Clinical trial NCT05391893
Conditions: Atrial Fibrillation Atrial Flutter
Sponsor: Spectrum Health - Lakeland
Start date: 2020-06-19; Completion date: 2023-04-01
Enrollment: 444 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to reduce hospital admission and decrease time to disposition through establishing an effective treatment protocol for AF and Atrial Flutter in the Emergency Department of Spectrum Health Lakeland. Secondary outcome is to measure if oral diltiazem is an effective HR controlling agent in AF RVR and Flutter.

Detailed description:

Arms: arm 1: Diltiazem 0.25mg/kg injection, give over 2 minutes, max dose 30mg. 15 minutes following Diltiazem Infusion administer oral Diltiazem 60mg IR Tablet, do not give if BP\<100 arm 2: these patients will receive traditional treatments at provider discretion. To be included in teh study their initial heart rate must also be over 125, and they must receive at least one intravenous medication for atrial fibrillation with rapid ventricular response. This will be a heterogenous group of patients receiving digoxin, amiodarone, various beta-blockers, and intravenous diltiazem without oral diltiazem.
Interventions: intervention 1: Oral intervention 2: Intravenous drug
Intervention descriptions: intervention 1: Diltiazem 0.25mg/kg injection, give over 2 minutes, max dose 30mg intervention 2: these patients will receive traditional treatments at provider discretion. They must receive at least one intravenous medication for atrial fibrillation with rapid ventricular response. This will be a heterogenous group of patients receiving digoxin, amiodarone, various beta-blockers, and intravenous diltiazem without oral diltiazem.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Effect of Oral and Intravenous Diltiazem Protocol for Emergency Department Atrial Fibrillation 
NCT #: NCT05391893 
Date: 12/3/2024 
 
 
 
 
 


Title: Effect of Oral and Intravenous Diltiazem Protocol for Emergency Department Atrial Fibrillation 
Authors: Jared Sustad DO, Taylor Huizenga DO, Matthew Hysell MD 
Introduction or Background  
Atrial Fibrillation (AF), a supraventricular tachyarrhythmia, is the most common sustained cardiac 
arrhythmia (Nileshkumar et al., 2014). The number of hospitalizations yearly for AF is increasing 
progressively from 312,926 in the year 2000, to 409,854 in 2010, with a total of 3,960,011 
hospitalizations for AF reported in the United States over that same time period (Nileshkumar et al., 
2014). In 2005, the total cost for the treatment of non-valvular atrial fibrillation was estimated at 6.65 
billion dollars (Coyne et al., n.d.). Further, the prevalence of AF has been projected to increase to 15.9 
million by the year 2050 with more than half of these patients ≥80 years of age (Nileshkumar et al., 
2014). Considering all of these factors, the total economic burden and public health concern regarding AF 
is of increasing significance, therefore it is important to determine effective treatment strategies that can 
help reduce hospital admissions, costly ICU admissions, and length of stay.  
There are two approaches to managing AF in the emergency department (ED): rate control and 
rhythm control. The AFFIRM trial in 2002 found no significant survival advantage in rate vs rhythm 
control strategies. Rate control was associated with less adverse drug effects and hospitalizations (Wyse 
et al., 2002). The RACE II trial in 2010 established that less aggressive rate control (110 bpm) was as 
effective in preventing adverse cardiovascular events as strict control (80 bpm) (Van Gelder et al., 2010).  
Beta blockers and non-dihydropyridine calcium channel blockers are accepted rate controlling agents. 
Emergent treatment of stable AF with rapid ventricular response (RVR) in the ED should aim to achieve 
lenient heart rate control for improved patient outcomes to reduce side effects while providing equal 
treatment outcomes. 
Problem and Purpose Statement-Objective of the Research  
The primary objective of this study is to reduce hospital admissions and decrease time to 
disposition through establishing an effective treatment protocol for AF and Atrial Flutter in the 
Emergency Departments of Spectrum Health Lakeland.  Additionally, there is a secondary outcome to be 
measured. Is oral Diltiazem (a non-dihydropyridine calcium channel blocker) an effective HR controlling 
agent in AF RVR and Flutter. Currently, treatment of AF can be performed with multiple drugs and 
formulations, resulting in different dispositions from the ED.  Previous studies have shown that ED AF 
observation is an effective strategy that can reduce admissions and time to disposition. (WW et al., 2008) 
In 2018 researchers at VCU retrospectively compared heart rate control with oral Diltiazem vs. 
continuous IV infusion of Diltiazem. Their study exhibited that oral Diltiazem was as effective in HR 
control for AF RVR, with less treatment failures. (Means et al., 2018) We hope to add to the supportive 
data for using oral Diltiazem for heart rate control in AF RVR or Flutter. An oral one-time medication 
administration would reduce strain on nursing staff, medication costs, and decrease disposition time. 
Improving efficient and effective treatment of AF in the ED. 
Throughout the Spectrum Health Lakeland System in 2018 - 68.5% of patients with a primary 
diagnosis of AF were admitted to the hospital, the cost of care for these patients was nearly 16.5 million 
dollars. Of AF patients who presented to Spectrum Health Lakeland, 8% were observed from the 
emergency department for a total cost of 1.27 million dollars. Is it possible that some of those admitted 
patients could have been observed, and discharged more expediently while reducing healthcare costs? 
 


