|Effects of diltiazem prophylaxis on the incidence and clinical outcome of atrial arrhythmias after thoracic surgery
|Amar D, Roistacher N, Rusch V W, Leung D H, Ginsburg I, Zhang H, Bains M S, Downey R J, Korst R J, Ginsberg R J
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The study examined diltiazem as a prophylaxis for atrial arrhythmias after thoracic surgery. The dosage regimen comprised an intravenous loading dose of 0.25 mg/kg (50 mL) given over 30 minutes, followed by 0.1 mg/kg per hour (constituted as 1 mg/mL) intravenously for 18 to 24 hours. Starting in the morning of postoperative day 1, patients received diltiazem SR 120 mg orally, twice daily, for 14 days. The placebo group received the same pattern of administration.
Economic study type
The study population comprised patients in sinus rhythm and at increased risk for postoperative arrhythmias, either because they were due to undergo pneumonectomy or were 60 years of age and scheduled for lobectomy. Patients were excluded if they had a history of chronic atrial arrhythmia or second-degree atrioventricular block, or were taking Class I or Class III anti-arrhythmic drugs or calcium-channel blockers for ischaemic heart disease. Patients who had new signs of myocardial ischaemia or infarction, or who required inotropic support on arrival in the postanaesthesia care unit, were also excluded.
The setting was secondary care.
Dates to which data relate
The effectiveness data related to a period between February 1997 and August 1999. The dates for resource use and the price year were not stated.
Source of effectiveness data
The effectiveness data were derived from a single study.
Link between effectiveness and cost data
The costing appears to have been conducted retrospectively on the same sample of patients as that included in the effectiveness analysis.
Power calculations were performed in the determination of the sample size. To detect a reduction of 10% in the incidence of early AF with a 2-tailed test at an alpha of 5% with 80% power, a sample size of 330 patients (165 per arm) would be required. From an initial total of 503 eligible patients, 173 were excluded from the sample for a variety of reasons, as determined by the inclusion and exclusion criteria of the study population. Therefore, 330 patients were given either intravenous diltiazem (n=167) or placebo (n=163) immediately after lobectomy (age 60 years or more) or pneumonectomy (age 18 years or more), and orally thereafter for 14 days. Patients taking L-type calcium-channel blockers for hypertension (n=8) received other antihypertensive medications postoperatively. As clinically indicated, beta-blockers were continued postoperatively to avoid withdrawal.
The study was a randomised, double-blind, placebo-controlled trial that was conducted in a single centre. Patients were stratified according to the type of operation (lobectomy, pneumonectomy or extrapleural pneumonectomy). Randomisation was undertaken using sealed, opaque, treatment-code envelopes. All clinical and study personnel were blinded to the study group arrangements throughout the trial. The period of follow-up was 14 days for treatment, but continued to a 30-day inpatient or outpatient point. The loss to follow-up at 30 days was 3 patients in the placebo group and 1 patient in the study group, all due to mortality.
Analysis of effectiveness
The analysis of effectiveness was based on the intention to treat principle. The primary outcomes used in the effectiveness analysis were sustained (>/= 15 minutes) or clinically significant (requiring intervention) AF or SVT during treatment. AF was determined by Holter criteria or clinical criteria. The duration of hospitalisation was also recorded as a secondary outcome of interest. At baseline, the patient groups were shown to be statistically similar in terms of age, sex distribution, severity of tumour stage, co-morbidity, heart rate (although it was statistically significantly higher by 6 to 7 beats/minute postoperatively in the placebo group) and surgical data.
Postoperative atrial arrhythmias (60 AF; 5 SVT) occurred in 15% of the diltiazem group and 25% of the placebo group, (p=0.03).
In comparison with the placebo group, diltiazem almost halved the incidence of clinically significant arrhythmias (10% versus 19% for the placebo group; p=0.02).
The maximal ventricular rate during AF was significantly lower in the diltiazem group (145 +/- 34 versus 163 +/- 26 beats/minute; p=0.02).
The two groups did not differ in terms of postoperative complications, mortality, or the duration of hospitalisation.
In the sub-group analysis there was a lower incidence of early postoperative AF for the diltiazem group in patients undergoing lobectomy (16 out of 117 versus 29 out of 115; p=0.03). This was also the case for all patients aged older than 60 in all three sub-groups.
The use of beta-blockers did not influence the incidence of AF in either group.
After major thoracic operations, the use of prophylactic diltiazem reduced the incidence of clinically significant atrial arrhythmias in patients at high risk for this complication.
Measure of benefits used in the economic analysis
No summary measure of benefit was used in the economic analysis. The health benefits are therefore those associated with the effectiveness results and the authors, in effect, conducted a cost-consequences analysis.
Discounting was not relevant because of the short timeframe of the analysis. The costs and the quantities were not reported separately although the principal driver of costs, length of hospital stay, was provided separately for the two groups. The data on total hospitalisation costs were derived from the commercially available decision-support information software system (Financial Management System, Shared Medical System, Malvern) used by the patient account office at the study's institution. Professional service fees were not included in these charges. Adjustments were made for age, gender, operation and interactions among these variables. A relative weight resource weight was therefore established for each patient. The unit costs were not reported for each resource. The resources and costs were estimated from actual data. The price year was not stated.
