EAL

DLM: Homocysteine, Folate, B-12 (2001)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To study the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease (CAD).

Inclusion Criteria:

Adult patients of both sexes who underwent diagnostic coronaryangiography.

Exclusion Criteria:

Previous percutaneous transluminal coronary angioplasty (PTCA)
Prior MI
Free of CAD.

Description of Study Protocol:

802 consecutive adult patients undergoing coronary angiography at a university hospital, Bergen, Norway
Follow-up for five years
Definition of CAD: Stenosis of more than 50% on angiography with scoring for degree of stenosis
Baseline data collected:
- Questionnaire: History of angina, HTN, diabetes, MI, family history of CVD, other diseases, use of medications, smoking history and if following a lipid-lowering diet
- Blood sample for lipids, homocysteine (hcy) and folate.

Data Collection Summary:

Median follow-up time: 4.6 years
64 patients
10.9% died; 50 died of CVD
After four years, 3.8% of patients with hcy levels less than 9mmol per L had died compared to 24.7% of those with hcy levels greater than15.0mmol per L
When patients with a hcy level less than 9mmol per L were used as the reference group, the mortality ratios were 1.9 for patients with hcy levels of 9.0 to 14.9mmol per L, 2.8 for those with levels of 15.0 to 19.9mmol per L and 4.5 for those with levels of 20.0mmol per L or higher (P for trend=0.02)
After adjustment for age and sex, the strongest predictors of the total hcy level were serum folate level (r=-0.36, P<0.001), serum vitamin B₁₂ level (r=-0.15, P<0.001) and the left ventricular ejection fraction (r=0.13, P<0.001).

Description of Actual Data Sample:

587 subjects had complete data (478 men; 109 women)
Median age of 62 years.

Summary of Results:

After a median follow-up of 4.6 years, 64 patients (10.9%) had died. Authors found a strong, graded relation between plasma homocysteine levels and overall mortality.
After four years, 3.8% of patients with hcy levels below micromole (µmol) per liter had died, as compared with 24.7% of those with hcy levels of 15µmol per liter or higher. Homocysteine levels were only weakly related to the extent of CAD, but were strongly relatedto the history with respect to MI, the left ventricular ejection fraction and the serum creatinine level.
The relation of hcy levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with hcy levels below 9µmol per liter were used as the reference group, the mortality ratios were 1.9 for patients with hcy levels of 9.0 to 14.9µmol per liter, 2.8 for those with levels of 15.0 to 19.9µmol per liter and 4.5 for those with levels of 20.0µmol per liter or higher (P for trend=0.02). When death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between hcy levels and mortality was slightly strengthened.
The extent of CAD (graded as no coronary artery disease or single-vessel, two-vessel, or three-vessel disease) was only weakly related to the total hcy level, but was strongly associated with the lipid-related factors.

Biochemical measurements according to the extent of CAD among men who underwent cardiac catheterization for suspected ischemic heart disease in 1991 or 1992*

Variable	No. of Main Coronary Arteries with Clinically Significant Stenosis				P-value for Linear Trend
	0	1	2	3
No. of Patients	51	94	172	321
Total Homocysteine (µmol/L)
Mean	10.4	10.9	10.9	11.4	0.05
95% CI	9.53-11.4	10.2-11.6	10.4-11.4	11.0-11.8
Total Cholesterol (mmol/L)					<0.001
Mean	6.32	6.69	6.76	7.01
95% CI	5.92-6.72	6.40-6.97	6.55-6.95	6.86-7.16
High-density lipoprotein cholesterol (mmol/L)	0.04
Mean	1.20	1.03	1.04	1.04
95% CI	1.10-1.29	0.96-1.10	0.99-1.09	1.00-1.07
Lp(a) lipoprotein (U/L)					<0.001
Mean	115	206	303	305
95% CI	80.0-164	160-266	251-364	266-350

*The levels have been adjusted for differences in sex and age between the groups. Log-transformed levels of homocysteine and Lp (a) lipoprotein were used in the analysis. Total homocysteine was measured in plasma, and cholesterol and Lp (a) lipoprotein in serum. To convert values for cholesterol to milligrams per deciliter, divide by 0.02586. CI denotes confidence interval.

Author Conclusion:

Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease
This prospective study does not prove a casual relationship between total homocysteine and mortality, but our results should strongly serve as an additional strong incentive to the initiation of intervention trials with homocysteine-lowering therapy.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

This is a prospective cohort study very well-written paper
The results are showing significant relationship of homocysteine and CAD events
Further studies are required to study the relationship of change in folic acid, vitamin B₁₂ and homocysteine levels and CVD risk and events in different population groups
The extent of coronary artery disease (graded as no CAD or single-vessel, two-vessel, or three-vessel disease) in relation to vitamin B₁₂, folic acid deficiency or low status levels in relation to homocysteine levels in different population groups need to be studies in future.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	???
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	???
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		???
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	???
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	???
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	???
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	???
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	N/A
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	???
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes