|MP 2.04.23||Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/4:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Homocysteine is an amino acid found in the blood; levels are inversely correlated with folate levels. Homocysteine has been evaluated as a potential marker of cardiovascular disease (CVD) in the general population and as a potential risk marker among people with CVD. The association between homocysteine-lowering interventions and risk of CVD has also been examined.
Homocysteine is a sulfur-containing amino acid that is rapidly oxidized in plasma into homocysteine and cysteine-homocysteine disulfide. Measurement of total plasma homocysteine is the sum of homocysteine and its oxidized forms. The laboratory test is referred to as either homocysteine or homocyst(e)ine.
Plasma levels of homocysteine have been actively researched as a risk factor for CVD, initially based on the observation that patients with hereditary homocystinuria, an inborn error of metabolism associated with high plasma levels of homocysteine, had a markedly increased risk of CVD. Subsequently, prospective epidemiologic studies were conducted to determine if an elevated plasma level of homocysteine was an independent risk factor for CVD and could be used to improve current risk prediction models.
Interest in homocysteine as a potentially modifiable risk factor has been stimulated by the epidemiologic finding that levels of homocysteine are inversely correlated with levels of folate. This finding has raised the possibility that treatment with folic acid might lower homocysteine levels and, in turn, reduce the risk of CVD. Therefore, homocysteine has potential utility both as a risk predictor and as a target of treatment.
Determination of homocysteine concentration may be offered as a component of a comprehensive cardiovascular risk assessment that may include evaluation of small-density lipoproteins, subclassification of high-density lipoproteins, evaluation of lipoprotein (A), high-sensitivity C-reactive protein, and genotyping of apolipoprotein E.
Several homocysteine test systems have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. These include the liquid-stable 2-part homocysteine reagent test by Catch Inc. (Maple Valley, WA) in 2006. Catch Inc. was purchased by Axis-Shield (Scotland) in 2010 and the Catch branded products were phased out in 2011. The test is indicated for the in vitro quantitative determination of total homocysteine in serum and plasma to assist in diagnosing and treating patients with suspicion of homocystinuria and hyperhomocysteinemia. Other homocysteine test systems cleared for marketing by FDA include the Diazyme Enzymatic Homocysteine Assay (General Atomics, Poway, CA) cleared in 2012, and the A/C Automatic Enzymatic Hcy [Homocysteine] Assay (AntiCancer Inc., San Diego, CA) cleared in 2008.
Measurement of plasma levels of homocysteine is considered investigational in the screening, evaluation, and management of patients for cardiovascular disease.
There is a CPT code specific to this test:
BlueCard/National Account Issues
Determination of homocysteine may be included as a component of a comprehensive cardiovascular risk assessment offered by reference laboratories. Comprehensive risk assessment may include evaluation of small low-density lipoproteins, subclassification of high-density lipoproteins, evaluation of apolipoprotein E genotype or phenotype, total plasma homocysteine, apolipoprotein B, and lipoprotein A.
This policy was originally created in 2001 and was updated regularly with searches of the MEDLINE database. The most recent literature review was performed through February 26, 2014. Following is a summary of the key literature to date:
Homocysteine testing can be evaluated in a similar framework as other novel cardiac risk factors. There are several conditions that must be met for a cardiovascular risk factor to demonstrate clinical utility. A 2002 TEC Assessment(1) summarized 3 steps necessary for clinical utility:
- Standardization of measurement of the risk factor.
- Determination of its contribution to risk assessment. As a risk factor, it is important to determine whether the novel risk factor contributes independently to risk assessment compared with established risk factors.
- Determination of how the novel risk factor will be used in the management of the patient, compared with standard methods of assessing risk, and whether any subsequent changes in patient management result in an improvement in patient outcomes.
Is measurement of homocysteine standardized?
There are FDA-cleared commercially available kits for measuring homocysteine.
Is homocysteine an independent risk factor for cardiovascular disease?
