Efficacy and Safety of Pharmacological Options for Rate Control in Atrial Fibrillation

Transcription

1 AACN Advanced Critical Care Volume 23, Number 2, pp , AACN ECG Challenges Earnest Alexander, PharmD, and Gregory M. Susla, PharmD Department Editors Efficacy and Safety of Pharmacological Options for Rate Control in Atrial Fibrillation Katie O Brien, PharmD Earnest Alexander, PharmD L indsay Patel, PharmD, BCPS Atrial f ibrillation (AF) is the most common arrhythmia, and its prevalence will continue to increase as people age. Approximately 3 million people in the United States currently have AF, with an estimated 7.5 million people by the year Atrial fibrillation is characterized by uncoordinated atrial firing, which disrupts the normal sinus rhythm of the heart. The arrhythmia can be classified by the occurrence of its symptoms, such as first episode, recurrent, paroxysmal, and persistent. When AF is not controlled, the symptoms may be severe and interrupt a patient s activities of daily life. Mortality rates of patients with AF are double those of patients in normal sinus rhythm. 2 Furthermore, AF may require urgent treatment to prevent or correct events suc h as stroke, thromboembolism, and hemodynamic compromise. Although the underlying cause of AF is unknown, several disorders contribute to its development. Hypertension, diabetes, and congestive heart failure are just a few causes that can contribute to the clinical risk factors for AF. On the basis of the potential negative clinical outcomes, health care providers must understand the role of pharmacological management strategies that can improve quality of life and care in patients with AF. Rhythm Control Versus Rate Control When a patient is diagnosed with persistent or permanent AF, pharmacological management of either heart rate or rhythm is the mainstay of treatment. Under normal conditions, cardiac output is directly related to heart rate and stroke volume. Increases in heart rate and/or stroke volume generally result in a proportional increase in cardiac output. During AF, the atria of the heart quiver, resulting in diminished atrial filling, decreased stroke volume, and decreased cardiac output. During AF with rapid ventricular response (RVR), cardiac output is further decreased by both quivering atria and fast ventricle contraction because of reduced atrial and ventricular filling. Pharmacological management strategies are based on improving atrial and ventricular filling and increasing cardiac output. Rate control therapy aims to manage the ventricular rate, whereas rhythm control strives to restore or maintain normal sinus rhythm. Both strategies result in increased cardiac output. Over the last 10 years, a few trials have shed light on the ongoing controversy concerning the rhythm versus management strategies and which is Katie O Brien is Clinical Pharmacist, Tampa General Hospital, 1 Tampa Genera l Circle, Tampa, FL (ko brien@tgh.org). Earnest Alexander is Clinical Manager, Department of Pharmacy Services, and Critical Care Pharmacy Residency Program Director, Tampa General Hospital, Tampa, Florida. Lindsay Patel is Clinical Pharmacist, Tampa General Hospital, Tampa, Florida. The authors have no relevant financial or personal relationships to disclose. DOI: /NCI.0b013e318242fdd0 120