Statistical analysis of costs
Mean and standard deviation values were used in the cost data. The authors utilised Student's t-test and Fisher's exact test, although it was unclear whether these were the actual statistical tests applied to the cost data.
The indirect costs were not included.
Sensitivity analyses were not performed.
Estimated benefits used in the economic analysis
Owing to the cost-consequences approach taken, the reader is referred to the 'Effectiveness Results' section.
The mean total hospitalisation costs were $23,773 (+/- 19,443) for the diltiazem group compared with $23,515 (+/- 18,152) for the placebo group, (non significant, p=0.9).
No serious side effects were observed in the diltiazem group.
There was a trend for the sub-group of patients who had clinically significant arrhythmias and received diltiazem to have lower hospitalisation costs, but this difference was not significant.
Synthesis of costs and benefits
Not applicable because of the cost-consequences approach taken.
The use of prophylactic diltiazem starting immediately after thoracic operations and continuing for two weeks was well tolerated and reduced the incidence of clinically significant atrial arrhythmias by approximately 45%.
CRD COMMENTARY - Selection of comparators
The comparator was placebo, which enabled the relative cost-effectiveness of diltiazem to be assessed. Other alternative therapies were not evaluated, although they were referred to, and the authors discussed the results of other studies (e.g. verapamil and short-term diltiazem). You should consider if the study health technology and these comparators are relevant to your own setting.
Validity of estimate of measure of effectiveness
The effectiveness data were derived from what appeared to be a well-run randomised, double-blind controlled trial. A power calculation was used in the determination of sample size, the analysis was based on intention to treat, the patients were shown to be comparable at baseline, and sub-analyses were performed according to clearly specified clinical and demographic criteria. The sample was also shown to be representative of the study population. These aspects of the study enhance its internal and external validity. The authors pointed out some limitations. For example, patients undergoing pneumonectomy were younger than those undergoing lobectomy and this, combined with the smaller sample size in the pneumonectomy groups and lower than anticipated AF occurrence, limited the potential of finding a meaningful comparison between diltiazem and control patients. Holter monitoring was limited to the first 72 - 96 hours after operation (when most episodes of AF occur), and after this the conclusions were limited to clinical criteria.
Validity of estimate of measure of benefit
As the authors conducted a cost-consequences analysis, the comments in the "Validity of estimate of measure of effectiveness" field (above) apply.
Validity of estimate of costs
The authors noted that their practice setting precluded undertaking a more exact cost analysis to assess the true burden of AF. As such, the costing was reported at an aggregated level, although statistical analyses were appropriately performed. It is likely that the costing was based on charges, although no cost-to-charge ratio was specified in the paper. If this assumption is correct, the cost data have limited generalisability to other settings as charges do not reflect true opportunity costs. Discounting was appropriately not conducted, owing to the short period of analysis, but dates for resources and a price year were not provided, which limits the opportunity to perform reflation exercises on the cost data.
The authors made clear and detailed comparisons with other studies and explained relevant issues surrounding similar drugs and findings for this patient domain. The issue of generalisability was not specifically addressed although, from a clinical effectiveness point of view, this aspect of the study is likely to be strong as detailed information was provided on the population and sample characteristics, and on the intervention itself. As outlined already, the cost data are likely to have limited generalisability outside of the USA, although the finding of no significant differences may hold true in other settings. The authors comprehensively discussed the caveats and limitations of their results.
Implications of the study
In terms of clinical practice, the authors consider it appropriate to use diltiazem prophylaxis as standard care in patients over the age of 60 years undergoing major pulmonary section. They also noted that the cost-effectiveness of diltiazem could be improved by beginning oral therapy before the operation, shortening the course of intravenous therapy after the operation, and reducing the duration of postoperative therapy to 10 days, as most arrhythmias occurred before this time in the present study.
Source of funding
Supported in part by a grant from the International Anesthesia Research Society.
Amar D, Roistacher N, Rusch V W, Leung D H, Ginsburg I, Zhang H, Bains M S, Downey R J, Korst R J, Ginsberg R J. Effects of diltiazem prophylaxis on the incidence and clinical outcome of atrial arrhythmias after thoracic surgery. Journal of Thoracic and Cardiovascular Surgery 2000; 120(4): 790-798
Subject indexing assigned by NLM
Administration, Oral; Aged; Atrial Fibrillation /epidemiology /prevention & Atrial Flutter /epidemiology /prevention & Calcium Channel Blockers /therapeutic use; Diltiazem /therapeutic use; Double-Blind Method; Female; Hospital Costs; Humans; Incidence; Injections, Intravenous; Male; Middle Aged; Postoperative Complications /epidemiology /prevention & Pulmonary Surgical Procedures; Tachycardia, Supraventricular /epidemiology /prevention & Treatment Outcome; control; control; control; control
Date bibliographic record published
Date abstract record published