In 2002, the Homocysteine Studies Collaboration published a meta-analysis of observational studies evaluating the association between homocysteine concentration and risk of ischemic heart disease (IHD) or stroke.(2) A total of 30 studies were identified that had individual patient data available; this included 18 retrospective studies and 13 prospective studies. In the prospective studies, blood for measuring homocysteine concentration was collected before the clinical onset of disease. The adjusted odds ratio (OR) of ischemic heart disease associated with a 25% lower homocysteine level was 0.83 (95% confidence interval [CI], 0.77 to 0.89) in prospective studies, 0.67 (95% CI, 0.62 to 0.71) in retrospective studies using population controls, and 0.73 (95% CI, 0.64 to 0.83) in retrospectives studies with other controls. The adjusted OR of stroke associated with a 25% lower homocysteine level was 0.77 (95% CI, 0.66 to 0.90) in prospective studies, 0.86 (95% CI, 0.73 to 1.01) in retrospective studies with population controls, and 0.46 (95% CI, 0.30 to 0.70) in retrospective studies with other controls. The risk of IHD and stroke was significantly weaker in the prospective studies than the retrospectives studies, which may reflect biases in retrospective studies.
Among the prospective studies was one by Folsom et al that identified patients who developed coronary heart disease (CHD) among an initial cohort of 15,792 patients participating in the Atherosclerosis Risk in Communities (ARIC) trial.(3) The median follow-up time was 3.3 years. Plasma homocysteine was evaluated from the stored blood samples of the 232 patients plus a random sample of the rest of the cohort. While homocysteine was a significant univariate predictor of coronary artery disease (CAD), this association was not significant after adjusting for other cardiac risk factors in multivariate analysis. Another prospective study was published by Evans et al.(4) The investigators identified 240 cases of nonfatal myocardial infarction (MI) or coronary death among a cohort of 12,866 men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Homocysteine from stored blood samples from these patients plus 472 control patients were evaluated. With a follow-up ranging from 11 to 17 years, homocysteine levels did not appear to be an independent risk factor for CHD. In contrast, in a nested case-control study derived from a prospective cohort study of 21,520 men enrolled in the British United Provident Study, Wald et al reported that the initial stored plasma level of homocysteine was significantly higher among 229 men who ultimately died of IHD compared with a control group of 1126 men who did not die of IHD and did not have a history of IHD.(5)
For patients with known cardiovascular disease (CVD), prospective data more consistently support the utility of homocysteine as a risk factor for future events. In 1997, for example, Nygard et al reported on a prospective study of the plasma homocysteine levels in 587 patients with angiographically confirmed CAD.(6) After a median follow-up of 4.6 years, the authors compared the initial homocysteine levels of the 64 patients (10.9%) who had died with those of the remaining 523 survivors. The authors reported a strong graded dose-response relationship between plasma homocysteine and mortality. In addition, Knekt et al reported the outcomes at 13-year follow-up for 3471 middle-aged Finnish men, 884 of whom had known CVD at baseline.(7) Using the homocysteine values from stored blood samples, a strong positive correlation was noted between homocysteine concentration and subsequent major coronary events in men with known CVD at baseline. However, they found no association between serum homocysteine concentration and the incidence of major coronary events (death from CHD or nonfatal MI) among men originally free of heart disease.
Since the publication of the Homocysteine Studies Collaboration meta-analysis, a number of studies have reported on the association between homocysteine and CVD. In 2010, Park et al published an analysis of data from a large nationally representative survey of U.S. residents.(8) The analysis was restricted to the 6371 individuals aged 40 to 79 years who had no history of MI, stroke, peripheral artery disease, or stroke. The investigators stratified participants according to their estimated 10-year risk of CVD, using the Framingham risk score; low-risk, less than 10% (n=2527), intermediate-risk, 10% to 20% (n=3336), and high-risk, greater than 20% (n=508). Information on homocysteine level was available for 3860 (61%) patients. There was a statistically significant association between elevated homocysteine levels (defined as at least the 85th percentile) and being categorized as having a high 10-year risk of CVD (OR=2.11; 95% CI, 1.48 to 3.01). The association between elevated homocysteine levels and intermediate cardiovascular risk was not significant (OR=1.11; 95% CI, 0.89 to 1.38). The survey was cross-sectional rather than prospective, limiting possible/potential conclusions about the predictive value of homocysteine levels.