2 VOLUME 23 NUMBER 2 APRIL JUNE 2012 Drug Update the preferred option. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial sought to determine whether the strategy or the rhythm control strategy was associated with a better survival outcome. 3 The AFFIRM study was a large, randomized controlled trial evaluating a population of more than 4000 patients with AF with RVR. Inclusion criteria led to the enrollment of patients who were at least 65 years old or had 1 other risk factor for stroke or death. Mean duration of patient follow-up for the trial was 3.5 years. Patients in the arm of the study received digoxin, -blockers, or calcium-channel blockers. Amiodarone and sotalol were the agents used in the rhythm control arm. The stu dy defined as an average heart rate of less than 80 beats per minute and a maximum heart rate of less than 100 beat s per minute during a 6-minute walk or an average heart rate of less than 100 beats per minute over a 24-hour period. No statistically significant differences in overall mortality were reported between the 2 groups (25.9% and 26.7%, respectively; heart rate: 1.15 beats per minute; 95% confidence interval: ; P.08). 3 The study was the first of its kind to show that is equally effective as rhythm control in terms of overall mortality. This study has changed the management of patients with AF with RVR, shifting the focus of treatment to strategies rather than rhythm control. The AFFIRM study has helped to establish the role of in the management of patients with AF with RVR. With trials such as AFFIRM and other studies establishing a role for strategies, this topic deserves further elaboration. Compared with antiarrhythmic medications (used in rhythm control), agents used for are generally considered safer and better tolerated. Agents used for include digoxin, -blockers, and nondihydropyridine calcium-channel blockers. Refer to Table 1 for an overview of dosing and other considerations. This column discusses and evaluates specific nuances of, targeting efficacy and safety of specific agents, management of in an emergent setting, and the intensity of rate control. Digoxin Digoxin is a cardiac glycoside exhibiting its mechanism of action by binding to the sodium and potassium adenosine triphosphatase pump, which eventually increases calcium ions, which results in a prolonged cardiac action potential decreasing heart rate. Once considered the firstline agent in emergent settings for, digoxin has since fallen out of favor with the publication of studies proving other agents to be more appropriate in certain settings. Digoxin acts relatively slowly when given intravenously, taking approximately 60 minutes to work, with peak effects not being reached for at least 6 hours. Furthermore, digoxin has a narrow therapeutic index, with a target dose range of to mg orally once daily. The drug may have toxic or suboptimal effects when levels fall outside the therapeutic range of 0.5 to 2.0 ng/ml. Appropriate dosing is critical, especially in patients with renal dysfunction, and close monitoring for therapeutic levels is a key consideration with this agent. Despite these considerations, digoxin may benefit patients who do not respond to other options alone. Previous studies have examined the usefulness of digoxin and its efficacy in AF therapy. Wattanasuwan and colleagues 4 evaluated the differences between intravenous diltiazem alone to control rate in patients with AF with RVR and a combination of intravenous digoxin and diltiazem. Successful was defined as a ventricular rate of less than 100 beats per minute persisting for 1 hour or conversion to sinus rhythm. Loss of was significantly less in the combination group than in the diltiazem-alone group (14 vs 39 episodes; P.05). The length of time taken to achieve (mean SD) was also shorter for the combination group (15 16 minutes vs minutes; P.20), but this difference was not statistically significant. 4 Patients who are sedentary and do not require exercise tolerance may benefit from digoxin therapy because it is not effective when sympathetic activity is increased. Digoxin is a positive inotropic agent and can be advantageous to patients with AF and heart failure with systolic dysfunction, especially when used in combination therapy with diltiazem in situations in which conversion to sinus rhythm is not indicated. Digoxin is also an option for patients who cannot tolerate further blood pressure lowering as seen with other agents. -Blockers -Blocke rs work by blocking the effects of norepinephrine and epinephrine. -Blocke rs are 121

3 Drug Update AACN Table 1: Rate Control Medication Overview Drug Purpose Dose Administration Acebutolol Maintenance Maintenance: mg/d Oral orally in divided doses (max: 1200 mg/d) Digoxin Emergent or maintenance Emergent: Normal renal function: 500 mcg IV x 1, then 250 mcg IV (6 h after the first dose) x 2 Renal failure: 250 mcg IV x 1, then 125 mcg IV (6 h after the first dose) x 2 Oral or IV Monitoring Parameters glucose, blood pressure, orthostatic hypotension, heart rate, CNS effects Monitor for low blood pressure when given IV; monitor digoxin levels: therapeutic range ng/ml Maintenance: mg orally daily Diltiazem Emergent or maintenance Emergent: Rate control: 0.25 mg/kg over 2 min, if no response, may repeat with 0.35 mg/kg after 15 min Oral or IV pressure, LFTs, heart rate Lenient : 0.2 mg/kg over 10 min Maintenance: Continuous infusion: Start at 5-10 mg/h, increase up to 15 mg/h Oral maintenance: dosing varies Esmolol Emergent rate control Emergent: 1000 mcg/kg IV bolus over 30 s, followed by a 50 mcg/kg per min continuous infusion; may increase in 50 mcg/kg per min increments as needed every 4 min to a max rate of 300 mcg/kg per min IV pressure, MAP, heart rate, respiratory rate Metoprolol Emergent or maintenance Emergent: mg IV every 2 5 min (max: 15 mg over a 10-min period) Oral or IV pressure, heart rate Pindolol Maintenance Maintenance: mg/d orally immediate release (max: 400 mg/d) Maintenance: mg orally daily (max: 60 mg/d) Oral pressure, heart rate, respiratory function Abbreviations: CNS, central nervous system; IV, intravenous; LFTs, liver function tests; MAP, mean arterial pressure; max, maximum. 122

