Randomized Trial Comparing Diltiazem and Metoprolol For Atrial Fibrillation Rate Control

If either an initial DT or MET strategy are shown to be more effective in obtaining rate and
rhythm control, decreasing length of stay in the ED, and decreasing admissions and
readmissions, there is a potential for: 1.) Major health cost savings; 2.) Improved bed
utilization for our hospital, which is frequently at capacity and unable to accept transfers
from outlying hospitals; and, 3.) Education of ED and non-ED health care providers of optimal
AF/FL medication options.

Sample

Preliminary information obtained from CAMC's Data Warehouse from July 1, 2011 to June 30,
2012 revealed 370 patients were seen in the Emergency Department (ED) at either CAMC Memorial
or General Hospitals with a diagnosis of AF/FL, without any other acute co-morbidity. The
investigators will identify which Hospital the patient was enrolled.

The investigators will enroll a total of 150 patients based on the following:

Prior data indicate that the conversion to a normal sinus rhythm by 8 hours is approximately
20%. If the investigators wish to detect a 25% change between medications then the
investigators would need to include a total of 150 patients (75 in each cohort) to reject the
null hypothesis that the conversion rates are equal between the 2 medications with
probability (power) 0.8 and Type I error < 0.05. The investigators will use a
continuity-corrected chi-squared statistic or Fisher's exact test to test our hypothesis.
Power analysis performed using GPower Version 3.

Procedures

Potential study patients will be identified by an ED nurse or a member of the study team
using the inclusion and exclusion criteria. ED nurses will be informed of the study by charge
nurses who have been educated about the protocol by the research team. The purpose, content
and logistics of the study will also be described to ED physicians participating in the
study. Research assistants, when available, will be notified by cell phone or pager to see
patient in the ED within 20 minutes. The attending physician or resident will be informed of
the potential study patient. The attending physician or resident will give the research
associate/member of the study team permission to discuss the study with the patient. If the
patient is interested in participating in the study, the research associate/member of the
study team will discuss the details of the study and review the consent form. It is likely
the onset of treatment with DT or MET will be delayed 30 to 40 minutes due to the consenting
process and study enrollment. The attending physician must agree to this delay.

At this point the attending physician will discuss the study with the patient and answer
questions. The physicians or resident initially talking with the patients about being in the
trial will have Collaborative Institutional Training Initiative (CITI) training. General
education to the ED staff will be made concerning aims and objectives of the strategy study.
If the patient is still interested and willing to participate, the informed consent and
Health Insurance Portability and Accountability Act (HIPAA) privacy statement will be signed.

Following consent, patients will be randomized to either IV diltiazem (DT) or IV metoprolol
(MET). Sealed envelopes containing the randomized treatment protocol will be maintained on
the ED premises to be pulled consecutively after a patient has been consented to be in the
study. Inside the envelope, the specific treatment plan will be revealed. Treatment with
either DT or MET will be initiated using standard CAMC protocol. Deviations from the randomly
assigned medication regimen would be at the attending physician's discretion pending vital
signs response. If the study drug is stopped or changed to a different type of medication,
the patient's participation will continue and medications will be documented with the
analysis of results being the intent to treat.

The same physicians rotate at both General and Memorial Hospitals. The investigators will
start at the Memorial Hospital, but after experience with enrollment the investigators may
enroll patients from both Hospitals.

Data Analysis

Basic descriptive statistics including means and standard deviations for continuous variables
and proportions and frequencies for categorical variables will be used to describe the
patient sample and disease characteristics.

To determine if a medication regimen (MET vs DT) is noted by descriptive analysis to be
associated with primary aim 1 for treating AF/FL in the ED or during hospitalization (Primary
Aim-1), the investigators will describe the proportion of patients with rhythm control
(defined as normal sinus rhythm) by time of ED discharge using Chi-square analysis with
continuity correction. Using the same statistical tests, the investigators will describe the
proportion of patients with normal sinus rhythm at time of hospital discharge, in patients
admitted to CAMC. Possible confounders, including patient characteristics, co-morbid
conditions, ED events, or deviation from medicine regimen on achieving NSR will be examined
by comparing patients with the confounder to those without the confounder of interest using
Chi-square with continuity correction analyses if data is categorical, t-test or Mann-Whitney
U analysis if data is continuous. In addition, the investigators will examine the effect of
medication regimen on rate control (defined as heart rate < 100 bpm) (Primary Aim-2) at 2, 4,
6, 8 hours in the identical manner as described for rhythm control including the examination
of confounding variables.

