EAL

HF: Thiamine (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess the clinical and hemodynamic effects of thamine repletion in patients with moderate to severe congestive heart failure, who had received long-term ferosemide therapy.

Inclusion Criteria:

Chronic congestive heart failure (CHF)
NYHA Class Two to Four, due to chronic ischemic heart disease or idiopathic dilated cardiomyopathy
=80mg furosemide for at least three months.

Exclusion Criteria:

Diuretics other than furosemide
Valvular heart disease
Atrial fibrillation
Recent myocardial infarction
Heart failure induced by acute myocardial ischemia
Left ventricular ejection fraction (LVEF) >45%
Recent thiamine or multivitamin supplements
Identifiable causes of thiamine deficiency
Malignancy, myeloproliferative disorders, acute infection, thyrotoxicosis, liver disease, uremia, anemia or insulin-dependent diabetes mellitus.

Description of Study Protocol:

Recruitment: All patients with chronic CHF and NYHA Class Two to Four at the Department of Medicine, Sheba Medical Center, Tel-Hashomer, Israel, meeting the above inclusion and exclusion criteria
Design: RCT
Blinding used: Double-blinded
Intervention: 200mg thiamine per day by IV or placebo for one week, followed by 200mg per day of oral thiamine for an additional six weeks.

Statistical Analysis

The sign and Wilcoxon two-sample tests were used to compare changes in means of measured variables between the thiamine and placebo groups
The Wilcoxin matched-pair test was used for within-group comparisons
For LVEF, changes of 0.04 or less were considered equal to zero, based on estimated beat-to-beat variability of the echocardiographic measurement of left ventricular dimensions
A two-tailed P-value of 0.05 or less was taken to indicate statistical significance.

Data Collection Summary:

Timing of Measurements

Two-dimensional echocardiographic examination before the IV treatment and at the end of the inpatient week
The NYHA function class was assessed at baseline and on Day Seven
Blood pressure, heart rate, body weight and 24-hour urine output were measured daily
Thiamine status was evaluated by prior to and at the end of the week of IV treatment
The thiamine-phosphate effect (TPPE) and echocardiography were repeated six weeks following oral thiamine.

Dependent Variables

Variable One
- End-diastolic volume, end-systolic volume and LVEF were calculated based on the apical four-chamber view, according to the recommendations of the American Society of Echocardiography
- Doppler echocardiographic determination of cardiac output was measured at the left ventricular outflow tract
- All echocardiographic studies were obtained by the same technician using standard parasternal and apical views
- Measurements were made on the echocardiographic images that were identified as the best by two cardiologists who viewed the studies together
- These observers were blinded to patient identity and treatment.
Variable Two
- NYHA functional class was assessed at baseline and on Day Seven
- Blood pressure, heart rate, body weight and 24-hour urine output were measured daily.
Thiamine status was evaluated by measuring thiamine-pyrophosphate effect (TPPE) on erythrocyte transketolase activity prior to and at the end of the week of IV treatment
Blood was drawn after an overnight fast and TPPE was expressed as percentage stimulation of enzyme activity by addition of thiamine-pyrophosphate in quadruplicates to enhance assay precision
A TPPE of >15% was considered indicative of thiamine deficiency
Thiamine concentration in plasma was determined as by Weber and Kewitz, with a normal range of 2.3 to 14.3 µg per L
Urinary sodium and creatinine concentrations were determined by standard laboratory methods
Atrial natriuretic peptide (ANP) in plasma was measured by radioimmunoassay, with a normal range 20 to 40 pg per mL
Plasma norepinephrine levels were determined by high performance liquid chromatography after 30 minutes of supine rest, with a normal range of 100pg to 500pg per mL
Red blood cell levels of magnesium were measured with an atomic absorption spectrometer.

Independent Variables

IV and oral thiamine.

Control Variables

Not specified.

Description of Actual Data Sample:

Initial N

30: 22 male, eight female.

Attrition (Final N)

29 for the controlled IV study and 27 for the follow-up phase

One patient died of an acute myocardial infarction on the fifth day of the IV placebo
One died of refractory pulmonary edema during the fifth week of oral thiamine
A third died three days after undergoing cardiac transplantation during the sixth week of oral thiamine therapy.

Age

53-87 years.

Ethnicity

Not specified.

Other Relevant Demographics

Anthropometrics: Both groups were similar in all measurements, although statistical significance was not given.
Patients were receiving other drugs including digoxin, nitrates, and ACE inhibitors (not further description given).

Location

Israel.

Summary of Results:

Variables	Treatment Group (One Week IV Thiamine)	Control Group (One Week IV Placebo)	Statistical Significance of Group Difference
TPPE	11.7±6.5% to 5.4±3.2%	14.0±10.0% to no change	P<0.01
Plasma Thiamine	4.3±3.4µg/L to 90.4±63.2µg/L	2.6±1.1µg/L to no change	P<0.001
Mean LVEF	0.28±0.11 to 0.32±0.09	0.26±0.09 to no change	P<0.05
Daily Urine Output	1,731±800ml to 2,389±752ml	2,078±820ml to 2.039±783ml	P<0.02
Urinary Sodium Excretion	84±52mEq/d to 116±83mEq/d	140±90mEq/d to 106±57mEq/d	P<0.05

Other Findings

Red blood cell magnesium did not change during the study, nor did blood pressure, heart rate or body weight
Daily creatinine excretion, norepinephrine and ANP did not change during the study
After six weeks of oral therapy, LVEF increased 22% (P<0.01) and mean NYHA class decreased from 26±0.6 at baseline to 2.2±0.7 (P<0.01)
TPPE decreased in 22 of the 27 patients (P<0.01) and plasma thiamine levels were significantly higher (P<0.001)
One patient developed nausea and insomnia during the first week of oral thiamine therapy, which stopped when the dosage was halved. He did not experience any symptoms during the IV thiamine.

Author Conclusion:

Thiamine supplements are a beneficial adjutant to conventional treatment in some patients with moderate to severe heart failure, who have received long-term therapy with furosemide.

Funding Source:

University/Hospital:

Sheba Medical Center, Sackler School (Israel)

Reviewer Comments:

Small number of subjects
High degree of variability in the the measured changes in LVEF
Assessment of functional capacity by NYHA criteria was unsupported by exercise testing.

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?	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?	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.)	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?		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?	N/A
	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?		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?	N/A
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?	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?	Yes
	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?	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?	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