4 VOLUME 23 NUMBER 2 APRIL JUNE 2012 Drug Update sympatholytic drugs affecting both beta1 ( 1 ) receptors and beta2 ( 2 ) receptors, depending on the drug s selectivity. The heart contains both 1 and 2 receptors but mostly comprises 1 receptors. 2 Receptors are located in the vascular smooth muscle. By blocking both these effects, heart rate (chronotropy) and contractility (inotropy) are decreased by -blockers. 5 The intravenous use of -blockers can be beneficial in an acute setting in patients who are candidates for -blocker therapy for whom rate control is indicated. Esmolol, propranolol, and metoprolol have been used intravenously in the emergent setting to control rate. These agents have a rapid onset of about 5 minutes. Esmolol has a very short half-life of approximately 9 minutes and has the advantage of its metabolism being independent of both hepatic and renal function. This unique characteristic provides value in patients who have multisystem organ failure or who are critically ill and their organ function cannot be assessed. However, esmolol must be given as a continuous infusion, whereas metoprolol and propranolol can be administered as intermittent intravenous injections. Esmolol is dosed as an initial 1000 mcg/kg loading dose over 30 seconds, followed by a 50 mcg/kg per minute infusion. Infusions may be titrated by 50 mcg/kg per minute increments as needed every 4 minutes up to a relative maximum dose of 3 00 mcg/kg per minute. Esmolol is a popular agent of choice in situations where flexible control of -blockade is necessary because of its rapid onset and short duration. Platia and colleagues 6 studied esmolol compared with verapamil in the short-term treatment of AF with RVR (heart rate of at least 120 beats per minute), demonstrating the value of -blocker use for. The authors reported that heart rate declined from 139 to 100 beats per minute (P.001) with esmolol and from 142 to 97 beats per minute (P.001) with verapamil. Moreover, the AFFIRM trial showed that more than 70% of patients achieved rate control with the use of -blockers, compared with 54% with the use of calcium channel blockers. 4 In patients for whom emergent is not indicated, the oral dosage forms of -blockers provide another alternative for their use. However, -blockers may not be the optimal choice for every patient, because -blockers can result in excessive bradycardia, lethargy, and shortness of breath. Although the effects of -blockers on 2 receptors are less pronounced, the effects of vasoconstriction on the vascular bed are still of concern because of the negative inotropic and chronotropic actions. In patients who experience bradycardia, hypotension, or heart block, -blockers are not the drug of choice. However, these adverse effects may be avoided by using -blockers with intrinsic sympathomimetic activity (ISA). These ISA agents work by exhibiting a low level of agonist activity at the site, while producing antagonistic effects. Pindolol and acebutolol are the most common agents used, at oral doses of 15 to 20 mg daily and 200 to 1200 mg once or twice daily, respectively. Although these agents are potential options, more trials and clinical evidence support the use of -blockers without ISA activity. Because -blockers without ISA have a long and successful history of use, they should be considered safe and effective options both in the emergent setting and for the long term to control rate. Calcium Channel Blockers Calcium channel blockers exhibit their mechanism of action by blocking the voltage-gated calcium channels in cardiac and blood vessels. Decreased intracellular calcium reduce s muscle contraction. Less contractility in the vascular smooth muscle can result in vasodilation, which can lead to afterload reduction (pressure against which the heart pumps). Afterload reduction ameliorates symptoms of ischemic heart disease and angina pectoris. Both verapamil and diltiazem are nondihydropyridine calcium-channel blocking options for patients with AF. Verapamil exerts most of its effects on the myocardium, with minimal afterload reduction, whereas diltiazem exhibits effects on both myocardium and vascular smooth muscle. The 2006 American College of Cardiology, American Heart Association, and European Society of Cardiology guidelines, Recommendation for Rate Control During Atrial Fibrillation, suggest the use of diltiazem in the instance of emergent AF. 7 The most efficacious and safe dose of diltiazem is still up for debate. According to these guidelines, 7 the current recommended dose of diltiazem to be given intravenously in emergency situations is a load of 0.25 mg/kg over 2 minutes. 7 A recent study suggests that lower doses of diltiazem are safer, producing less hypotension. In their study, Lee and colleagues 8 evaluated low-dose diltiazem in patients with AF with RVR. The 123

