EAL

HF: Carnitine (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To test the acute and chronic effects of propionyl-L-carnitine on the hemodynamics, ventricular function, exercise capacity and plasma hormones of patients with chronic congestive heart failure.

Inclusion Criteria:

Admission for investigation or treatment of congestive failure.

Exclusion Criteria:

Patients on digitalis or ACE inhibitors
History of myocardial infarction within the past six months
Unstable angina
Pericarditis
Conduction disturbances
Chronic obstructive airway disease
Arrhythmias.

Description of Study Protocol:

Recruitment

Patients being admitted for the investigation or treatment of congestive heart failure at the University of Chandigarh, India. The diagnosis was on the basis of clinical, echocardiographic (M-mode, 2-D, Doppler), hemodynamic and angiographic data.

Design

A randomized, single-blind parallel design. All patients were observed at weekly intervals during a six-week pre-inclusion period, to confirm the stability of their clinical condition on the same dose of diruetics. During this period, preliminary exercise tests with monitoring of gas exchange were performed to familiarize the patients with the procedure and to establish their stable baseline exercise capacity. A variation in exercise capacity of over 10% during this period was necessary to confirm stability.
Patients were studied on Days One, 15 and 30 of the study period. Baseline measurements before randomization included clinical evaluation, chest X-ray, assessment of LV function using echocardiography and a symptom-limited incremental exercise test with measurements of gas exchange and plama neurohormones. The subjects were then randomized to the active drug propionyl-L-carnitine (1.5g per day, 500mg t.i.d. after meals) or to placebo.
The treated group was subjected to the first hemodynamic study and neuroendocrine determination before and after acute administration of propionyl-L-carnitine (30mg per kg of body weight, IV as bolus). All patients returned to the clinic on Day 15 and all of the same measurements except the hemodynamic and hormone studies were repeated. On Day 30, the patients were reassessed the same as on Day One. However, those in the treatment group had measurements of resting hemodynamics and the neuroendocrine response before and after acute administration of propionyl-L-carnitine.

Blinding Used

Single-blind.

Intervention

Propionyl-L-carnitine was given to 18 of the 30 subjects
They received 1.5g per day, 500mg t.i.d. after meals for 30 days
The treated group also was given an IV bolus of 30mg per kg body weight on Days One and 30.

Statistical Analysis

The significance of changes in baseline parameters between Days One and 30 was assessed by using the paired T-test
Multiple measurements in the data were evaluated by fixed effects analysis of variance for repeated measures
All statisical analyses were done using ANOVA module of Statistica, Syssoft
P<0.05 was considered significant.

Data Collection Summary:

Timing of Measurements

Days One, 15 and 30.

Dependent Variables

Variable One
- Hemodynamics were measured only in the treated group with a Swan-Ganz thermodilution catheter on Days One and 30
- All measurement started two hours after inserting the catheters
- Measurements of baseline hemodynamics were made for one hour prior to administration of the drug and were repeated every 10 minutes for one hour after adminstration of the drug
- Cardiac output was measured in triplicate by thermodilution (Gould SP 1445 monitor), with the limit of variation between values being 10%
- The ECG, heart rate, pulmonary artery pressure, wedge pressure, right atrial pressure and systemic arterial pressure were measured and the vascular resistances were calculated.

Variable Two
- Resting hormone measurements were made in all patients on Days One and 30
- In the propionyl-L-carnitine group, hormone levels were also measured during each hemodynamic study after acute administration of propionyl-L-carnitine
- Three measurements were made on each occasion in the treated group: Before giving the drug and at 10 and 60 minutes after the intravenous administration of the drug
- Hormone assays were carried out on a 30-ml sample of blood drawn from the forearm vein
- Plasma noradrenaline and epinephrine were meaured by high-performance liquid chromatography with electrochemical detection
- Plasma renin activity, aldosterone, cortisol, prolactin, vasopressin and growth hormone were measured by radioimmunoassay (RIA), using a standard commercial kit
- Atrial natriuretic peptide was measured by a RIA method.

Variable Three
- Graded symptom-limited maximal exercise tests were performed on a treadmill three to four hours after a light meal, using the Bruce protocol
- All patient exercise was stopped because of fatigue
- Oxygen consumption measurements were made simultaneously, using a morga exercise test system.