Research Questions or Hypothesis  
Below are the 2 main research hypotheses that we aim to test. 
1. Instituting an ED AF observation treatment protocol will reduce admissions and time to disposition in 
observation.  
2. Oral Diltiazem is an effective heart rate controlling agent for AF RVR in the ED 
 
Theoretical Framework-Present Knowledge /Literature Review 
The RACE and AFFIRM trials have shown that rate control is as effective, and a potentially 
safer, treatment for AF RVR than electrical or chemical cardioversion (JL and RE, 2003). The RACE II 
trial has also shown that lenient HR control with HR <110 is as effective as strict control HR<80, and 
easier to achieve (Van Gelder et al., 2010). Accepted rate controlling agents include Metoprolol, 
Diltiazem, and Digoxin. Metoprolol and Diltiazem are often chosen for treatment of AF with RVR, given 
as intravenous boluses or infusions. They have been shown to have no statistical difference in their ability 
to achieve rate control, with a similar adverse effect profile (Hirschy et al., 2019). Traditionally, patients 
are treated with an initial IV bolus of medication followed by an infusion or additional IV pushes until 
HR is achieved. After heart rate goal is achieved, they are transitioned to oral medications, and observed 
until deemed stable for discharge. An observation protocol for AF can reduce time to disposition and 
admissions as shown in a study published in Annals of Emergency Medicine in 2008 (WW et al., 2008). 
This study had inclusion criteria of <48hrs of symptom onset, and also included electrical cardioversion 
as a possible endpoint. There have been other published protocols for AF RVR observation that displayed 
decreased admission rates, but there is also a focus on optional cardioversion (Koenig et al., 2002). The 
RACE, RACE II, and AFFIRM trials have shown that lenient HR control is a safe and equally effective 
treatment modality for AF RVR, regardless of time of onset.  
Diltiazem is a non-dihydropyridine calcium channel blocker useful in the management of AF in 
the absence of pre-excitation (Ganz, n.d.). In the ED, acute rate control using Diltiazem is accomplished 
with a loading dose, given as an IV infusion, plus or minus a second dose given after 15 minutes if there 
was not a 20 percent reduction in heart rate from the baseline, or a heart rate less than or equal to 100 
BPM after the initial dose (Ganz, n.d.). Individuals who respond to the first or second bolus can be 
initiated on a continuous infusion of IV Diltiazem or be given PO immediate release tablets for continued 
management of heart rate. Patients who are treated with oral Diltiazem require less resources, given that 
IV continuous infusion patients must have their dose frequently titrated by nursing. Oral Diltiazem with 
ED observation has the potential to effect overall visit healthcare costs and length of stay. A 2018 VCU 
retrospective study found that PO immediate-release Diltiazem was associated with a lower rate of 
treatment failure (sustained heart rate >110 beats/min at four hours or conversion to another agent) as 
compared to IV continuous infusion Diltiazem in patients with AF with RVR (Means et al., 2018). 
However, no study has yet to be completed implementing oral Diltiazem treatment uniformly amongst 
patients presenting in AF with RVR. We aim to test the external validity of the 2018 VCU study and add 
to the data on oral Diltazem as a rate-controlling agent for AF RVR. 
A new ED observation unit at SHL has been built with hopes to be up and running in 2020. AF 
will be one of the conditions treated in this new unit. To ensure all patients receive excellent and efficient 
care, the oral Diltiazem AF RVR protocol will be instituted as the AF treatment protocol. 
 