In 2011, Veeranna et al published a posthoc analysis of national survey databases to evaluate whether adding homocysteine to the Framingham risk score model improves risk classification.(9) The data were taken from the nationally representative surveys Multi-Ethnic Study of Atherosclerosis (MESA), which included subjects between the ages of 45 and 84 years with no prior history of CVD and the National Health and Nutrition Survey III (NHANES III), a sample of noninstitutionalized subjects. Homocysteine level was associated with CVD risk in both databases. In a receiver-operating curve analysis, the area under the curve (AUC) for predicting CHD events in the MESA database was 0.74 using the Framingham risk score and 0.76 when homocysteine level was added to the Framingham score. The improvement in risk prediction was statistically significant (p<0.001). The AUC for predicting CHD deaths in NHANES III was 0.84 using the Framingham risk score alone and 0.87 when homocysteine level was added to the Framingham score; this difference was statistically significant (p<0.001). Adding homocysteine to the Framingham model resulted in reclassification of 832 (12.9%) subjects in the MESA cohort and 1243 (18%) in the NHANES III cohort. This study does not address whether testing for homocysteine would improve health outcomes. This would involve evaluating the impact of homocysteine-lowering interventions on risk of CVD, which is discussed in the next section of the policy.
A meta-analysis of observational studies found a statistically significant moderate association between homocysteine levels and risk of CVD. Studies have also found a significant correlation between homocysteine levels in patients with known CVD and subsequent coronary events. One recent study analyzing nationally representative survey data found that adding homocysteine level to the Framingham risk score significantly improved risk prediction.
Will identification of homocysteine level lead to changes in patient management, and will these changes in management lead to improved patient outcomes?
Vitamin B and folic acid supplementation are potential interventions that could be used for patients with homocysteine levels to improve health outcomes. However, public health measures are already in place that require all enriched grain products be fortified with folic acid to reduce the risk of neural-tube defects in newborns. This fortification has been associated with a decrease in plasma homocysteine concentration in a population-representative adult sample.(10) Trials evaluating the impact of homocysteine-lowering therapy on health outcomes should thus evaluate the utility of treatments that lower homocysteine levels beyond those achieved by these general public health measures. In addition, clear target levels for homocysteine concentration would need to be established for translating information on homocysteine lowering into clinical practice.
Numerous randomized controlled trials (RCTs) have been published that provide evidence on the benefit of vitamin therapy to reduce homocysteine levels and prevent cardiovascular events. Moreover, several meta-analyses have synthesized the available RCT evidence on this question. Most recently, in 2013, a Cochrane systematic review on the effectiveness of homocysteine-lowering interventions for preventing cardiovascular events, including both MI and stroke, was updated.(11) The review included trials that recruited adults with established CVD and had at least 1 year of follow-up and excluded trials with end-stage renal disease patients. Twelve trials with a total of 47,429 subjects met eligibility criteria. Nine of the studies included more than 1000 participants. Nine studies used placebo controls, 2 used usual care controls and 1 compared high and low doses of homocysteine-lowering therapy. In a pooled analysis of 11 trials, there was no statistically significant difference in nonfatal or fatal MI between intervention and control groups (relative risk [RR], 1.02; 95% CI, 0.95 to 1.10). In a pooled analysis of 9 studies, there was no significant difference between groups in the rate of nonfatal or fatal stroke (RR=0.91; 95% CI, 0.82 to 1.00). There was also no significant mortality benefit in groups assigned to homocysteine-lowering therapy. For mortality of any cause, the relative risk was 1.01 (95% CI, 0.96 to 1.07) in a meta-analysis of data from 10 trials.