Variable Four
- Echocardiographic recordings were made with either an ATL Ultramark 8 or Hewlett-Packard equipment, using a 2.5-MHz transducer in both the treated and placebo groups
- Left ventricular shortening fraction, left ventricular ejection fraction and chamber dimensions were evaluated.

Independent Variables

Propionyl-L-carnitine.

Control Variables

Hemodynamics
Hormones
Wxercise testing
Oxygen consumption
Echocardiography.

Description of Actual Data Sample:

Initial N

30 (22 males and eight females)
18 in the treated group and 12 in the placeo group.

Attrition (Final N)

11 in the treatment group and 12 in placebo
In the treatment group, one withdrew for personal reasons, three did not have first hemodynamic study for techical reasons and another three did not consent to the second hemodynamic study.

Age

45 to 47 years.

Ethnicity

East Indian.

Anthropometrics

14 patients in the treated group and 10 in placebo were in New York Heart Association (NYHA) Clinical Class II. Their left ventricular ejection fraction (LVEF) was 33±5% and their peak oxygen consumption was 18±5ml per kg per minute.
The remaining six patients were in NYHA Class III (four in the propionyl-L-carnitine and two in placebo) with a LVEF of 26±9% and peak oxygen consumption of 14±6ml per kg per minute
Heart failure was caused by ischemic heart disease in four of the propionyl-L-carnitine group and in three of the placebo group. The remaining 23 patients had heart failure as a result of idiopathic dilated cardiomyopathy.
All subjects were on diuretics.

Location

India.

Summary of Results:

Acute Effects of L-Carnitine on Hemodynamics Before (Day One) and After (Day 30) Oral Drug Administration (Tests Given Before and After 10, 30 and 60 Minutes)

[Only 11 patients in the treated group completed the studies, thus data are expressed for 11 cases.]

Variables		Measures and Confidence Intervals	Measures and Confidence Intervals	Statistical Significance of Group Difference
		Mean, CI	Mean, CI	Statistical Significance of Difference Between Groups
Dependent Variable One
	Pulmonary artery pressure with IV administration baseline	Before: 37.6±3.2	60 minutes: 38.4±3.5	P≤0.05
	Pulmonary artery pressure with IV administration day 30	Before: 30.8±5.6	60 minutes: 29.8±4.7	P≤0.05
	Pulmonary wedge pressure with IV administration baseline	Before: 24.7±2.3	60 min: 21.5±2.7	P≤0.01
	Pulmonary wedge pressure with IV administration day 30	Before: 19.1±2.8	60 minutes: 17.3±3.0	P≤0.01
	Pulmonary artery pressure with chronic administration	37.6±3.2	30.8±5.6	P=0.01
Dependent Variable Two
	Hormones			NS

Other Findings with Chronic Administration of Propionlyl-L-Carnitine

	Before Tx	After Tx
Exercise Time (Treadmill Time)	8.1±0.5	9.8±0.4	P≤0.01
Peak Oxygen Consumptions (ml/kg/min)	16.0±3	23.5±2	P=0.001
Peak Heart Rate	Increased 12% in l-carnitine	P=0.01
End-Diastolic Dimension (cm)	5.9±0.2	5.5±0.2	P=0.004
No Change in Ejection Fraction
Endpoint Septal Separation (cm)	1.73±0.08	1.56±0.05	P=0.03
Left Atrial Dimension	Decreased significantly

Delta between placebo and treated group for end-dialstolic dimension and end-point septal separation was statistically significant (P<0.05)
None of the patients reported complications during the study.

Author Conclusion:

Chronic administration of propionyl-L-carnitine has a beneficial effect on the exercise capacity of patients with congestive heart failure
The drug reduces left ventricular filling pressures and pulmonary artery pressures, but has no other significant effects on either hemodynamics or the neurohormonal axis.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

The results had different P-values in the tables and the text, although both were significant
Tables were given the wrong number in the text. Footnotes beneath the tables did not have a corresponding superscript in the table.
A very small study, as 11 of the 18 in the treated group were analyzed. Although there is a large drop-out, they tried to controlled for this by only reporting the findings on the 11 completors for the hemodynamics. It does not appear that this is the case for the hormone levels. There was no attrition for the results on exercise time and peak oxygen consumption.
Population is East Indian
Subjects had different causes of congestive heart failure and different clinical classes of failure.

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?		No
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	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?	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?		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?	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?	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?	N/A
	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?		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