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Heart Failure

L-arginine and coronary outcomes

Citation:

Prior DL, Jennings GLR, Chin-Dusting JPF. Transient improvement of acetylcholine responses after short-term oral L-argininen in forearms of human heart failure. J Cardiovascular Pharmacology. 2000; 36: 3-37.

 
Study Design:
Randomized Crossover Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

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.

Inclusion Criteria:

Heart failure (New York Heart Assocation Functional Class Two and Three).

Exclusion Criteria:
  • 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.
Description of Study Protocol:
  • 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.
Data Collection Summary:

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.

Description of Actual Data Sample:
  • 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.
Summary of Results:

 

Variables

Placebo Visits
Measures and Confidence Intervals

L-arginine Visits
Measures and Confidence Intervals

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.

Author Conclusion:
  • 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.
Funding Source:
Government: national health and medical research council of australia
Reviewer Comments:
  • 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
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