In 2011 Zhou et al conducted a systematic review of double-blind placebo-controlled RCTs evaluating the impact of folic acid supplementation on cardiovascular outcomes.(12) Interventions were included whether or not they involved supplementation with vitamin B in addition to folic acid. The review was limited to trials that included at least 100 patients and had at least 6 months follow-up. Of 66 articles retrieved for detailed inspection, 16 trials with data on 44,841 patients met the review’s inclusion criteria. In a meta-analysis of findings from 12 trials, folic acid supplementation was not found to have a significant effect on major cardiovascular events compared with placebo (RR=0.98; 95% CI, 0.93 to 1.04). In addition, folic acid supplementation did not have a significant effect on individual outcomes including stroke (12 trials; RR=0.89; 95% CI, 0.78 to 1.01), MI (11 trials; RR=1.00; 95% CI, 0.93 to 1.07), or all-cause mortality (14 trials; RR=1.00, 95% CI, 0.96 to 1.05).
Also in 2011, Clarke et al published a meta-analysis of placebo-controlled homocysteine-lowering RCTs.(13) This meta-analysis was limited to studies that included at least 1000 participants and have at least 1 year of follow-up. A total of 8 trials with 37,485 individuals met the review’s inclusion criteria. In a pooled analysis of findings from the 8 trials, vitamin B supplementation did not have a significant effect on risk of CHD events compared with placebo (RR=1.01; 95% CI, 0.96 to 1.07). In addition, in pooled analyses of data from the 8 trials, vitamin B supplementation was not found to have a significant effect on stroke events (RR=0.96; 95% CI, 0.87 to 1.07), cancer events (RR=1.08; 95% CI, 0.99 to 1.17) or all-cause mortality (RR=1.02; 95% CI, 0.97 to 1.07).
A fourth meta-analysis, published in 2012 by Huang et al, included RCTs evaluating B vitamin supplementation in patients with preexisting vascular disease.(14) This review had more lenient inclusion criteria, as there was no limitation on study size or intervention duration. A total of 19 trials with 47,921 patients were included in the meta-analysis. Unlike the other meta-analyses previously discussed, in a pooled analysis of study data, the authors found a statistically significant benefit of vitamin B supplementation on stroke (RR=0.88; 95% CI, 0.82 to 0.95). Similar to the other meta-analyses, vitamin B supplementation was not found to have a statistically significant impact on other outcomes, including CHD, MI, and all-cause mortality. Given the more relaxed entry criteria, the meta-analysis may have included some lower-quality studies; the authors did not present a formal analysis of trial quality.
Representative RCTs are described next:
The HOPE-2 trial included 5522 patients with preexisting vascular disease. Patients were randomized to treatment with a regimen of folate, vitamin B6, and vitamin B12 or placebo and followed up for an average of approximately 5 years.(15) There were no significant differences in the composite outcome of cardiovascular death, MI, or stroke (RR=0.95; 95% CI, 0.84 to 1.07). However, there was a significant decrease in the risk of stroke for patients in the treatment group (RR=0.75; 95% CI, 0.59 to 0.97; p=0.03). For the secondary outcome of hospitalization for unstable angina, a significantly increased risk was reported for the treatment group (RR=1.24; 95% CI, 1.04 to 1.49; p=0.02).
The NORVIT enrolled 3749 patients with a recent MI and randomized patients to combinations of folate and/or B vitamins.(16) Patients were followed up for a mean of 3.3 years for the primary outcome, which was a composite of recurrent MI, stroke, and sudden cardiac death. For patients assigned to the active treatment groups, no significant reductions were noted in any of the primary or secondary outcomes. For patients assigned to the combined folate/vitamin B6/vitamin B12 group, an increased risk that was marginally significant (RR=1.22; 95% CI, 1.00 to 1.50; p=0.05) was observed for the primary composite outcome group.