Methodology  
Patients will be entered into the protocol from the ED if they are deemed to meet the inclusion 
criteria specified below. The St. Joseph and Niles Emergency Departments will be used to enroll 
participants. Patients who meet criteria will be transferred to the observation unit and will receive the 
treatment protocol listed below. The treatment protocol will be explained to them by the ED Physician or 
Resident responsible for their care. Nurses and techs using the Phillips monitors in each patient room will 
collect data and enter it into the Epic EHR. HR and BP will be recorded as listed below in the order set 
for the protocol. The outcome of rate of treatment success defined as HR <110 at 4 hours post study entry 
(as was defined in the 2018 VCU study) will be measured. (Means et al., 2018) This will be compared 
with data from the 2018 study at VCU using chi-squared test. Additional outcomes including length of 
stay from time of arrival in the ED to discharge from the observation unit, and admission rates will be 
recorded. Admission rates and length of stay will be compared to historical data from Lakeland. 
This data will be maintained only upon Lakeland severs and computers.  
Time to discharge can be compared to retrospective means from 2018-2019 using students t-test. 
This data will be gathered from Epic EHR for AF patients treated at either emergency department 
participating in the study. Admission rates will be analyzed using chi-squared testing.  We will gather this 
data from time of study start in 2020 to that exact date in 2021. ED return visits within <72hrs will be 
recorded. Patient characteristics including age, sex, race, and weight will also be gathered. Deidentified 
data will ultimately be sent to the SASS group at Spectrum in GR for statistical analysis. 
Research Design- Proposed Observation Protocol 
This includes AF Protocol formatted as an Orderset which will contain orders for data gathering, 
medications, and patient care- to be selected in EPIC. 
Atrial Fibrillation Observation Treatment Protocol – Orderset  
Use ED to Obs AF Protocol if patient meets the following inclusion criteria. 
Inclusion Criteria: 
Patient is stable, HR>110 with Systolic BP>100, afebrile, Atrial Fibrillation/Flutter confirmed on ECG. 
Meets observation unit requirements (performs certain ADLS), Age>18. If patient has history of Atrial 
Fibrillation and takes rate controlling/anti-arrhythmic agent please still use observation Diltiazem 
protocol. If unstable cardiovert. 
Exclusion Criteria: 
WPW, STEMI, Pregnant, Sepsis, Decompensated HF, allergy to Diltiazem, provider discretion  
 
Start with ED order set, when completed use observation order set when admitting to observation. 
ED Orderset – Use First 
Meds: 
Diltiazem 0.25mg/kg injection, give over 2 minutes, max dose 30mg (Ross et al., 2016).  


15 minutes following Diltiazem Infusion administer oral Diltiazem 60mg IR Tablet, do not give if 
BP<100 
Labs: 
Thyroid Function Cascade  
Comprehensive Metabolic Panel 
Complete Blood Count-w/ Diff 
Magnesium 
PT 
PTT 
High Sensitivity Troponin Initial – If indicated/Provider Discretion  
 
 
Imaging/ECG 
12 Lead ECG 
Chest Xray AP/PA one view 
Nursing: 
Prior to Starting Diltiazem Infusion- Obtain HR, BP, and RR 
-1st Hour following Diltiazem Infusion 15min Vitals HR/BP 
-Hourly post Diltiazem Infusion- HRx3 1 minute apart, BP 
- Insert peripheral IV 
-Cardiac telemetry class II 
-Continuous pulse oximetry 
  
Obs Orderset – Use Second 
Admit to Observation order, place in bed for observation services emergency medicine, provider 
Diet-General 
Code status order 
Oxygen Therapy Per Protocol: Routine, PRN to maintain SpO2>92% 
Nursing Care 
Nursing interventions 


UNTIL DISCONTINUED, Notify provider for pulse less than 60 or greater than 150, respiratory 
rate less than 12 or greater than 25, temperature greater than 38.5, urinary output less than 30 
mL/hr for four hours, systolic BP less than 90 or greater than 180, diastolic BP less than 60 or 
greater than 90. 
Notify provider if HR>130 at 2hour mark post Diltiazem Infusion (Provider consider starting IV 
infusion/medication change) 
Notify Provider if HR<110 for >1hr at any time- patient may be ready for discharge 
Vital Signs 
-Hourly post PO Diltiazem- HRx3 1 minute apart, BP - continued from ED set  
Cardiac telemetry class II 
Continuous pulse oximetry 
Nursing to call cardiology for follow up appointment. Goal for appointment to be made within 3 days 
Activity as tolerated  
 
