Article Archive
May/June 2015

Rate Control Drugs in Atrial Fibrillation
By Mark D. Coggins, PharmD, CGP, FASCP
Today's Geriatric Medicine
Vol. 8 No. 3 P. 6

Atrial fibrillation (AF) is the most common type of arrhythmia and the leading cause of cardioembolic stroke, with AF patients being five times more likely to experience a stroke than those without AF.1 The median age for patients with AF is approximately 75, with an increase in incidence occurring with advancing age. About 1% of patients with AF are under the age of 60, whereas up to 12% of patients are between the ages of 75 and 84. More than one-third of patients with AF are aged 80 or older.2

The atrioventricular (AV) node serves as a gatekeeper in the atrium, delaying electrical pulses before they move on to the ventricles, causing contraction.1 In AF, the AV node is unable to adequately manage all of these electrical pulses, and the loss of coordinated atrial contractions results in a sequela of clinical implications including increased ventricular rate; decreased diastolic filling; and reduced cardiac output, blood stasis, and blood clot formation.1,3 As a result, impaired cardiac function and increased stroke risk lead to significant morbidity and mortality.1-3 Additionally, the cost of caring for patients with AF is estimated to be five times greater than caring for patients without the condition.3

Symptomology for individual patients with AF ranges from no symptoms to fatigue, palpitations, dyspnea, hypotension, syncope, lightheadedness, chest pain, or heart failure, stroke or cardiovascular collapse. Because of the nonspecific nature of symptoms, an electrocardiogram (ECG) is often required to evaluate for the onset and diagnoses of AF.1-3 ECG results can vary depending on the type of AF; however, common interpretation shows irregular R-R intervals (when AV conduction is present), the absence of distinct repeating P waves, and irregular atrial activity.2 If electrocardiography fails to demonstrate AF, the use of a Holter or cardiac event monitor may be required to document the arrhythmia.1-3

Rate Control vs Rhythm Control
Decreasing the ventricular response rate, known as rate control, improves diastolic filling and coronary perfusion, decreases myocardial energy demand, and prevents tachycardia-mediated cardiomyopathy.3 Most experts recommend aiming for a ventricular response of less than 80 beats per minute at rest and less than 110 beats per minute during exercise.3,4 One randomized controlled trial showed that lenient rate control, defined as a ventricular rate of less than 110 beats per minute at rest, was not inferior to strict rate control in preventing cardiac death, heart failure, stroke, and life-threatening arrhythmias.3,5 At this time, it may be best to reserve this less aggressive approach for patients with no symptoms or acceptable symptoms and left ventricular (LV) ejection fraction > 40%.6

The use of rate control medications (eg, calcium channel blockers, beta blockers) avoids subjecting patients to riskier rhythm control medications (eg, antiarrhythmics). The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial showed that a rhythm control strategy was not better than a rate control strategy for improving survival in patients with AF. Data show that patients assigned to rhythm control medications experience more hospitalizations from adverse cardiovascular events, more serious adverse medication effects, and the same rate of thromboembolic events compared with patients using rate control medications.3

Because of lower cost, improved tolerability, and ease of use, most prescribers will first utilize a rate control strategy before progressing to rhythm control. Studies indicate that unless rate control has not worked, it is less important to aggressively drive patients into a normal sinus rhythm. Whether a rate control or rhythm control strategy is used, the utilization of anticoagulant medication is considered critical to help reduce the risk of stroke.1-4

Rate Control Medications
Beta Blockers
Beta blockers block sympathetic tone, relaxing blood vessels and lowering ventricular rate. Intravenous beta blockers (eg, esmolol, propranolol, and metoprolol) are effective for acute treatment of AF. Oral beta blockers (eg atenolol, carvedilol, metoprolol, nadolol, and sotalol) are commonly used for ongoing AF treatment. In the AFFIRM study, beta blockers were the most effective and commonly used drug class for rate control (70% on beta blockers vs 54% on calcium channel blockers). In patients with heart failure, carvedilol showed efficacy for heart rate control and, in combination with digoxin, resulted in improved LV function. Combination therapy of beta blockers with other agents, including digoxin, is effective in ventricular rate control; however, drugs should be titrated to avoid excessive bradycardia.2

Although beta blockers are the most effective medications for maintaining rate control in AF, especially during exercise, their use can cause fatigue, and exercise intolerance may limit their use. Because beta blockers can cause increased bronchial obstruction and airway reactivity, these agents should be used with caution in patients with reactive airway disease (but not COPD) such as asthma and/or acute allergic or exercise-induced bronchospasm.2 Also, beta-blocking agents may mask the signs and symptoms of hypoglycemia, so increased monitoring for possible low blood sugar levels may be appropriate.

Nondihydropyridine Calcium Channel Blockers
Diltiazem and verapamil have direct effects on the AV node by blocking calcium channels, relaxing blood vessels, and lowering the ventricular rate. Both verapamil and diltiazem reduce resting and exercise heart rate and can improve exercise tolerance. Because of their negative inotropic effects, these nondihydropyridine calcium channel blockers (CCBs) should not be used in patients with LV systolic dysfunction and decompensated heart failure, but they may be used in patients with heart failure with preserved LV systolic function.2 Constipation is a common side effect of verapamil.