In 2010, findings from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) in the U.K. were reported.(17) A total of 12,064 adult patients with a history of MI were randomized to receive folic acid and vitamin B12 or placebo. An additional eligibility criterion was blood cholesterol of at least 135 mg/dL if taking a statin or 174 mg/dL otherwise. Before randomization, patients participated in a run-in period to confirm that they were adherent to treatment. (Patients were also randomized to receive different doses of simvastatin; those findings are not reported here.) After 3 to 4 years of follow-up, due to the low number of major coronary events in the treatment group, the steering committee (blinded to interim between-group outcomes) decided to change the primary outcome from major coronary events to major vascular events. This composite variable included nonfatal MI, death from CHD, fatal or nonfatal stroke, or any arterial revascularization. After a mean follow-up of 6.7 years, vitamin treatment was not associated with a statistically significant reduction in the primary outcome. The number of major vascular events were 1537 (25.5%) in the vitamin group and 1493 (24.8%) in the placebo group (RR=1.04; 95% CI, 0.97 to 1.12). There were no significant differences in risk for any of the components of the composite outcome. In addition, death from all causes did not differ significantly between groups; there were 983 (16.3%) deaths in the vitamin group and 951 (15.8%) in the placebo group (RR=1.04; 95% CI, 0.96 to 1.13).
Numerous large placebo-controlled RCTs have been published that evaluate the impact of folic acid/ vitamin B supplementation on risk of cardiovascular events, including MI and stroke. With few exceptions, meta-analyses of these RCTs have found that homocysteine-lowering interventions do not have a statistically significant effect on the rate of major cardiovascular events.
Ongoing and Unpublished Clinical Trials
A search of website ClinicalTrials.gov on February, 26, 2014with the term homocysteine identified several ongoing trials evaluating the role of homocysteine in CVDs. There was 1 comparative trial currently enrolling patients:
- Efficacy of Amlodipine-Folic Acid Tablets on Reduction of Blood Pressure and Plasma Homocysteine (NCT01956786). This study randomizes patients with elevated blood pressure, plasma homocysteine 10 micromole/L or more, and ACE-inhibitor intolerance to an active comparator group of amlodipine or an amlodipine-folic acid combination, with either a high or low dose of folic acid. Enrollment is planned for 540 subjects; the planned study completion date is February 2014.
Observational evidence generally supports the association of homocysteine levels with risk of cardiovascular disease, especially in patients with preexisting vascular disease. However, evidence from randomized controlled trials (RCTs) does not support the hypothesis that lowering homocysteine levels by treatment with folate and/or B vitamins improves cardiovascular outcomes. Numerous large RCTs and meta-analyses of these trials are consistent in reporting that homocysteine-lowering treatment is ineffective in reducing major cardiovascular events. Due to the large amount of evidence from placebo-controlled RCTs that homocysteine-lowering interventions do not improve health outcomes, routine testing for homocysteine and intervention for patients with hyperhomocysteinemia is considered investigational.
Practice Guidelines and Position Statements
In 2009, the U.S. Preventive Services Task Force issued a recommendation statement that the evidence is insufficient (one statement) to assess the benefits and harms of using nontraditional risk factors to screen asymptomatic adults with no history of coronary heart disease (CHD) to prevent CHD events. Homocysteine was one of the nontraditional risk factors considered in the recommendation.(18)
A 2010 statement (updated March 2014) issued by the American Heart Association states that the organization does not consider high homocysteine levels in the blood to be a major risk factor for cardiovascular disease.(19) It further states that a causal link between homocysteine levels and atherosclerosis has not been established.
A 2010 guideline from the American College of Cardiology Foundation and the American Heart Association on assessment of cardiovascular risk in asymptomatic adults did not address measurement of homocysteine levels.(20)
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). C-reactive protein as a cardiac risk marker (special report). TEC Assessments 2002; 17 Tab 23.
- The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288(16):2015-22.
- Folsom AR, Nieto FJ, McGovern PG et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1998; 98(3):204-10.
- Evans RW, Shaten BJ, Hempel JD et al. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 1997; 17(10):1947-53.
- Wald NJ, Watt HC, Law MR et al. Homocysteine and ischemic heart disease: results of a prospective study of implications regarding prevention. Arch Intern Med 1998; 158(8):862-7.
- Nygard O, Nordrehaug JE, Refsum H et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337(4):230-6.
- Knekt P, Reunanen A, Alfthan G et al. Hyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med 2001; 161(13):1589-94.
