Oral vs Intravenous Diltiazem for Rapid Atrial Fibrillation/Flutter Trial
Phase: PHASE4
Conditions: Atrial Fibrillation and Flutter
Sponsor: Virginia Commonwealth University

 
 
Title: Oral vs Intravenous Diltiazem for Rapid Atrial Fibrillation/Flutter Trial (OVID RAF) 
 
NCT #: NCT03472495 
 
Document date: 01/03/2018 
 
Document Type: Protocol and SAP 
 
 
 

ORAL IMMEDIATE RELEASE VS. INTRAVENOUS CONTINUOUS INFUSION DILTIAZEM IN THE 
MANAGEMENT OF ATRIAL FIBRILLATION OR FLUTTER WITH RAPID VENTRICULAR RATE IN 
THE EMERGENCY DEPARTMENT: RANDOMIZED, CONTROLLED TRIAL 
 
Study Protocol 
 
 
 
 
AFF > 110 
beats/min 
(asymptomatic + 
symptomatic)
Assessed for 
eligibility (n= )
Randomization 
(n= )
Diltiazem 0.25 
mg/kg IVP x1
HR <110 
beats/min
Oral: Diltiazem 60 mg PO q6h (or 30 
mg PO q6h if pt <60 kg), titrated 
PRN
IV: Diltiazem continuous infusion 
drip 5 mg/h, titrate by 2.5 mg/h 
q15 min, max 15 mg/h
HR > 110 
beats/min
Diltiazem 0.35 
mg/kg IVP x1
HR <110 
beats/min
Oral: Diltiazem 60 mg PO q6h (or 30 
mg PO q6h if pt <60 kg), titrated 
PRN
IV: Diltiazem continuous infusion 
drip 5 mg/h, titrate by 2.5 mg/h 
q15 min, max 15 mg/h
HR >110 
beats/min: 
Excluded from 
study
Excluded (n= )

Exclusion:  
Unable to take PO, SBP <90 mmHg, HR <60 mmHg, WPW, history of allergy or idiosyncratic 
reaction to diltiazem 
INTRODUCTION 
Diltiazem, a non-dihydropyridine calcium channel blocker, is often the medication of choice in the rate 
control management of atrial fibrillation and flutter (AFF) due to its proven superiority over other rate 
control agents such as amiodarone, digoxin, and metoprolol.i,ii,iii It has a rapid onset of action, high 
response rate, and minimal negative inotropic effect. In the ED, a weight-based loading dose (LD) of IV 
diltiazem is usually administered followed by PO immediate release tablet or IV continuous infusion. Both 
options allow for dose titration in the short term before converting to the extended release PO formulation. 
The PO immediate release diltiazem tablet has a fast onset of action of 30-60 minutes and is dosed every 
6 hours.iv Intravenous continuous infusion diltiazem has a variable onset of action with a titration 
frequency of every 15-30 minutes.  
The route of diltiazem after the initial IV LD can potentially influence the disposition of the patient from the 
ED, the level of care needed, and hospital length of stay (LOS). However, no studies exist comparing PO 
immediate release and IV continuous infusion diltiazem. The objective of this study was to compare the 
incidence of patients who have a HR <110 beats/min or conversion to sinus rhythm at 2 hours after 
medication administration 
 
METHODS 
Study Design: 
This was a prospective, open label, randomized non-inferiority trial to compare the effectiveness of PO 
immediate release diltiazem to IV continuous infusion diltiazem in achieving rate control in adult patients 
with atrial fibrillation or atrial flutter (AFF). This single center study was conducted at Virginia 
Commonwealth University Medical Center in Richmond, VA between 2018 and 2020.  Approval of the 

study was obtained from the hospital’s institutional review board. All enrolled patients provided written 
informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization 
documentation. This study is registered with clinicaltrials.gov, number _____. 
 
Setting and Population: 
The study was conducted in a tertiary medical center ED that treats over 95,000 patients annually. 
Patients were evaluated for enrollment if they were ≥ 18 years old, had a 12-lead electrocardiogram 
(ECG) showing AFF with a ventricular rate of >110 beats/min, and systolic blood pressure (SBP) of ≥ 90 
mmHg. Patients were excluded if they were < 18 years old, pregnant, a prisoner, history of Wolff-
Parkinson-White syndrome, received electrical therapy for cardioversion, or received other medications 
for acute HR control (besides adenosine) randomization, or had a history of allergic reaction to diltiazem. 
 
Interventions: 
Eligible patients gave written informed consent before entry into the study and the following data was 
obtained: demographics, medical history, vital signs, ECG findings. At the discretion of the health care 
provider, IV adenosine was administered to facilitate identification of the underlying arrhythmia.  
 
Upon enrollment, patients received a diltiazem bolus of 0.25 mg/kg over 2 minutes. If the patient’s HR did 
not decrease to <110 beats/min or decrease by 20% from baseline ventricular rate with the first diltiazem 
bolus within 15 minutes, but was well tolerated, patients were given a second bolus of 0.35 mg/kg IVP 
over 2 minutes. If the patient’s HR did not decrease to <110 beats/min or decrease by 20% from baseline 
ventricular rate with the second diltiazem bolus they were excluded. Responders to the diltiazem bolus 
were then randomized in a 1:1 ratio, to receive diltiazem 60 mg PO immediate release (or 30 mg PO 
immediate release if patient was <60 kg) or be started on a diltiazem drip at 5 mg/h to be titrated by the 
nurse 2.5 mg/h every 15 minutes to a maximum of 15 mg/hr or until a HR of <110 beats/min or 

conversion to normal sinus rhythm (NSR) occurred. Randomization was performed using block 
randomization. 
 
Study data were collected and managed using REDCap electronic data capture tools hosted at Virginia 
Commonwealth Univeristy.5 Baseline demographic information recorded included the patient’s age, sex, 
race, vital signs (HR, BP, RR, oxygen saturation and oxygen requirement), weight, history of AFF, 
hypertension (HTN), congestive heart failure (CHF), and prior medication therapy (calcium channel 
blockers, beta-blockers, digoxin, other anti-arrhythmics). Diltiazem characteristics included initial IV 
diltiazem LD; maintenance oral and continuous infusion doses at 60 minutes, 2 hours, and 4 hours; and 
the use of adjunctive therapy for HR control at 4 hours was also collected. Clinical outcomes collected 
include HR and blood pressure (BP) at baseline, 60 minutes, 2 hours, and 4 hours; ED disposition; and 
hospital LOS.  
 
Outcome Measures: 
The primary efficacy outcome measures the incidence of patients who have a HR <110 beats/min or 
conversion to sinus rhythm at 2 hours after medication administration. Two hours was selected to give 
time for the PO IR diltiazem to have an effect, time for the diltiazem drip to be titrated and the ED 
physician to decide on disposition. Failure was defined as either a switch in therapy from PO immediate 
release diltiazem to IV continuous infusion diltiazem (or vice versa), the addition or switch of therapy to 
other rate control or antiarrhythmic agents within 2 hours, or a HR of > 110 beats/min at 2 hours. 
 
Secondary outcomes included rate of conversion to sinus rhythm and identifying patient characteristics 
associated with HR control at 2 hours such as route of administration, age, weight, race, sex, initial heart 
rate and BP, and initial diltiazem LD.  Safety outcome measures were HR <60 beats/min and SBP <90 
mmHg for 15 minutes. 

 
Statistical Methods: 
Analysis of efficacy used the intent to treat principle that included all randomized patients. The null 
hypothesis is that there is no difference in the achievement of HR <110 beats/min, decrease in ventricular 
rate by at least 20%, or conversion to sinus rhythm between the PO and IV diltiazem group at 2 hours.  
 
Power calculation:  A “Sealed Envelope Ltd” program was used to calculate sample size. The standard 
deviations used to calculate the sample size were based on an internal retrospective study that looked at 
immediate release PO vs. continuous infusion diltiazem for HR control in patients with atrial fibrillation. An 
estimate of 92 patients assigned in a 1:1 ratio to receive immediate release PO and continuous infusion 
IV diltiazem would achieve 90% power to detect non-inferiority using a one-sided, two-sample t-test. 
Margin of equivalence 10%. 
 
Data were analyzed using Excel, R 3.2.2, and JMP 11.0.0 (Copyright 2013 SAS Institute, Cary, NC). 
Nominal variables were evaluated with Χ2 and continuous variables were compared using the Student’s t-
test.  Logistical regression modeling was used to identify patient characteristics associated with HR 
control at 2 hours. An a priori α level of ≤0.05 was used to determine statistical significance. 
 
RESULTS 
 
 
 
 
 
 
 

Figure 1: Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESULTS 
 
A convenience sample of __ patients who met inclusion criteria were enrolled in the study from ___ to 
___. ___ were randomized to immediate release PO diltiazem and ___ were randomized to continuous 
infusion IV diltiazem. ___ patients were excluded for ___. Patient recruitment and randomization 
assignment for the trial are shown in Figure 1. 
 