Beta blockers and verapamil or diltiazem are recommended first-line medications for rate control for most patients with persistent or permanent AF and are effective at rest and with exertion (eg, exercise). The acute treatment of AF with a rapid ventricular response often involves intravenous diltiazem or metoprolol.2 Beta blockers and CCB agents are also used for hypertension and can cause side effects that can include fatigue, dizziness, and possible orthostatic hypotension.

Despite the common use of digoxin, it is not considered first-line therapy for rate control in acute or chronic AF. Digoxin's effect on ventricular rate is due to its effects in increasing vagal tone, making it ineffective as monotherapy in reducing ventricular response during exercise. Digoxin should not be used alone for rate control in patients with paroxysmal AF; its limited efficacy may result in prolonged episodes of paroxysmal AF in some patients. Digoxin may provide an option for combination therapy with beta blockers or CCBs for patients in whom rate control remains uncontrolled or for patients to control ventricular rate during exercise. In heart failure, digoxin is a fourth- or fifth-line agent, and its role is to provide symptomatic relief, improve exercise tolerance, and prevent hospitalization. Digoxin should not be used alone in heart failure but is a potential option when used in combination with a beta blocker in heart failure patients.2

Dose adjustment is required in patients with renal dysfunction, the elderly, and in the presence of drugs that reduce its excretion such as amiodarone, propafenone, or nondihydropyridine CCBs. Also, hypothyroidism is a risk factor for digoxin toxicity due to reduced digoxin clearance, while hyperthyroidism can increase the clearance of digoxin.2,7

Serum digoxin concentrations may be used to supplement clinical judgment; however, toxicity can occur even when the level is within normal therapeutic ranges. While monitoring of digoxin levels is less useful in stable patients, it may provide some benefit when there is suspected toxicity (eg, arrhythmia, gastrointestinal symptoms, changes in vision, or confusion); if there is suspected nonadherence; in the presence of diseases or physiologic changes that can affect levels (eg, renal impairment); in starting or stopping an interacting drug (eg, macrolide antibiotics); or with digoxin initiation or dosage change. Reaching steady-state concentrations after digoxin initiation or dosage changes may take at least five days. It is best to check digoxin levels at least six hours after the dose to allow for distribution into the tissues. When using digoxin, renal function should be monitored as should potassium, magnesium, and calcium levels, due to the risk of digoxin toxicity even when serum digoxin concentrations are within the therapeutic range.7

Symptomatic benefit in heart failure is often seen in low levels between 0.5 to 0.9 ng/mL, with some patients benefiting at levels of less than 0.5 ng/mL.7 In the Digitalis Investigation Group (DIG) trial, levels over 1 ng/mL were associated with higher mortality. Toxicity is common at levels over 2ng/mL, but can occur even at lower levels. Use the lowest dose necessary to control rate, keeping in mind that toxicity may occur before rate control is achieved. Consider starting with 0.125 mg every other day in patients with renal insufficiency, low lean body mass, or in patients aged 70 or older. Doses over 0.25 mg per day are rarely appropriate.7,8

In the AFFIRM trial, digoxin was associated with an increase in mortality. The occurrence of arrhythmias, which are dose related, are a potential source of mortality; in the DIG trial, serum levels > 0.9 ng/mL were associated with increased mortality. Among patients assigned to the rate control group in AFFIRM, there were 96 additional deaths for every 1,000 patients taking digoxin at baseline vs those not taking digoxin at baseline. The mechanism behind this excess mortality is unknown, but it may involve bradycardia or other arrhythmias. Based on findings from DIG and AFFIRM, there may be a better benefit/risk ratio for digoxin use in patients with heart failure without AF compared with patients with AF.2

Amiodarone is the most widely prescribed antiarrhythmic medication in the United States, due largely to its efficacy in the management of both supraventricular and ventricular arrhythmias. In addition to the superior efficacy compared to most other antiarrhythmic drugs, amiodarone has very little negative inotropic activity and a low rate of ventricular proarrhythmia, making it advantageous for use in patients with heart failure.8 Despite these advantages, the use of amiodarone is associated with a relatively high incidence of side effects, making it a complicated drug to use safely. Due to the high risk of side effects, amiodarone should be reserved for patients who are intolerant of or unresponsive to other agents.2

Due to the high risk of stroke with AF, the use of anticoagulation therapy is critical regardless of whether rate control or rhythm control is used. Warfarin is superior to aspirin and clopidogrel in preventing stroke despite its narrow therapeutic range and increased risk of bleeding. Newer novel anticoagulant agents may also be used, but these carry their own risks and most require dosage reduction considerations based on renal function. Tools that predict the risk of stroke (eg, CHADS2) and the risk of bleeding (eg, Outpatient Bleeding Risk Index) are helpful in making decisions about anticoagulation therapy.2,3