5 Drug Update AACN study compared 3 different doses of diltiazem in the emergent setting to control rate: low dose ( 0.2 mg/kg), standard dose (0.25 mg/kg), and high dose ( 0.3 mg/kg). The study reported no therapeutic benefits to using lower doses of diltiazem, but low doses were statistically significant for producing fewer hypotensive adverse effects (18%, 34.9%, and 41.7%, respectively; P.037). 8 Limitations to this study include its retrospective nature and small sample size. Perhaps differences in efficacy may have been noted if more patients had been compared. This low-dose strategy may be considered with clinical judgment for instances in which hypotension may lead to adverse outcomes. Emergent Rate Control Although long-term management of AF is the primary goal for patient care, emergent situations require a quick resolution on the basis of short-term goals. Long-term goals can be developed and adjusted later as needed. When a patient with signs of symptomatic AF arrives at the emergency department but is hemodynamically stable, the main goal for short-term management is. Rate control is achieved by the use of atrioventricular nodal-blocking a gents, which are the mainstay of therapy. Digoxin has been the favored drug in years past to control rate, but over time it has become a lesspopular option. Diltiazem has become a standard therapy and drug of choice for acute care settings. The study that brought diltiazem to the forefront compared intravenous diltiazem with intravenous digoxin in controlling acu te AF with RVR. The study used a dose of intravenous digoxin bolus of 0.25 mg initially and then another 0.25 mg at 30 minutes, compared with a diltiazem bolus of 0.25 mg/kg followed by a dose of 0.35 mg/kg and then a titratable infusion at a rate of 10 to 20 mg/h to maintain heart at a ventricular rate of less than 100 beats per minute. The authors concluded that for emergency management of rate control in AF, diltiazem is the drug of choice because of its rapid onset within 5 minutes (P.037). 9 The study used an unconventional dose of digoxin; the standard dose is usually 0.5 mg given intravenously once, followed by 0.25 mg every 6 hours for 2 doses. Diltiazem, although known to have negative inotropic effects, is thought to have fewer negative inotropic effects than verapamil. Effectiveness of diltiazem has been proven in previous studies, and because of its less significant inotropic effects compared with verapamil, diltiazem is considered a safe choice for nondihydropyridine calcium-channel blockade in the condition of acute AF. Intensity of Rate Control Today, the optimal level of is unknown. A recent study titled Rate Control Efficacy in Permanent Atrial Fibrillation (RACE II) by Van Gelder and colleagues 10 sought to determine the ideal heart rate for optimal rate control therapy. The study also evaluated the effect of preventing cardiovascular morbidity and mortality in patients diagnosed with permanent AF. Strict was defined as a resting heart rate of less than 80 beats per minute, and lenient heart rate was defined as a resting heart rate of less than 110 beats per minute. Patients were followed for a maximum of 3 years. The primary outcome was defined as a composite of stroke, death from cardiovascular events, hospitalization for heart failure, systemic embolism, bleeding, or life-threatening arrhythmic events. The primary outcome after 3 years was 12.9% in the lenient heart rate group and 14.9% in the strict-control group (P.001). In addition, more patients achieved successful (as defined per group) in the lenient heart rate group than in the strict-control group (97.7% vs 67%, respectively; P.001). 10 Worsening heart failure is of concern in patients with AF with preexisting heart failure because of venous pooling and increased preload. A limitation of RACE II is that worsening heart failure was not evaluated. However, the study population for both lenient and strict groups had similar incidences of heart failure at enrollment (3.8% vs 4.1%, respectively). 10 The study also included only low-risk patients who had not previously had a stroke and were physically active. The risk of primary outcome adverse events beyond that of 3 years is unknown. Although lenient heart may be a future direction for treatment goals, more studies are needed to confirm its place in therapy. However, the newly released 2011 American College of Cardiology, American Heart Association, and Heart Rhythm Society 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 suggests that strict heart is unnecessary in all patients and lenient heart is 124

6 VOLUME 23 NUMBER 2 APRIL JUNE 2012 Drug Update more convenient for patients. 11 The consensus recommendation states that lenient heart rate control may be a good option for patients with permanently diagnosed AF with RVR. Conclusions Studies now confirm that is an accepted method of management of patients with AF with RVR. Pharmacological agents such as -blockers, digoxin, and nondihydropyridine calcium channel blockers provide patients with safe and efficacious options to control their symptoms and prevent adverse outcomes. -Blockers have a long-standing history of efficacy and safety demonstrated in both clinical experience and randomized controlled trials. Over time, digoxin has lost its popularity but still provides value in specific populations if appropriately monitored. In emergency situations, diltiazem is the nondihydropyridine calcium-channel blocker of choice. Furthermore, clinicians trying to treat patients with AF with RVR should consider a lenient heart approach rather than a strict-control approach, particularly in patients with permanent AF with RVR. REFERENCES 1. Naccarelli GV, Varker H, Lin J, et al. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol. 2009;104: Flegel KM, Shipley MJ, Rose G. Risk of stroke in nonrheumatic atrial fibrillation. Lancet. 1987;1: Olshansky B, Rosenfeld LE, Warner AL, et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol. 2004;43: Wattanasuwan N, Khan IA, Mehta NJ, et al. Acute ventricular in atrial fibrillation: IV combination of diltiazem and digoxin vs IV diltiazem alone. CHEST. 2001;119: Opie LH. Drugs and the heart. Lancet. 1980;1(8170): Platia EV, Michelson EL, Porterfield JK, et al. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol. 1989;63: Fuster V, Ryden LE, Ainger RW, et al; and American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257 e Lee J, Kim K, Lee CC, et al. Low-dose dilt iazem in atrial fibrillation with rapid ventricular response. Am J Emerg Med. 2011;29(8): Schreck DM, Rivera AR, Tricarico VJ. Emergency management of atrial fibrillation and flutter: intravenous diltiazem versus intravenous digoxin. Ann Emerg Med. 1997;29: Van Gelder IC, Van Veldhuisen DJ, Crijns HJ, et al. Rate control efficacy in permanent atrial fibrillation: a comparison between lenient versus strict in patients with and without heart failure: background, aims, and design of RACE II. Am Heart J. 2006;152: Wann SL, Curtis AB, Crait T, et al 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. Heart Rhythm. 2011;8: