L-arginine and coronary outcomes
To determine whether conflicting results observed between oral and intraarterial administration of L-arginine in heart failure patients were attributable to a short-lived effect of the drug.
Heart failure (New York Heart Assocation Functional Class Two and Three).
- Subjects were excluded if they had conditions reported to cause abnormal endothelium-dependent vascular responses independent of the presence of heart failure including smoking
- Drinking more than three standard alcoholic drinks per day
- Systolic blood pressure over 140mmHg
- Diastolic blood pressure over 90mmHg
- Total serum cholesterol levels more than 6.2mMsaf
- Diabetes.
- Recruitment: Patients who were being assessed for or who were awaiting cardiac transplantation.
Design
- Blood flow measurement was performed by using forearm venous occlusion plethysmography
- The blood flow to the hand was excluded by using a cuff placed at the wrist, which was inflated at the time of blood flow measurements
- Venous occlusion was achieved with a brachial cuff and rapid cuff inflator.
- Baseline measurements: Basal blood flow measurements were taken
- The brachial cuff was inflated to produce forearm ischemia for five minutes
- On release of the cuff, the post-ischemia hyperemic response was recorded for three minutes
- Complete data was obtained in 13 patients
- Responses to intrarterial infusion of acetylcholine and sodium nitroprusside were then obtained (N=18), followed by responses to norepinephrine (N=10).
- Basal blood flow, hyperemic response to ischemia and responses to acetylcholine, sodium nitroprusside and norepinephrine were then measured at 60, 120 and 180 minutes after dosage of L-arginine or placebo. Patients were crossed over 14 days later.
Blinding Used
Double-blind.
Intervention
All patients received 20g of L-arginine or placebo orally in 60ml of aromatic syrup.
Statistical Analysis
- Data presented as mean±SEM
- Comparison between measurements at baseline pre-arginine vs. pre-placebo were made by students' paired T-test
- Measurements made at different timepoints after drug administration were compared by two-way repeated-measures analysis of variance
- Post-hoc analysis of significant differences between placebo and l-arginine visits was made by using a paired T-test.
- A two-tailed P-value of under 0.05 was considered significant.
Timing of Measurements
- Before and after infusion of test drug
- Crossover 14 days later.
Dependent Variables
- Plasma L-arginine levels at baseline and at 60, 120 and 180 minutes after oral supplementation
- Resting forearm blood and mean arterial blood pressure at baseline and 60, 120 and 180 minutes after oral supplementation
- Plasma nitriate and nitrite levels before and after treatment
- Blood flow response to ischemia measured as the area under the curve (AUC) for the three-minute period from the peak response at baseline and after supplementation with L-arginine or placebo
- Blood flow responses to infusions of acetylcholine before and after treatment
- Blood flow responses to infusions of sodium nitroprusside and norepinephrine before and after treatment, etc.
Independent Variables
20g of L-arginine orally in 60ml of aromatic syrup.
Control Variables
20g of placebo orally in 60ml of aromatic syrup.
- Initial N: 18
- Attrition (final N): Varied by test
- Age: Mean age was 51.1±2.3 years
- Ethnicity: Not noted
- Other relevant demographics: 13 men, five women
- Location: Australia.
Variables |
Placebo Visits |
L-arginine Visits |
Statistical Significance of Group Difference |
Baseline Forearm Blood Flow |
2.39±0.25ml/100ml tissue/min |
2.29±0.34ml/100ml tissue/min |
NS |
Pre-Treatment L-arginine Levels |
97.1±6.4mcg/M |
100.5±6.2mcg/M |
NS |
Response to Acetylcholine at 60 Minutes |
413±64% |
587±94% |
P<0.05 |
Response to Acetylcholine at 180 Minutes |
425±74% |
532±71% |
NS |
Other Findings
Blood L-arginine levels increased four-fold with arginine infusion and remained high throughout the test, but the increased response to acetylcholine was not significantly different by 120 minutes.
- Short-term oral supplementation of L-arginine in heart failure results in a marked increase in plasma L-arginine levels, which is sustained for a period of 180 minutes
- Brief oral supplementation improves forearm vasodilator responses to acetylcholine
- The enhanced vasodilator response is only transient and no longer present after 180 minutes, despite persistent elecvation of plasma L-arginien levels.
Government: | national health and medical research council of australia |
- This clinical significance of transient improvements in forearm vasodilator response to acetylcholine remains to be proven
- The study N was smaller for some tests (e.g. norepinephine, N=10), with no explanation.
Medication
The study protocol states that nitrate-containing medications were withheld for 24 hours before each study and all other medications except diuretics were withheld on the day of the study.
Quality Criteria Checklist: Primary Research
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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? | N/A | |
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? | Yes | |
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? | ??? | |
3. | Were study groups comparable? | N/A | |
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.) | Yes | |
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? | ??? | |
4.1. | Were follow-up methods described and the same for all groups? | ??? | |
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%.) | No | |
4.3. | Were all enrolled subjects/patients (in the original sample) accounted for? | Yes | |
4.4. | Were reasons for withdrawals similar across groups? | ??? | |
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? | N/A | |
5.1. | In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? | Yes | |
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.) | Yes | |
5.3. | In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? | N/A | |
5.4. | In case control study, was case definition explicit and case ascertainment not influenced by exposure status? | N/A | |
5.5. | In diagnostic study, were test results blinded to patient history and other test results? | Yes | |
6. | Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? | N/A | |
6.1. | In RCT or other intervention trial, were protocols described for all regimens studied? | Yes | |
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? | Yes | |
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? | Yes | |
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? | Yes | |
6.8. | In diagnostic study, were details of test administration and replication sufficient? | Yes | |
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? | Yes | |
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? | ??? | |
8. | Was the statistical analysis appropriate for the study design and type of outcome indicators? | N/A | |
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)? | N/A | |
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? | N/A | |
9. | Are conclusions supported by results with biases and limitations taken into consideration? | N/A | |
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? | N/A | |
10.1. | Were sources of funding and investigators' affiliations described? | Yes | |
10.2. | Was the study free from apparent conflict of interest? | Yes | |