In March, CredibleMeds, a leading resource for evaluating agents that may prolong QTc interval and possibly lead to the life-threatening arrhythmia Torsade de Pointes (TdP) added the Alzheimer's medication donepezil (Aricept) and the antiplatelet medication cilostazol (Pletal) to the list of agents with a "known risk of TdP," while the ADHD medication atomextine (Strattera) was added to the list of agents with "possible risk of TdP." Neither donepezil or cilostazol should be given together with amiodarone because of the high risk of TdP, while the combination of atomoxetine with amiodarone should be avoided if possible.9

— Mark D. Coggins, PharmD, CGP, FASCP, is senior director of pharmacy services for skilled nursing centers operated by Diversicare in eight states, and is a director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

1. When the beat is off — atrial fibrillation. American Heart Association website.
. Accessed March 21, 2015.

2. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circ. 2014;130(23):e199-267.

3. Gutierrez C, Blanchard DG. Atrial fibrillation: diagnosis and treatment. Am Fam Physician. 2011:83(1);61-68.

4. Whitbeck MG, Charnigo RJ, Khairy P, et al. Increased mortality among patients taking digoxin—analysis from the AFFIRM study. Eur Heart J. 2013;34(20):1481-1488.

5. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010;362:1363-1373.

6. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57(2):223-242.

7. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol. 2012;28(2):125-136.

8. Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm. 2007;4(9):1250-1259.

9. Changes made to CredibleMeds lists. CredibleMeds website. Updated March 30, 2015. Accessed April 8, 2015.


Table 1: Factors Contributing to Atrial Fibrillation

Cardiac Factors Noncardiac Factors
Cardiomyopathy Cigarette smoking
Cardiothoracic surgery COPD
Coronary artery disease Cor Pulmonale
Heart failure Diabetes
Heart valve disease Excessive alcohol consumption
Infiltrative heart disease Hyperthyroidism
Longstanding hypertension Periods of extreme stress/fatigue
Myocardial infarction Pneumonia
Myocarditis/pericarditis Pulmonary disease
Pericarditis Sleep apnea
Wolff-Parkinson-White syndrome Stimulant use (eg, caffeine, amphetamines)


Gutierrez C, Blanchard DG. Atrial fibrillation: diagnosis and treatment. Am Fam Physician. 2011:83(1):61-68

When the beat is off — atrial fibrillation. American Heart Association website.
. Accessed March 21, 2015.


Table 2: Risk Factors for Stroke in Patients With Nonvalvular Atrial Fibrillation

Risk Factors Relative Risk
Prior stroke or transient ischemic attack 2.5
History of hypertension 1.6
Heart failure and/or reduced left ventricular function 2.5
Advanced age 1.4 for each decade
Diabetes 1.7
Coronary artery disease 1.5

Woolfenden R, Albers GW. Long-term stroke prevention in atrial fibrillation. BCMJ. 2002;44(3):135-140.


Table 3: Conditions Affecting Digoxin Levels/Toxicity

Renal impairment Reduced excretion of digoxin leading to increased blood levels
Advancing age Reduced renal perfusion, creatine clearance rate and volume of drug distribution, almost always requires reduced maintenance dose of digoxin
Dehydration Electrolyte imbalances and reduced renal function

Medication-related kidney injury

Medications which affect renal function (eg, NSAIDs) and as seen with acute kidney injury can increase blood levels. For more information on medication-related kidney injury, visit
Hypercalcemia Increased intracellular calcium leading to increased cardiac contractility (eg, thiazide diuretics)
Hypokalemia Imbalance in electrolytes leads to increased cardiac contractility (eg, thiazide and loop diuretics)
Antiarrhythmics1 eg, propafenone, quinidine, procainamide, nifedipine
Amiodarone2 Among top 10 particularly dangerous drug interactions in long term care. Reassess the need for digoxin therapy when initiating amiodarone; if combination therapy required, reduce digoxin dose by 50% when amiodarone is started. Monitor thyroid function as amiodarone may damage thyroid, increasing the risk of digoxin toxicity.2
Verapamil2 Among top 10 particularly dangerous drug interactions in long term care. Interaction can cause serum digoxin concentration to rise by 60% to 75%. Also causes a synergistic effect of slowing impulse conduction and muscle contractility, leading to bradycardia and possible heart block.2
Macrolide Antibiotics3 Clarithromycin (13-fold increased risk of hospitalization due to digoxin toxicity). Azithromycin/ Erythromycin (3.7 times increased risk of hospitalization)
Medications affecting digoxin absorption1 Metoclopramide (reduced gastrointestinal absorption of digoxin, resulting in low levels). Antacids (eg, aluminum hydroxide, magnesium hydroxide, magnesium trisilicate). Separate doses as much as possible.

1. Digoxin. website. Accessed April 7, 2015.

2. Top 10 particularly dangerous drug interactions in long term care. AMDA website.

3. Gomes T, Mamdani MM, Juurlink DN. Macrolide-induced digoxin toxicity: a population-based study. Clin Pharmacol Ther. 2009;86(4):383-386.