Diltiazem in the Treatment of Atrial Fibrillation or Atrial Flutter With Rapid Ventricular Rate (AFF RVR): Comparing Calcium Pre-treatment vs Placebo in Prevention of Diltiazem Induced Hypotension
Phase: PHASE4
Conditions: Atrial Fibrillation With Rapid Ventricular Response, Hypotension Drug-Induced
Sponsor: Wake Forest University Health Sciences

Official Title:  Diltiazem in the Treatment of Atrial Fibrillation or Atrial Flutter With Rapid Ventricular Rate (AFF 
RVR): Comparing Calcium Pre-treatment vs Placebo in Prevention of Diltiazem Induced Hypotension  
NCT05661942
IRB Approval Date:  11/06/2024

PROTOCOL TITLE    
Diltiazem in the treatment of atrial fibrillation or atrial flutter with rapid ventricular rate (AFF 
RVR): Comparing calcium pre-treatment vs placebo in prevention of diltiazem induced 
hypotension 
  
•                       SPONSOR    
N/A 
  
•                       PROTOCOL Version Number and Date: 
Version 2. June 22nd, 2023 
  
•                       PRINCIPAL INVESTIGATOR      
Michael Cirone, MD 
                                                                       
•                       STUDY SUMMARY 
Non-dihydropyridine calcium channel blockers (CCB) are routinely used in the 
treatment of atrial fibrillation or flutter with rapid ventricular response (AFF with 
RVR) however, their use can be limited by drug induced hypotension. This drug 
induced hypotension limits and complicates CCB use in the treatment of AFF with 
RVR. Calcium pre-treatment with calcium channel blocker administration has been 
studied extensively with verapamil administration in preventing drug induced 
hypotension however, similar studies evaluating calcium pretreatment with diltiazem 
administration in the prevention of drug induced hypotension are limited. 
The purpose of our study is to compare the relative efficacy and safety for calcium 
pretreatment with diltiazem in the treatment of AFF with RVR in preventing drug 
induced hypotension. This prospective, randomized double-blinded study will evaluate 
patients who present to the emergency department at Advocate Christ Medical Center 
(ACMC) with a diagnosis of AFF RVR with ventricular rate greater than or equal to 
120 bpm from IRB approval to June 1, 2024. Via simple randomization, patients will 
be administered Calcium pre-treatment vs control prior to diltiazem administration. 
Calcium gluconate 1gm or 100 mL of normal saline will be administered as an 
intravenous infusion over 5 minutes followed by bolus diltiazem 0.25 mg/kg IV push 
(with a 20mg max) with repeat diltiazem bolus dose after 15 minutes if rate control not 
achieved 0.35mg/kg IV push. Calcium gluconate will not be administered with repeat 
doses of diltiazem. Weight-based dosing of diltiazem was most utilized, though some 

providers may elect to modify based on the clinical scenario. The primary outcome will 
be the mean difference in systolic blood pressure (SBP) evaluated at 5 and 15 minutes 
after administration of diltiazem bolus. Secondary outcomes include decrease in heart 
rate, conversion to sinus rhythm, and adverse effects of medication administered. 
  
  
•                       OBJECTIVES 
To compare the relative efficacy for calcium pre-treatment in decreasing incidence of drug 
induced hypotension after diltiazem administration for treatment of AFF with RVR. 
Null Hypothesis: There will be no difference between groups in incidence of hypotension after 
pretreatment with calcium prior to bolus of diltiazem. 
  
•                       BACKGROUND/LITERATURE REVIEW             

Atrial fibrillation accounts for more than 454,000 hospitalizations each year in the United 
States.1  Rapid ventricular response (RVR) is a potential sequelae of atrial fibrillation which 
results in loss of atrial kick, shortened ventricular filling, increased myocardial oxygen demand 
and ultimately hemodynamic instability.2  Treatment guidelines from the American Heart 
Association recommend intravenous beta blockers, non-dihydropyridine calcium channel 
blockers, or Amiodarone/Digoxin in the treatment of atrial fibrillation with RVR.3 Diltiazem is 
one of the most commonly used CCB to treat AFF with RVR.4  
Despite AFF with RVR being a common disorder and commonly treated with diltiazem, there 
are known limitations and complications of drug induced hypotension. Nationally, and within 
the ACMC ED, there is no consensus to the management of atrial fibrillation with rapid 
ventricular response. Management options include calcium channel blockers (predominantly 
diltiazem), beta blockers (predominantly metoprolol), and antiarrhythmics like amiodarone and 
digoxin. When employing calcium channel blockers standard of care includes the possibility of 
calcium pretreatment in an effort to prevent drug induced hypotension. Several studies have 
shown that verapamil with calcium pretreatment results in decreased incidence of drug induced 
hypotension; however, studies analyzing pretreatment of calcium with diltiazem in decreasing 
drug induced hypotension are limited .5,6 In recent years, physician preference and comfort has 
led to increased utilization of diltiazem (rather than verapamil) in managing atrial fibrillation 
with RVR. As a result, evidence of calcium’s efficacy in conjunction with this specific 
nonDHP is lacking.  
 