Medications 
IV fluids 
0.9% NS Infusion- provider discretion 
325mg Aspirin PO- if suspected ACS  
 
 
Assessments: 
Chads2Vasc Calculator: 
Age <65-0, 65-74-+1, >75 +2 
Sex Male-0, Female-+1 
CHF history Yes +1. No-0 
HTN History Yes+1, No-0 
Stroke/TIA/Thromboembolism History- Yes+2, No-0 
Vascular Disease History (Prior MI, PAD, Aortic Plaque)  
Diabetes History- Yes +1, No-0 
Score of 0-1 – no anticoagulation indicated, consider daily 81mg Aspirin 
2+- Anticoagulation indicated- start Eliquis 


 
Anticoagulation for Discharge 
Eliquis- 5mg BID (unless age≥80, weight ≤60kg, Creatinine ≥1.5mg/dL, then reduce dose to 2.5mg BID) 
(ZA and SK, 2018)  
If patient has mechanical heart valve and not anti-coagulated, start on Coumadin with dosing below. Also, 
start if patient has known moderate/severe mitral stenosis. 5mg x 3 days- INR check morning of day 4 
If frail, elderly (eg, woman >70 years, man >80 years), malnourished, has liver or kidney disease or heart 
failure, or is receiving a medication known to increase warfarin sensitivity (eg, Amiodarone) - 2.5mg x 
3days INR check day 4 
Perform Lovenox bridging 1mg/kg Subcutaneous daily until INR check. Give first dose prior to 
discharge.  (Ha et al., 2017)  
Order 1mg/kg Lovenox Daily, route Subcutaneous 
Discharge order 1mg/kg Lovenox Daily, route subcutaneous X 4 days 
Imaging  
Cardiac Transthoracic Echo – if patient has not had echo in last 6 months. Indication Atrial 
Fibrillation  
Consult: Cardiology- Reason Atrial Fibrillation 
On call provider – *Optional -Concern for ACS, chest pain 
Discharge: 
If patient does not require further CPU management/Cardiology Evaluation and does not require 
admission discharge if HR is <100, SBP>100  
Discharge patient with proper anticoagulation based on above. If already on rate controlling agent assess 
reason for elevated HR. If appropriate, resume home rate controlling agent or make dosage adjustment. 
Phone consult to cardiology if change in agent considered.    
If no prior rate controlling agent, discharge with 120mg ER PO Diltiazem tab- Once Daily. Give prior to 
discharge.    
All patients need cardiology/PCP follow up preferably within 3 days – Nursing make appointment prior 
to discharge  
 
End of Protocol and Orderset 
 
Consent/Ethical Considerations 
Since this is a new observation protocol that all patients treated for AF in the ED will receive, 
patients will not be signing consent. The treatment will be explained to them by the ED physician or 
resident providing their care. As stated previously by the RACE II trial, lenient rate control is not inferior 