- Park CS, Ihm SH, Yoo KD et al. Relation between C-reactive protein, homocysteine levels, fibrinogen and lipoprotein levels and leukocyte and platelet counts, and 10-year risk for cardiovascular disease among healthy adults in the USA. Am J Cardiol 2010; 105(9):1284-88.
- Veeranna V, Zalawadiya SK, Niraj A et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol 2011; 58(10):1025-33.
- Jacques PF, Selhub J, Bostom AG et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340(19):1449-54.
- Marti-Carvajal AJ, Sola I, Lathyris D et al. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2013; 1:CD006612.
- Zhou YH, Tang JY, Wu MJ et al. Effect of folic acid supplementation on cardiovascular outcomes: A systematic review and meta-analysis. PLoS ONE 2011; 6(9-Jan):e25142.
- Clarke R, Halsey J, Bennett D et al. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis 2011; 34(1):83-91.
- Huang T, Chen Y, Yang B et al. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clin Nutr 2012; 31(4):448-54.
- Lonn E, Yusuf S, Arnold MJ et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354(15):1567-77.
- Bonaa KH, Njolstad I, Ueland PM et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354(15):1578-88.
- Cholesterol SotEoARi, Homocysteine Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 2010; 303(24-Jan):2486-94.
- Force USPST. Using Nontraditional Risk Factors In Coronary Heart Disease Risk Assessment, Topic Page. 2009. Available online at: http://www.uspreventiveservicestaskforce.org/uspstf/uspscoronaryhd.htm. Last accessed March, 2014.
- American Heart Association. AHA Recommendation: Homocysteine, Folic Acid and Cardiovascular Risk. Available online at: http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/Homocysteine-Folic-Acid-and-Cardiovascular-Disease_UCM_305997_Article.jsp. Last accessed March, 2014.
- Greenland P, Alpert J. S., Beller G. A. et al. American College of Cardiology Foundation American Heart Association Task Force on Practice Guidelines: 2010 ACCF/AHA guideline for assessment of cardiovascular risk on asymptomatic adults. Circulation 2010; 122:e584-636.
|ICD-9 Diagnosis||Investigational for all cardiovascular disease codes|
|ICD-10-CM (effective 10/1/15)||Investigational for all cardiovascular disease codes|
|I25.10-I25.119||Atherosclerotic heart disease of native coronary artery|
|I25.700-I25.799||Atherosclerosis of coronary artery bypass graft(s) and coronary artery of transplanted heart with angina pectoris|
|Z13.6||Encounter for screening for cardiovascular disorders|
|ICD-10-PCS (effective 10/1/15)||Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.|
|Type of Service||Pathology/Laboratory|
|Place of Service||Outpatient|
Cardiovascular Risk Assessment, Homocysteine
|05/31/01||Add to Medicine section||New policy|
|04/29/03||Replace policy||Policy updated; no change in policy statement; new references added|
|11/9/04||Replace policy||Policy updated with literature search; no change in policy statement; new references added|
|08/17/05||Replace policy||Policy updated with literature search; no change in policy statement, references 18 and19 added|
|10/10/06||Replace policy||Policy updated with literature search; no change in policy statement; reference numbers 24 to 26 added.|
|02/14/08||Replace policy||Policy updated with literature search. No change in policy statement. References 27-29 added.|
|04/24/09||Replace policy||Policy extensively revised with literature search; previous updates condensed. References condensed and reordered; reference numbers 12, 15, 17, and 20 added. No change to policy statement|
|4/14/11||Replace policy||Policy updated with literature review. References 9, 19-20, 22, 25-27 added; other references reordered. No change to policy statement.|
|04/12/12||Replace policy||Policy updated with literature review. References 1, 9, 11 and 12 added; other references renumbered or removed. No change to policy statement.|
|04/11/13||Replace policy||Policy updated with literature review through March 6, 2013. References 11 and 14 added; other references renumbered or removed. No change to policy statement. The MPP decided to retain the policy in active status.|
|4/10/14||Replace policy||Policy updated with literature review through February 26, 2014; no references added; no change to policy statement. Rationale section reorganized and editorial changes made.|