EAL

HF: Magnesium (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of the study was to assess the role of electrolyte imbalance in cardiac arrhythmias associated with congestive heart failure and the effectiveness of magnesium supplementation in patients with hypomagnesemia and ventricular arrhythmias.

Inclusion Criteria:

Clinical heart failure of six months
NYHA Classes II to IV
Left ventricular ejection fraction below 40%
Sinus rhythm; serum creatinine below two mg per dL.

Drug Treatment Before Hospitalization

Digoxin
Furosemide
Thiazide diuretic
Spironolactone
Amiloride
ACE inhibitor
Nitrate.

Drug Treatment While Hospitalized

All hospitalized study patients received triple therapy (diuretic, ACE inhibitor and digoxin)
Patients with decreased serum magnesium or potassium levels were given oral supplementation (500mg magnesium subcarbonide or 2,250mg potassium chloride), daily.

Exclusion Criteria:

History of CHF of less than six months
LVEF at 40%
Kidney or liver insufficiency
Systemic illness, including diabetes, cor pulmonale, infections, atrial fibrillation and chronic antiarrhythmic therapy.

Description of Study Protocol:

Recruitment

Patients were recruited from 588 patients admitted to a municipal hospital with exacerbation of CHF
588 patients were screened; 78 were included in the study.

Design

Following admission to the study, 78 heart failure patients were assessed for hypomagnesemia and ventricular arrhythmias
- All patients received triple therapy for heart failure (diuretic, ACE-inhibitor and digoxin)
- At baseline, hypomagnesemia was found in 38% of patients and excessive magnesium loss in 72% of patients
- Individuals who had decreased serum magnesium (N=30) or potassium levels (N=15) were given oral supplementation (500mg magnesium subcarbonide or 2,250mg potassium chloride) daily
- After supplementation, 20 patients still had hypomagnesemia.
On admission, 72% of patients (N=56) exhibited complex arrhythmias
- After oral supplementation, 36 patients continued to have complex arrhythmias
- These patients (N=36) were randomized to intravenous magnesium supplementation or placebo.
Serum magnesium and potassium levels, urine magnesium excretion and the incidence of ventricular arrhythmias were assessed thorughout the study.

Blinding Used

Double-blind.

Intervention

In the magnesium-treated group, (N=24) eight g of magnesium (66.6mmol) was dissolved in 250ml of 5% glucose and administered as IV infusion over 12 hours
In the placebo group, (N=12) 250ml of glucose was given.

Statistical Analysis

Paired or unpaired Student's T-tests were used to assess changes within each group or differences between two groups, respectively, with regard to the biochemical parameters measured, as well as the number of different arrhythmic events
Clinical characteristics of the placebo- and magnesium-treated groups were compared using a chi-square test
A P-value of 0.05 was considered statistically significant.

Data Collection Summary:

Timing of Measurements

Serum magnesium and potassium levels, urine magnesium excretion and the incidence of ventricular arrhythmias were assessed on admission to the study, at Day Eight and after treatment with magnesium or placebo.

Dependent Variables

Variable One: Ventricular ectopic beats (VEBs); average number of VEBs per hour of recording time, by Holter monitor
Variable Two: Couplets were calculated as the number of events per 24 hours of Holter monitoring
Variable Three: Episodes of non-sinus ventricular tachycardia (nsVT); number of events per 24 hours of Holter monitoring.

Independent Variables

Infusion of eight g of magnesium dissolved in 250ml of 5% glucose and administered as IV infusion over 12 hours.

Control Variables

Infusion of 250ml of 5% glucose, as IV infusion over 24 hours.

Description of Actual Data Sample:

Initial N: 78 (40 male, 38 female)
Attrition (final N): 68 (seven died during first week of hospitalization, three refused to participate in magnesium treatment)
Age: 67±11 years
Ethnicity: Polish
Location: Poland.

Summary of Results:

Variables	Treatment Group (N=24) Measures and Confidence Intervals		Statistical Significance of Group Difference	Placebo Group (N=12) Measures and Confidence Intervals		Statistical Significance of Group Difference
	Before	After		Before	After
VEBs (No. per Hour)	37±22	13±14	0.0001	26±31	5±15	NS
Couplets per Day	5.6±6.6	0.7±2	0.003	8.2±14.4	6.7±12.6*	NS
NsVT per Day	2±2.7	0.5±1.7	0.01	1±2	0.2±0.6	NS

* This result was significantly different than the respective value in the magnesium treated group (P<0.03).

Other Findings

On admission, hypomagnesemia was found in 38% and excessive magnesium loss in 72% of patients
Serum magnesium levels were lower and urine magnesium excretion was greater in patients with complex ventricular arrhythmias, both on admission and after treatment for heart failure
Patients with complex arrhythmias showed a greater loss of magnesium in daily urine than those with sinus rhythm, 3.28±2.21 vs. 2.30±0.86mmol per 24 hours (P=0.02)
In the patients who improved after magnesium infusion (N unknown), serum magnesium increased from 0.71±0.13mmol to 0.84±0.14mmol L^-1.
No patient side effects were noted.

Author Conclusion:

Increased urinary magnesium excretion and hypomagnesemia occur frequently in patients with CHF and are associated with the presence of complex ventricular arrhythmias
Intravenous magnesium sulphate seems to be a simple, safe and often effective antiarrhythmic intervention, which should be considered more often in medical practice before resorting to specific antiarrhythmic drugs.

Funding Source:

University/Hospital:

Post-Graduate Medical School

Reviewer Comments:

Following treatment with oral magnesium supplements, 20 patients (29%) had persistently low serum magnesium. 36 patients (53%) had persistent complex arrhythmias. Therefore, it appears that 16 patients with complex arrhythmias had normal serum magnesium levels (assuming that all of the subjects with low serum magnesium are in the arrhythmia group, which is not made clear). All patients with arrhythmias were randomized to IV magnesium treatment or placebo, regardless of serum magnesium level. In terms of clinical application, this raises the questions: "Should everyone with HF and ventricular arrhythmias be supplemented?" and "How do we know who will benefit?"
Further, although the mean serum magnesium level in the arrhythmia group was lower than in the normal sinus rhythm group after oral supplementation, it was still in the normal range. It is unclear how many of these patients had low serum magnesium.
The authors noted that the variability of ventribular ectopic activity was large. Although the number of arrhythmias dropped in the placebo group as well as the treatment group, the difference was not significant, due to the large standard deviation. However, the sample size in the placebo group was half that of the treatment group.
588 CHF patients were screened to obtain a sample size of 78. Thus, this sample may not be representative of the heart failure population.
In this study, many patients did not respond to oral supplementation, so treatment efficacy may be limited to IV supplementation.

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?	???
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")?	Yes
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?	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?	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?	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)?	Yes
	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?		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