to strict rate control in management of AF. It resulted in a 12.9% rate of cardiovascular morbidity as 
defined by a composite of death from cardiovascular causes, hospitalization for heart failure, stroke, 
systemic embolism, bleeding, and life-threatening arrhythmic events. Strict rate control had a rate of 
14.9% p<0.001. (Van Gelder et al., 2010). Lenient rate control is achieved with Diltiazem, Metoprolol, or 
Digoxin traditionally. As stated earlier, Diltiazem and Metoprolol both effectively achieve HR control 
(Hirschy et al., 2019). The 2018 study at VCU exhibited that PO diltiazem was associated with treatment 
success (HR<110 @ 4hrs) vs. IV Diltiazem infusion.  Therefore, patients entered into the AF observation 
protocol will be receiving accepted medications and treatment strategies effective for AF with RVR. In 
fact, the American College of Emergency Physicians guidelines recommends an IV Diltiazem bolus 
followed by PO Diltiazem as an optional treatment protocol for AF RVR (Baugh et al., 2018). Patients 
are not required to sign consent when treated with antibiotics for an infection or analgesics for a 
headache. Consent is not then required to partake in the protocol. As stated previously, all patient data 
will be kept on SHL computers and servers only. Deidentified data will be given to the statistical analysis 
team.  
All patients that meet the criteria for the AF observation protocol will be entered. There is no 
placebo group or alternate interventions. When considering risk, any medication or medical procedure 
carries with it some inherent risk but, in the case of atrial fibrillation with a rapid ventricular response, the 
potential benefit of said therapy is thought to outweigh the risk. The possible side effects of Diltiazem 
include: an allergic reaction, blistering/red skin rash, nausea, vomiting, dizziness, loss of appetite, 
stomach pain, a fast, slow, uneven, or pounding heartbeat, rapid weight gain, or swelling in the hands, 
ankles, or feet. The incidence of side effects is generally low and usually from <1% to 10% depending on 
the reaction (UpToDate). As outlined above the patient’s will be monitored for possible adverse effects 
while under observation in the emergency department with cardiac monitoring, pulse oxymetry 
monitoring and regular measurements of vital signs (including heart rate and blood pressure). Patients 
with significant CHF or autonomic instability who are not diagnosed or new onset may have increased 
risk for hemodynamic complications. These patients should be excluded by the exclusion criteria, vitals, 
and clinical history, but it is possible for a patient who should be excluded to be given the treatment.  
We do not predict there will be any breaches of confidentiality, however when working with 
electronic databases, there is always a small possible risk for loss of confidentiality. Efforts will be made 
to limit a patient’s personal information, including research study and medical records, to people who 
have a need to review this information. Raw data will be maintained electronically only upon Lakeland 
servers and computers. De-identified data may be sent to the SASS group at Spectrum for statistical 
analysis. Organizations that may inspect and copy the information for quality assurance and data analysis 
include: the investigators and their research staff, Spectrum Health Lakeland staff or its agents, the 
Spectrum Health Lakeland Institutional Review Board (IRB) and staff, the Sponsor(s) of the research or 
its agents (monitors, auditors) and/or agencies that accredit the hospital or the research program. 
Benefits of the study include that participation may help us to better understand the most effective 
treatment option for atrial fibrillation in the emergency department setting and reduce health care costs 
associated with the treatment of this diagnosis. This study will generate no additional costs to patients but 
patients will still be responsible for the payment of their standard treatment. It is possible that individuals 
who undergo ED observation with treatment as opposed to hospital admission will be discharged more 
expediently, thereby reducing their personal healthcare costs as well. 
There will be no recruitment materials, advertisements or press releases as part of this study.  No 
surveys, questionnaires or other research instruments will be used.  


Monitoring 
We will review an Epic report of patients who utilized the protocol on a monthly basis to assess for 
hypotensive episodes. 
 
Statistical Analysis Plan 
The initial data containing the demographics and medications contained 1745 unique individuals. 
This number decreased to 1106 unique individuals after filtering out patients who did not receive 
medication. Then, the four medication variables in the main spreadsheet were looked through and 
observations were dropped or placed in their group accordingly. This resulted in 363 patients in the 
treatment group (87 of whom needed rescue meds) and 549 patients in the comparison group for a total of 
912 patients.  
 
The heart rate spreadsheet contained 1524 unique patients. Only 1089 of these patients had heart 
rate data. 712 patients remained after filtering for an initial heart rate above 110. When the two 
spreadsheets were merged, many patients either did not have medication given (from heart rate 
spreadsheet) or their heart rate monitored (from demographic spreadsheet). This caused additional 
observations to be dropped. The hours from the first medication administered for each patient was 
calculated. Patients were only included in the analysis if any heartrate measurements were recorded 
between 2-4 hours of the first medication being given. If their heartrate fell below 110 at any point during 
that time period, the treatment was considered a success.  
There were 444 patients left to analyze after cleaning and filtering the data. The treatment group 
had 177 patients (55 of whom needed rescue meds) and the comparison group had 267 patients. 
Demographic data and the initial vital signs were compared across treatment groups. Treatment success 
was also determined and compared at the 3 ± 1 hour mark. 
 