 
 
 
 
 
Follow-Up 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Analysis 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Enrollment 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Allocation 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Randomized (n=  ) 
Excluded  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
  Other reasons (n=  ) 
Assessed for eligibility (n=  ) 

Table 1: Baseline demographics  
 
Variable 
Overall 
Summary  
N= (SD) 
PO 
Group 
N= 
(SD) 
IV Group 
N= (SD) 
P-value (for t-test or Χ2 ) 
Age, y, (mean) 
 
 
 
 
Sex (Male) 
 
 
 
 
Race (Caucasian) 
 
 
 
 
Weight (kg) 
 
 
 
 
History of atrial 
fibrillation/flutter 
 
 
 
 
History of atrial 
flutter 
 
 
 
 
History of HTN 
 
 
 
 
History of CHF 
 
 
 
 
Prior medication 
therapy 
     CCB 
     BB 
     Digoxin 
     
Antiarrhythmics 
 
 
 
 
Mean HR 
(beats/min) 
 
 
 
 
Mean SBP 
(mmHg) 
 
 
 
 
Mean DBP 
(mmHg) 
 
 
 
 
Atrial fibrillation on 
ECG 
 
 
 
 
Atrial flutter on 
ECG 
 
 
 
 
Duration of AFF 
episode 
     <48 hours 
     >48 hours 
unknown 
 
 
 
 
Received 
adenosine 
 
 
 
 
Mean initial 
diltiazem dose 
(mg/kg) 
 
 
 
 
 
 
 
Table 2:  Characteristics associated with the primary endpoint 
 
Variable 
Difference 
Unadjusted 
Odds Ratio 
(95% CI) 
P-
value 
Adjusted 
Odds Ratio 
(95% CI) 
P-value 
Age, y, (mean) 
 
 
 
 
 
Sex (Male) 
 
 
 
 
 
Race 
(Caucasian) 
 
 
 
 
 

Weight (kg) 
 
 
 
 
 
History of atrial 
fibrillation 
 
 
 
 
 
History of atrial 
flutter 
 
 
 
 
 
History of HTN 
 
 
 
 
 
History of CHF 
 
 
 
 
 
Prior 
medication 
therapy 
     CCB 
     BB 
     Digoxin 
     
Antiarrhythmics 
 
 
 
 
 
Mean initial HR 
(beats/min) 
 
 
 
 
 
Atrial fibrillation 
on ECG 
 
 
 
 
 
Atrial flutter on 
ECG 
 
 
 
 
 
Duration of 
AFF episode 
     <48 hours 
     >48 hours 
UNKNOWN 
 
 
 
 
 
Mean initial 
diltiazem dose 
(mg/kg) 
 
 
 
 
 
 
PO: Oral 
IV: Intravenous 
LD: Loading dose 
HR: Heart rate 
kg: Kilogram 
mg: Milligram 
CI: Confidence interval 
 
Table 3: Conversion to sinus rhythm 
 
Time 
PO (%) 
IV (%) 
P-value 
After 
bolus 
 
 
 
60 
minutes 
 
 
 
2 hours 
 
 
 
4 hours 
 
 
 
 
 
Table 4: ED Disposition 
ED Disposition 
PO Group 
IV Group 
Discharge 
 
 
General floor with telemetry 
 
 
Stepdown 
 
 

ICU 
 
 
Hospital LOS 
 
 
PO: Oral 
IV: Intravenous 
 
i Schreck DM, Rivera AR, Tricarico VJ. Emergency management of atrial fibrillation and flutter: 
intravenous diltiazem versus intravenous digoxin. Ann Emerg Med. 2016;29(1):135-140. 
ii Siu C, Lau C, Lee W, Lam F, Tse H. Intravenous diltiazem is superior to intravenous amiodarone or 
digoxing for achiving ventricular rate control in pateints with acute uncomplicated atrial fibrillation. Crit 
Care Med. 2009;37:2174-79. 
iii Fromm C, Suau SJ, Cohen V, Likourezos A, Jellinek-Cohen S, Rose J, Marshall J. Diltiazem vs. 
metoprolol in the management of atrial fibrillation or flutter with rapid ventricular rate in the emergency 
department. J Emerg Med. 2015;49(2):175-82. 
iv Lexicomp Online®, Lexi-Drugs® Hudson, Ohio: Lexi-Comp, Inc.; June 29, 2016.