Randomized Trial Comparing Diltiazem and Metoprolol For Atrial Fibrillation Rate Control
Randomized Trial Comparing Diltiazem and Metoprolol For Atrial Fibrillation Rate Control
Atrial Fibrillation and atrial flutter (AF/FL) is the usually irregular beating of the heart
 and is a rapidly growing cause of hospitalization. Between 1993 to 2007 AF/FL
 hospitalizations have increased 203% compared to a 71% increase for all hospitalizations.
 Changing procedure management such as ablation, transesophageal have had a minimal impact on
 the trends and there is a need to evaluate Emergency Department (ED) management options of
 AF/FL that may decrease hospitalizations.

 The most commonly used medications to control heart rate are metoprolol (MET), a beta
 blocker, or diltiazem (DT), a calcium channel blocker. Beta blockers are medications that
 cause the heart to beat more slowly and with less force. DT also helps blood vessels open up
 to improve blood flow. Both DT and MET are used alone or together with other medicines to
 treat severe chest pain (angina), high blood pressure (hypertension) or rapid heartbeat. Both
 are equally acceptable according to recent guidelines for AF/FL. There are limited studies
 comparing MET to DT for rate control for AF/FL.

 The initial goal for AF/FL management in the Emergency Department is usually rate control.

 The most commonly used rate control medications are metoprolol (MET), a beta blocker, or
 diltiazem (DT) a calcium blocker. Three major guidelines, including the American College of
 Cardiology (ACC) and the American Heart Association (AHA) indicate beta blockers and DT are
 equally acceptable medications for rate control in AF (3,4,5) assuming no contraindications.

 There are limited studies comparing beta blockers (BB) to DT for rate control for AF:

 1. Demircan, et. al., compared bolus intravenous BB and DT in 40 patients over a 20 minute
 period. No follow-up information after 20 minutes was reported. No attempt was made to
 look at intermediate or long term results. No patients converted to normal sinus rhythm
 over this short treatment period and there was slightly more rate decrease at 20
 minutes, with DT versus BB (6).

 2. Time from medication administration to heart rate and rhythm control. Additionally,
 currently guidelines consider BB or DT medications to slow AF/FL; however, there are
 some suggestions that BB may not only slow heart rate in AF/FL (as does DT) but also
 increase all AF/FL conversion from AF/FL to normal sinus rhythm(2), and aid in
 maintaining normal sinus rhythm (NSR) after cardioversion (10). With recent onset AF/FL
 occurring within 48 hours prior to the arrival to the ED, approximately 50% of AF/FL
 patients convert to normal rhythm spontaneously within 24 hours after arrival to the ED
 (6), making evaluation of current limited studies difficult. Thus, the investigators
 wish to examine the effect of initial medication strategy on time to NSR in a larger
 sample than has been previously performed.

 3. A randomized study of 48 patients in China reported significantly slower heart rate up
 to 20 minutes with DT 10mg IV versus metoprolol 5mg IV but not after 30 minutes (7).

 4. A retrospective study of post-operative coronary bypass patients showed the intravenous
 administration of the BB, esmolol, to be more effective than DT for rate control and
 conversion of AF/FL (8).

 5. Hassan et al reported no difference in conversion to regular rhythm with esmolol verses
 DT in a small, under powered, randomized study of fifty ED patients (9). Conversion to
 sinus rhythm occurred in 10 patients (42%) in the DT group compared with 10 patients
 (39%) in the esmolol group (P = 1.0). There were no statistically significant
 differences in heart rate between the two medications at 1, 6, 12, and 24 hours after
 initiation of esmolol or DT infusion.

 Examples of such well quoted strategy trials are the COURAGE trial published in the New
 England Journal of Medicine and the PROMISE Trial, a worldwide multi-centered study that is
 nearing completion goal of 10,000 patients of which, Charleston Area Medical Center (CAMC)
 has enrolled approximately 100 patients. In this trial, patients being evaluated for chest
 pain will be randomized to two treatment strategies and subsequent outcomes will be recorded.

 Strategy trials do not attempt to manage treatment after an initial management strategy has
 been determined by randomization, but, whether the initial treatment affects long-term
 outcomes.

 This will be a prospective, randomized study comparing the outcomes of a strategy using
 either MET or DT in patients with AF presenting to the Charleston Area Medical Center (CAMC)
 ED. After presentation and receiving consent, the patient will be randomized to receive
 either MET or DT.
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.