The proportion of patients receiving CAMC hospital admission versus discharged to home from
the ED will be described between the two medication regimens using Chi-square analysis with
continuity correction to determine if one regimen resulted in a greater percentage of home
discharges directly from the ED (Secondary Aim-1). The effect of possible confounders
including patient characteristics, ED events, achieving rate and/or rhythm control in the ED
or deviation from medication regimen will be examined by describing patients with the
confounder to those without the confounder of interest on the need for hospital admission
using Chi-square with continuity correction analyses if data is categorical, t-test or
Mann-Whitney U analysis, if data is continuous. Those confounders that are shown to associate
with ED discharge to home will be included in a multivariate analysis (binomial logistic
regression) to examine if medication regimen associates with ED discharge to home in the
presence of confounders.

To determine if a medication regimen (MET vs DT) associated with decreased financial costs
(Secondary Aim-2), ED costs will be examined between the 2 medication regimens in all
patients using t-tests, or Mann-Whitney U analysis. In addition, the total cost of
hospitalization (ED + hospital costs) of patients admitted to the CAMC hospital from the ED
will be examined between the medication regimens. Cost will also be examined in relationship
to length of stay by examining cost /length of stay between the two treatment groups using
the same statistical tests.

The need for readmission and atrial fibrillation reoccurrence as reported by the phone
questionnaire (Secondary Aim-3) will be compared between the two medication regimens using
Chi-square with continuity correction analyses. The investigators will also determine which
rate control medication at time of phone interview associates with freedom from atrial
fibrillation reoccurrence using chi-square analysis. Lastly, the time between discharge and
phone survey study completion (maximum: 6 months) will be determined and the investigators
will examine the effect of this lag time (4- 6 months) on the percentage of patients
requiring readmission and/or having a reoccurrence of atrial fibrillation via chi square
analysis.

For all applicable analyses described above, Fisher's exact tests will be substituted for Chi
square analysis when appropriate. For all comparisons, a p level of < 0.05 will be used to
determine statistical significance. The statistical package Statistical Analysis Software
(SAS) (Version 9.3) will be used to analyze data.

Confidentiality

Minimal patient identification information will be collected. The patient account number and
telephone number must be collected. Subjects will also be assigned a study number for data
analysis; account numbers will not be included in the data analysis. Personal health
information will be available only to the study investigators. All collected data will be
stored in a locked filing cabinet in the Emergency Department until it can be delivered to
CAMC Outcomes Research. Electronic data will be stored on a password protected computer. At
the conclusion of the study, all data collection sheets will be shredded and electronic data
destroyed.

Inclusion Criteria:

- Patients presenting to Charleston Area Medical Center (CAMC) General or Memorial
Hospital ED with a primary diagnosis of AF/FL

- Patients with a mean ventricular rate of 100 beats per minute or more within one hour
of presentation

Exclusion Criteria:

- Under age 18 years

- A diagnosis of acute coronary syndrome (ACS) made by the admitting ED physician (ST
elevation myocardial infarction, non-ST elevation myocardial infarction, unstable
angina) (beta blockers are a Class I medications for ACS)

- Known history of heart failure with an ejection fraction <50%

- Known ejection fraction <45%, regardless of a history of heart failure. Heart failure
and a history of heart failure with an ejection fraction of 40-50% may occur with a
normal ejection fraction now referred to as Heart Failure With Preserved Ejection
Fraction (HFpEF) or "diastolic dysfunction". A low ejection fraction is not always
associated with heart failure. Our technology of measuring ejection fraction is by no
means perfect. It is acceptable to use MET in larger than usual starting doses of MET
for rate control or patients with "diastolic dysfunction", but not systolic
dysfunction. Thus, a patient who has an ejection fraction of 42% may possibly have an
ejection fraction of 37%, possible lower. Thus the investigators want to avoid the
possibility of a patient with a history of heart failure does not receive MET unless
the investigators feel systolic heart failure is not present.

- Systolic blood pressure <90 mm Hg or between 90-99 AND patient is experiencing
symptoms of dizziness

- Known allergy or adverse reactions to diltiazem or metoprolol. This is very rare.

Exclusions from ECG readings:

- Current Atrioventricular (AV) block (2nd or 3rd degree)

- Pre-excitation syndromes - Wolfe Parkinson White (WPW) (Accelerated AV conduction- a
rare condition where MET and DT are not advised)

- Pulse rate less 100/minute on ED admission (already at rate control)

- Cardiogenic shock or heart failure requiring inotropic agents or intubation

- Respiratory failure requiring intubation

- Pregnancy or lactation (neither pregnancy or lactation are listed as definitely safe
for either medication)

- Asthma, defined as (asthma is a relative contraindication for MET:

- current use of inhaler

- use of steroids for dyspnea

- history of being treated for asthma

- Inability or unwillingness to provide informed consent

- Physician decision

- If either medication is a relative contraindication, the patient cannot be randomized.