Diltiazem has a mechanism which inhibits the flow of calcium into the myocardium and is 
widely used in the treatment of AFF with RVR. It has also been utilized in the treatment of 
paroxysmal supraventricular as its mechanism causes slowing of AV nodal conduction time 
and prolongs the AV nodal refractory period.7 Furthermore, diltiazem inhibits the inflow of 
calcium ions on vascular smooth muscle, causing vasodilation and ultimately decreasing 
peripheral vascular resistance. This, in combination with its negative inotropic effects, results 
in a decrease in blood pressure, which is frequently seen with its administration. Prior studies 
including in vitro and animal data suggest that pretreatment with calcium prior to CCB 
administration may minimize the effects on cardiac output and blood pressure.8 In the setting 
of AFF with RVR, these effects of decreased blood pressure and cardiac output can limit the 
safety of CCB use. This study aims to evaluate the impact of calcium pretreatment in 
decreasing the incidence of drug induced hypotension.  
  
  
  
  
•                       SUMMARY OF METHODS 
  
•     Study Design 

Single center, prospective, double-blinded (prescriber and patient), randomized-
controlled trial 
  
•     Setting 
Advocate Christ Medical Center Emergency Department (ACMC ED) 
  
•     Population 
Patients presenting to ACMC ED with a primary diagnosis of AFF with RVR from 
IRB approval to June, 2024 
  
•     Sample Size 
• A maximum of 92 subjects (46 subjects treated with Calcium 
and 46 subjects treated with control) will be included in this 
prospective randomized study based on estimates of patients 
presenting to the Emergency Department with a primary 
diagnosis of AFF RVR.  With this sample size, we will have 
80% power to detect a mean difference of 10.5 mmHg between 
groups for the primary outcome of mean Numeric Rating Scale 
with an alpha of 0.05, anticipating a 25% dropout rate (at most).  
 
  
•     Recruitment 
Patients presenting to Advocate Christ Medical Center emergency department with 
a diagnosis of AFF with RVR from IRB approval to (to be determined) seven days 
a week while a pharmacist is present. The ED physician or ED PharmD providing 
care for the patient will identify patients’ eligible for the study and one of the ED 
PharmDs listed on the personnel delegation log will consent the patient. The 
pharmacist will document consent in the EMR using an EPIC smartphrase.  
  
  
•     Inclusion criteria7 

•           Age > 18 years or older 
•           Able to provide informed consent 
•           Primary diagnosis AFF with RVR greater than or equal to 120 bpm 
  
  
  
  
  
  
  
  
•     Exclusion criteria7 
•           Pregnancy defined as a positive urine HCG 
•           Hemodynamically unstable patients (SBP <90, MAP <65) 
•           Stated history of systolic heart failure with reduced ejection fraction 
(<40%) or evidence of acute heart failure or reduced EF (peripheral edema, 
JVD, pulmonary edema) on clinical exam or bedside echo  
•          Patients with left ventricular assist device 
•           Sinus node dysfunction or preexcitation with accessory pathway (known 
diagnosis of SVT, WPW or sick sinus syndrome. Delta waves or other evidence 
of accessory pathway on EKG) 
•           2nd or 3rd degree atrioventricular block 
•           Allergy or sensitivity to any study drugs 
•           Previously enrolled in this trial during a different patient encounter 
•           Non-English speaking 
 
 
  
  
•     Vulnerable Populations 
N/A 
  
•     Study Endpoints 

Primary Endpoints:7 
•     Mean difference in SBP evaluated at 5 and 15 minutes 
after initiation of infusion of diltiazem 
Secondary Endpoints:7 
•     Change in heart rhythm at 5 and 15 minutes after initiation 
of infusion of diltiazem  
•     Mean change heart rate at 5 and 15 minutes after initiation 
of infusion of diltiazem 
•     Adverse effects due to administration of medications 
•     Clinical need for rescue medication administration   
  
