Baltimore, Md: Lippincott Williams & Wilkins; 1996.
4. Binns HJ, LeBailly SA, Fingar AR, Saunders S. Evaluation of risk assessment questions used to target blood lead screening in Illinois. Pediatrics 1999;103:100-106.
5. Rogan WJ, Dietrich KN, Ware JH, et al. The effect of chela-tion therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med 2001;344:1421-1426.
6. Haynes E, Lanphear BP, Tohn E, Farr N, Rhoads GG. The effect of interior lead hazard controls on children’s blood lead concentrations: a systematic evaluation. Environ Health Perspect 2002;110:103-107.
7. Hilts SR, Hertzman C, Marion SA. A controlled trial of the effect of HEPA vacuuming on childhood lead exposure. Can J Public Health 1995;86:345-350.
8. Ballew C, Bowman B. Recommending calcium to reduce lead toxicity in children: a critical review. Nutr Rev 2001;59(3 Pt 1):71-79.
9. Centers for Disease Control and Prevention. Screening Young Children for Lead Poisoning: Guidance for State and Local Public Health Officials. Atlanta, Ga: CDC, 1997.
10. AAFP Policy Recommendations for Periodic Health Examinations 2002. Available at http://www.aafp.org/ exam.xml. Accessed on February 9, 2003.
11. Lane WG, Kemper AR. American College of Preventive Medicine Practice Policy Statement. Screening for elevated blood lead levels in children. Am J Prev Med 2001;20:78-82.
Evidence-based answers from the Family Physicians Inquiries Network