 
 
 


References 
Baugh, C.W., Clark, C.L., Wilson, J.W., Stiell, I.G., Kocheril, A.G., Luck, K.K., Myers, T.D., Pollack, C. 
V, Roumpf, S.K., Tomassoni, G.F., Williams, J.M., Patel, B.B., Wu, F., Pines, J.M., 2018. Creation 
and Implementation of an Outpatient Pathway for Atrial Fibrillation in the Emergency Department 
Setting: Results of an Expert Panel. Acad. Emerg. Med. 25, 1065–1075. doi:10.1111/acem.13410 
Coyne, K., Paramor, C., Grandy, S., n.d. Assessing the direct costs of treating nonvalvular atrial 
fibrillation in the United States. Value Heal. 348. 
Diltiazem: Drug Information. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. 
Ganz, L., n.d. Control of ventricular rate in atrial fibrillation: Pharmacologic therapy. UpToDate. 
Ha, A.C.T., Verma, A., Verma, S., 2017. Oral anticoagulation for stroke prevention amongst atrial 
fibrillation patients with valvular heart disease: an update. Curr. Opin. Cardiol. 32, 174–180. 
doi:10.1097/HCO.0000000000000365 
Hirschy, R.A., Ackerbauer, K.A., Peksa, G.D., O’Donnell, E.P., DeMott, J.M., 2019. Metoprolol vs. 
diltiazem in the acute management of atrial fibrillation in patients with heart failure with reduced 
ejection fraction. Am. J. Emerg. Med. 37, 80–84. doi:10.1016/j.ajem.2018.04.062 
JL, B., RE, S., 2003. AFFIRM and RACE Trials: Implications for the Management of Atrial Fibrillation. 
Card. Electrophysiol. Rev. 7. doi:10.1023/B:CEPR.0000023140.38226.75 
Koenig, B.O., Ross, M.A., Jackson, R.E., 2002. An emergency department observation unit protocol for 
acute-onset atrial fibrillation is feasible. Ann. Emerg. Med. 39, 374–81. 
doi:10.1067/mem.2002.122785 
Means, K.N., Gentry, A.E., Nguyen, T.T., 2018. Intravenous continuous infusion vs. Oral immediate-
release diltiazem for acute heart rate control. West. J. Emerg. Med. 19, 417–422. 
doi:10.5811/westjem.2017.10.33832 
Nileshkumar, P., D, A., Pant, S., 2014. Contemporary Trends of Hospitalization for Atrial Fibrillation in 
the United States, 2000 through 2010. Circulation 2371–2379. 
Ross, A.L., O’Sullivan, D.M., Drescher, M.J., Krawczynski, M.A., 2016. Comparison of Weight-Based 
Dose vs. Standard Dose Diltiazem in Patients with Atrial Fibrillation Presenting to the Emergency 
Department. J. Emerg. Med. 51, 440–446. doi:10.1016/j.jemermed.2016.05.036 
Van Gelder, I.C., Groenveld, H.F., Crijns, H.J.G.M., Tuininga, Y.S., Tijssen, J.G.P., Alings, A.M., 
Hillege, H.L., Bergsma-Kadijk, J.A., Cornel, J.H., Kamp, O., Tukkie, R., Bosker, H.A., Van 
Veldhuisen, D.J., Van Den Berg, M.P., 2010. Lenient versus strict rate control in patients with atrial 
fibrillation. N. Engl. J. Med. 362, 1363–1373. doi:10.1056/NEJMoa1001337 
WW, D., PA, S., L, V., DG, G., ET, B., LG, S., DL, P., TD, M., AJ, B., LH, H., DA, L., JK, L., AT, S., 
RM, S., NE, S., DO, H., WK, S., 2008. A Prospective, Randomized Trial of an Emergency 
Department Observation Unit for Acute Onset Atrial Fibrillation. Ann. Emerg. Med. 52. 
doi:10.1016/J.ANNEMERGMED.2007.12.015 
Wyse, D.G., Waldo, A.L., DiMarco, J.P., Domanski, M.J., Rosenberg, Y., Schron, E.B., Kellen, J.C., 
Greene, H.L., Mickel, M.C., Dalquist, J.E., Corley, S.D., Atrial Fibrillation Follow-up Investigation 
of Rhythm Management (AFFIRM) Investigators, 2002. A comparison of rate control and rhythm 


control in patients with atrial fibrillation. N. Engl. J. Med. 347, 1825–33. 
doi:10.1056/NEJMoa021328 
ZA, S., SK, R., 2018. Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: Treatment 
Outcomes and Dosing in Special Populations. Ther. Adv. Cardiovasc. Dis. 12. 
doi:10.1177/1753944718787384