•     Measures/Instrumentation 
Blood pressure at baseline 5 and 15 minutes after administration of 
Diltiazem infusion 
  
  
  
  
  
  
  
  
  
 •   Study Procedures 

Patients presenting to Advocate Christ Medical Center emergency department (ED) 
with a diagnosis of AFF with RVR from IRB approval to June 1, 2024 twenty four 
hours a day, seven days a week. The ED physician will identify patients eligible for 
the study and alert the ED pharmacist who will consent the patient using the 
consent form (attached). An EPIC dot.phrase will utilized to capture informed 
consent for this study (example below). Each patient will be handed a copy of the 
consent form and signed consent forms will be kept at Advocate Christ Medical 
Center in the PI’s locked office.  This study will be registered at clinicaltrials.gov 
by Dr Cirone.  
 
 
Example/tentative dot.phrase for document informed consent for this study: 
.calciumpretreatmentvsplacebopreventiondiltiazeminducedhypo 
RESEARCH PROGRESS NOTE 
Study Title: 
IRB #: 
Brief Description: 
               PI: Dr. Cirone  
  
Via simple randomization, patients will be allocated to one of two study drug 
groups, either the intervention (calcium gluconate) or control (normal saline) group. 
Once the order for the study drug is put in by the ED physician or ED pharmacist 
and verified, the ED pharmacist will retrieve the study drug from the medicine 
automated dispensing cabinet (Pyxis) located in the ER. The study drug and the 
placebo will be stored in pyxis in a kit format which will include diluent (NS) and 
the study drug or placebo (NS) vials. These kits will be created by a pharmacist or 
technician not participating in the study according to a randomization schedule on a 
password encrypted excel sheet in the pharmacy G drive. This will only be 
accessible by the pharmacist creating these study kits. All the vials in the study kit 
will be covered to keep the drugs blinded to both investigators and the patients. The 
ED pharmacist will deliver the study drug to the bedside nurse for administration.    
The pharmacists, physicians, and nurses participating in administration of the 
medications will be blinded to which drug is being administered.  Inclusion in the 
study will not result in any additional cost to the patient. 
  
Medication administration: 
Study drug (Calcium gluconate 1 gram/100ml 0.9% NaCl or 100ml 0.9% 
NaCl)over 5 minutes). Immediately after administration of the study drug, diltiazem 
will be administered as an IV push over 5 minutes. Additional doses of diltiazem 

IV push over 5 minutes are permissible, however no additional doses of study drug 
will be administered. 
 
 The primary outcome of this study will be the Mean difference in SBP evaluated at 
5 and 15 minutes after administration of diltiazem bolus. Monitors were set to 
obtain an automated full set of vitals every 5 minutes after administration of 
diltiazem. Secondary endpoints include mean change heart rhythm at 5 and 15 
minutes after administration of diltiazem bolus, mean change heart rate at 5 and 15 
minutes after administration of diltiazem bolus, adverse effects due to 
administration of Calcium gluconate and adverse effects due to administration of 
Diltiazem infusion.  
Adverse events will be assessed by the ED pharmacist at the specified time 
intervals including but not limited to nausea, vomiting, lightheadedness, headache 
or extravasation.  
The following data points will be collected: medical record number (MRN), 
age, gender, race, weight, height, initial vitals (heart rate, blood pressure, 
respiratory rate, temperature, and oxygen saturation), repeated vitals, past 
medical history, medications taken prior to arrival, hospital length of stay 
and medications given for treatment failure along with their routes and 
dosages. 
  
Confidentiality will be maintained to the extent possible. Furthermore, information 
will be kept on a password protected computer located at Advocate Christ Medical 
Center in the PI’s locked office. The recorded data will be destroyed following 
completion of study, analysis of data and dissemination of our findings. 
 
Monitoring Plan:  
 
INTRODUCTION 
The monitoring plan includes reviews for both data integrity and minimization of risk to 
patients involved in the study. The principal investigators Dr. Cirone, co-investigators, 
research biostatistician Cindy Ndiaye, and the Advocate Aurora Health Care Institutional 
Review Board will be involved in the interim monitoring activities. Monitoring will be 
conducted in accordance with applicable regulations and institutional/IRB policies. 
 
PURPOSE 
The purposes of controlled trial quality monitoring reviews are to verify that: 
(a) The rights and well-being of human subjects are protected. 
(b) The reported trial data are accurate, complete, and verifiable from source 
documents. 

