Heart Failure

L-arginine and coronary outcomes


Bednarz B, Jaxa-Chamiec T, Gebalska J, Herbaczynska-Cedro K, Ceremuzynski L. L-arginine supplementation prolongs exercise capacity in congestive heart failure. Kardiol Pol. 2004, Apr; 60 (4): 348-353.

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

To investigate the effect of oral supplementation with L-arginine on exercise capacity and markers of oxidative stress in patients with mild to moderate CHF.

Inclusion Criteria:
  • New York Heart Association Class II to III heart failure
  • Ejection fraction (EF) below 40%.
Exclusion Criteria:
  • Overt atherosclerotic peripheral disease
  • Impairment of renal or liver function.
Description of Study Protocol:


Patients with CHF admitted to the department of Cardiology at Grochowski Hospital because of exacerbation of their disease.


  • Patients were randomized to L-arginine or placebo
    • Blood was drawn from the antecubital vein and an exercise test was performed
    • After seven-day treatment with L-arginine (three g orally, three times daily) or placebo (matching capsules of saccharum lactis), blood sampling and exercise test were repeated
    • After seven days of wash-out, the treatment was crossed-over for another seven days when final blood samples and exercise tests were performed.
  • Exercise tests were performed on Marquette CASE 12 treadmill exercise system, according to the modified Naughton protocol with increments of approximately one MET at each two-minute stage
    • Tests were performed the same time of day under identidal conditions
    • Patients were asked to exercise until fatigue or dyspnea forced them to stop.

Blinding Used


Intervention (if applicable) 

Seven-day treatment with L-arginine (three grams orally, three times daily) vs. placebo.

Statistical Analysis

  • Per author's statement, data are presented as mean ±SD
  • Student's T-test was used for analysis of normally distributed data
  • Wilcoxon signed ranks test based on analysis of median values was applied in case of abnormal distribution
  • Statistical significance was defined as P<0.05.

[Reviewer's note: Data tables referred to in the text were not included in the article made available for review.]

Data Collection Summary:

Timing of Measurements

Baseline, then at seven-day intervals.

Dependent Variables

  • Variable One: Total exercise time, calculated based on time to exhaustion
  • Variable Two: Maximal work load, in METS (METS not defined)
  • Variable Three: Serum urea, creatinine and electrolytes, by "routine laboratory methods"
  • Variable Four: Lipid peroxides, by method of Buege and Aust
  • Variable Five: Sulphydryl groups, by the method of Ellman
  • Variable Six: Oxygen free radical production, by lucigenin-amplified chemiluminescence, using a whole blood lumi-aggregometer.

Independent Variables

Oral administration of L-arginine: Three grams, three times a day for seven days.

Control Variables

Matching capsules of saccharum lactis for seven days.

Description of Actual Data Sample:
  • Initial N: 21 patients
  • Attrition (final N): 17 patients
  • Location: Poland.
Summary of Results:

[Reviewer's note: Data tables referred to in the text were not available for review.]

Other Findings

Authors found higher prolongation of exercise duration time after L-arginine than with placebo (99±106 vs. 70±99, P<0.05; units of measurement not defined, perhaps seconds).

Author Conclusion:
  • In patients with chronic stable CHF, oral supplementation with L-arginine prolongs exercise duration, which may be due to NO-induced peripheral vasodilatation
  • The antioxidant properties of L-arginine have not been confirmed in this ex-vivo study.
Funding Source:
Foundation associated with industry:
Reviewer Comments:
  • This was a well-designed study, which tested the effect of a feasible treatment on clinically-significant outcomes
  • However, the lack of critical data tables referred to in the text made it difficult to evaluate this article fully.


The medications taken by the study subjects were not described, but a statement was made that medications were unchanged before and during 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? No
  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) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? ???
  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? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  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? Yes
5. Was blinding used to prevent introduction of bias? Yes
  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? Yes
  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? No
  6.6. Were extra or unplanned treatments described? No
  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? ???
  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)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  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? 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