(c) The conduct of the trial follows the currently approved protocol/amendment(s) 
and applicable regulatory requirement(s). 
                 
ROLES/REVIEWS 
Principal investigators and co-investigators: The principal investigators, co-investigators, and 
research biostatistician will carefully assess and evaluate the first nine subjects enrolled in 
controlled trial to monitor for any rare adverse outcomes that may or may not have been 
known prior to study start. The same assessment will be performed at the midpoint of the 
study, after the 46th subject is enrolled. A stopping plan, explained further under the over-
view, will be enacted at the midpoint interim look. 
 
  
For all subjects, the Principal Investigators and co-investigators will continue to review all 
adverse outcomes and will regularly monitor the data to identify trends throughout the study.  
The Principal Investigator and co-investigators will be responsible for reporting all adverse 
events to the IRB and for revising the protocol as needed to maintain safety. Primarily, the 
Principal Investigators, co-investigators, and research biostatistician will be responsible for the 
IRB submissions, ClinicalTrials.gov registration, safety reporting and other regulatory 
components of the study. 
 
QUALITY MONITORING REPORT OVER-VIEW 
The primary and co-investigators will conduct a monitoring report with the research 
biostatistician to occur prior to enrollment of the 10th subject and again at the midpoint of the 
study after the enrollment of the 46th subject for a total of two interim looks. The quality 
monitoring review must include an assessment of the following records and results must be 
submitted to Advocate Aurora Health Institutional Review Board:  
1) Regulatory and IRB files (e.g., protocol, consent form, study team CITI training 
and curriculum vitae, delegation of authority log, IRB approvals and 
correspondence). 
2) Subject chart review for all subjects consented/enrolled, assessing for 
appropriately obtained consent, accuracy of eligibility, and all follow-up data 
collected. 
3) Any adverse events reported thus far. 
4) Drug accountability and storage. 
A stopping plan will also be put in motion to minimize risk of Type I error. The plan consists 
of using the O’Brien-Fleming boundary to test at the second interim look (n=46) if the 
probability of the randomized-control trial rejecting a false null hypothesis is <0.05. If the 
probability is >0.05, then the experiment will be stopped.  

 
  
  
•                       DATA MANAGEMENT PLAN      
The following study variables will be collected based on the study objectives: 
•           Medical Record Number (MRN) 
•           Age 
•           Gender 
•           Race 
•           Ethnicity 
•           Weight 
•           Height 
•           Initial vitals (heart rate, heart rhythm, blood pressure, 
respiratory rate, temperature and oxygen saturation) 
•           Past Medical History 
•           Serum Calcium if available prior to medication 
administration (as measured on complete metabolic panel) 
•           Hospital length of stay 
•           Medications given for treatment failure 
•           Dose and route of rescue medications given 
•           Time to administration of medication 
•           Repeat Vitals following medication administration (heart 
rate, heart rhyhtm, blood pressure, respiratory rate, temperature 
and oxygen saturation) 
  
All data will be collected, and confidentiality will be maintained. Furthermore, 
information will be kept on a password protected computer located at Advocate Christ 
Medical Center in the ED administration office. The recorded data will be destroyed 
following completion of study and analysis of data. Data collection and analysis will 
only be conducted by the members of the research team. If data is needed to 
transported, it will only be done by the research team and will only be transported 
between team members. Transfer of data will be done person to person or electronically 
via a password protected drive. 
All information gathered during this study will be kept confidential.  Study data will be 
managed using REDCap16 electronic data capture tools hosted by Advocate Health 
Care. REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing 1) an intuitive interface 
for validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from external sources.  The 

data will be accessible to only the study investigators and REDCap administrators. 
Subjects will be assigned case numbers. Data being extracted from the REDCap 
database will include only the case numbers and be de-identified via the electronic 
removal of PHI prior to data download.  After data collection is complete and records 
have been verified, identifiers will be permanently removed from the data set. Any 
study documentation including regulatory information, consent forms, and data 
collection forms will be secured in a locked cabinet in the pharmacy resident’s locked 
office and ill be destroyed upon completion of the study and analysis of the data. 
 
 
 
 
 

●      Data Analyses   
A  maximum of 92 subjects (46 subjects treated with Calcium and 46 subjects treated 
with control) will be included in this prospective randomized study based on estimates 
of patients presenting to the Emergency Department with a primary diagnosis of AFF 
RVR.  With this sample size, we will have 80% power to detect a mean difference of 
10.5 mmHg between groups for the primary outcome of mean Numeric Rating Scale 
with an alpha of 0.05, anticipating a 25% dropout rate (at most).  
  
Descriptive statistics will be calculated for all variables and presented overall and by 
group using mean ± SD for continuous variables and count/percentages for categorical 
variables. Comparisons will be made between groups for all outcomes using Chi-
Square or Fisher’s exact tests as necessary for categorical data and a one-way ANOVA 
as appropriate for all continuous data. All tests will be two-tailed and a p-value of 0.05 
will be considered statistically significant in all analyses. We will also assess utilizing 
multiple predictive multivariate logistic regression models. 
  
•                       BENEFITS    
There will be no direct benefit for participating in this study. 
  
  
  
  
•                       RISKS 
Common adverse effects associated with standard of care medications. 10-11 
•          Calcium: hypotension, bradycardia, tingling, upset stomach 
•          Diltiazem: lightheadedness, weakness, nausea, headache 
  
 
•                       AVAILABLE RESOURCES 

Advocate Christ Medical Center has a rich history of conducting clinical research by 
qualified and experienced investigators. Multiple resources will be available throughout 
the study. Members of the research team have extensive experience in conducting 
research and in their designated areas of practice. The research team is committed to 
the study and will be available to be reached at any time for questions or any problems 
that may arise. 
  
Michael Cirone, M.D. – Emergency Medicine Physician  
Marc McDowell, Pharm.D. – ED Clinical Pharmacist 
Cindy Ndiaye, MPH – Research Coordinator  
Nadine Lomotan, Pharm.D. – ED Clinical Pharmacist  
Barb Bukowski, Pharm.D. – ED Clinical Pharmacist 
Kara Fifer, Pharm.D. – ED Clinical Pharmacist  
Kate Roels, Pharm.D. – ED Clinical Pharmacist  
Andrew McInerney, Pharm.D – Emergency Medicine Pharmacy Resident 
Siri Krishna Khalsa, M.D. – Emergency Medicine Resident 
Connor Corrente, M.D. – Emergency Medicine Resident 
 
  
 
  
•                      REFERENCES         

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AP, et al. Heart disease and stroke statistics—2019 update: a report from the 
American Heart Association. Circulation. 2019;139(10):e56–528.  
2.     Moskowitz A, Chen KP, Cooper AZ, Chahin A, Ghassemi MM, Celi LA. 
Management of Atrial Fibrillation with Rapid Ventricular Response in the 
Intensive Care Unit: A Secondary Analysis of Electronic Health Record Data. 
Shock. 2017 Oct;48(4):436-440. doi: 10.1097/SHK.0000000000000869. PMID: 
28328711; PMCID: PMC5603354. 
3.     Craig T. J, L. Samuel W, Hugh C, et al. 2019 AHA/ACC/HRS Focused 
Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients 
With Atrial Fibrillation: A Report of the American College of 
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https://doi.org/10.1016/j.jacc.2019.01.011. 
4.     Lee J, Kim K, Lee CC, Nam YW, Lee JH, Rhee JE, Singer AJ, Kim KS, Ro 
Y. Low-dose diltiazem in atrial fibrillation with rapid ventricular response. Am 
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2010 May 1. PMID: 20825912. 
5.     Calcium before Diltiazem may reduce hypotension in rapid atrial 
dysrhythmias. ALiEM. (2016, November 12). Retrieved December 14, 2021, 
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hypotension/. 
6.     Salerno DM, Anderson B, Sharkey PJ, Iber C. Intravenous verapamil for 
treatment of multifocal atrial tachycardia with and without calcium 
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7.     Kolkebeck T, Abbrescia K, Pfaff J, Glynn T, Ward JA. Calcium chloride 
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10.  Diltiazem lexicomp 
11.  Calcium lexicomp 

  
•                       ABBREVIATIONS & ACRONYMS 
AFF with RVR - Atrial fibrillation or flutter with rapid ventricular response 
ANOVA – Analysis of Variance 
CCB – Calcium channel blocker 
ED – Emergency Department 
  
•                       DATA DICTIONARY 
•           Medical Record Number (MRN) 
•           Age 
•           Gender 
•           Race 
•           Weight 
•           Height 
•           Initial vitals (heart rate, blood pressure, respiratory rate, 
temperature and oxygen saturation) 
•           Past Medical History 
•           Hospital length of stay 
•           Medications given for treatment failure 
•           Dose and route of rescue medications given 
•     Time to administration of medication