Economic Burden of Atrial Fibrillation: Implications for Intervention

Atrial fibrillation (AF) is the most common cardiac dysrhythmia seen in clinical practice, affecting an estimated 2 to 3 million Americans.^1-5 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 or older.^6,7 This refl ects the improved survival of patients with cardiovascular comorbidities as well as the general aging and growth of the US population.^6,7

Atrial fibrillation is associated with significant clinical morbidity^4,8 and is also an independent risk factor for mortality. ^9,10 In the Framingham longitudinal study of 5209 American adults followed for up to 40 years, AF was found to be a predictor of increased mortality in men and women, with an odds ratio of 1.5 for men and 1.9 for women after multivariate adjustment.¹¹ The Marshfield Epidemiology Study Area population (central Wisconsin) also showed a hazard ratio for mortality of 2.5 for 577 patients with either AF or atrial flutter over a mean 3.6 years of follow-up.¹²

Thromboembolic stroke is the most serious and debilitating of all the complications of AF,¹³ and AF is an independent risk factor for stroke.¹⁴ In more than 34 years of follow-up in the Framingham Study, the annual risk of stroke attributable to AF was 1.5% among patients aged 50 to 59 years, increasing to as high as 23.5% among those older than 80 years.¹⁴ In this same population, patients with AF who had a stroke had twice the risk of mortality and 3 times the risk of recurrent stroke within 1 year compared with patients without AF.¹⁵ At 3 months after stroke, 3 of 4 patients with AF were severely or moderately dependent on others to perform activities of daily living compared with only about 1 in 3 stroke patients without AF.¹⁵

Atrial fibrillation is also known to precipitate and worsen the outcomes of congestive heart failure.¹⁰ In the Manitoba study of 3983 male air crew recruits, AF was associated with a 2.98-fold increase in the risk of congestive heart failure over 40 years of follow-up.⁹ In the Renfrew/Paisley community study (west Scotland) of 14,483 residents, there was a 3.4-fold increase in the risk of heart failure over 20 years of follow-up among those who had AF.¹⁰ In this same study, AF also independently predicted the risk of death, hospitalization, stroke, and all-cause mortality.¹⁰

Treatment of AF and its associated complications increases the use of healthcare resources and contributes to the ever-growing costs of healthcare, particularly costs associated with hospitalizations.^16,17 Between 1985 and 1999, for example, the number of hospitalizations with AF as a principal diagnosis increased by 144%, according to the National Hospital Discharge Survey.¹⁸ In the Fibrillation Registry Assessing Costs, Therapies, Adverse Events, and Lifestyle (FRACTAL) study of 973 North American patients with fi rst-detected AF, 47% of the mean annual costs over an average of 2 years of follow-up refl ected the costs of hospital care.¹⁹

This review summarizes the economic burden associated with AF, with a focus on the US healthcare system, and discusses the costs associated with varying practice patterns and current treatment options.

CURRENT ECONOMIC BURDEN OF ATRIAL FIBRILLATION

Estimating the costs of healthcare directly attributable to AF can be diffi cult since patients with AF often have comorbid cardiovascular and noncardiovascular health problems. As a result, when analyzing claims data, it becomes a challenge to disentangle the costs of AF from the costs of other patient health problems, some of which AF is known to exacerbate. Investigators may either overestimate (eg, by including the costs of unrelated health problems) or underestimate (eg, by failing to account for problems caused or worsened by AF) the costs of AF itself. Methodologic variations in handling these and other issues, such as the segment of the AF population studied (new-onset vs established AF; younger vs older patients; patients with or without a prior hospitalization for AF) have led to rather disparate estimates of the costs of AF care, both at patient and health-system levels.

The high morbidity and mortality associated with AF imposes substantial and rising societal and healthcare cost burdens. The total costs of AF care in the United States are estimated to be $6.65 billion per year (2005 dollars).16 Nearly 75% of the costs of AF represent the direct and indirect costs associated with hospitalization.¹⁶ In addition to hospitalization, the main drivers of costs for AF management include outpatient care and testing ($1.53 billion, or 23% of total costs) and outpatient prescription drugs ($235 million, or 4% of total costs), according to a retrospective analysis of 3 federally funded US databases (2005 dollars).¹⁶ The societal costs of lost productivity should also not be overlooked.

In a recent study in the United States, employees with an arrhythmia (approximately 40% AF) were compared with employees without an arrhythmia to determine the impact on costs, absences, and productivity. Employees with an arrhythmia had signifi cantly more annual workdays missed due to sick leave than employees without an arrhythmia (2.44 vs 1.85 adjusted mean days; P <.0001), as well as signifi cantly more short-term disability (2.38 vs 1.44 adjusted mean days; P <.0001).²⁰ In an observational study of 95 European centers, 391 employed patients lost an average of 9 to 26 days of work per year for AF-related reasons.²¹

In one privately insured population in the United States, direct costs were $15,553 per year among enrollees with AF, which were $12,349 higher than the costs per year for enrollees without AF (2002 dollars).²² Hospital costs are higher among AF patients not only because of the initial stay but also because of the frequent need for readmission. For example, a retrospective analysis of claims data from the Integrated Healthcare Information Systems National Managed Care Benchmark Database showed that 1 in 8 of the 1637 patients with AF were readmitted within 1 year after the index hospitalization, as were 1 in 10 of the 2537 newly diagnosed patients.²³ In a retrospective study of claims data (January 2004 to December 2007) for 32,905 adults discharged after a fi rst admission for AF or atrial fl utter, 42% were readmitted within 1 year, and inpatient costs represented 59% of the $38,270 mean per patient direct costs incurred during the year.²⁴ Another retrospective analysis of claims data examined the total costs among 35,255 inpatients and outpatients with AF.²⁵ At 12 months post-hospitalization for patients with a principal diagnosis of AF, inpatient costs were $11,307 and outpatient costs were $2827 (2006 dollars). Following hospitalization of patients with a secondary diagnosis of AF, incremental AF-related inpatient costs were $5181 and outpatient costs were $1376.²⁵

Adverse events and adverse event monitoring of AF pharmacologic treatment also contribute to the high costs of AF. In a retrospective study using data from the Integrated Healthcare Information Systems National Managed Care Benchmark Database,²⁶ the mean annual cost of adverse events and adverse event monitoring among patients treated with rhythm control or rate control was $3089 per patient, including $3080 for adverse events and $8.50 for adverse event monitoring. Inpatient costs accounted for 86% ($2660) of total costs and outpatient/ pharmacy costs accounted for 14% ($429). The most common adverse events were cardiovascular, occurring in 36.1% of all treated patients compared with 15.5% of patients receiving no AF therapy; heart failure was the most common adverse event.²⁶

Another factor contributing to the high costs of AF care is the need for inpatient monitoring at the time of initiating or changing antiarrhythmic drugs. The American College of Cardiology/American Heart Association/ European Society of Cardiology guidelines (2011 focused updates incorporated into the 2006 guidelines for the management of patients with AF) recommend that the older antiarrhythmic drugs quinidine, procainamide, and disopyramide be started while the patient is in the hospital. ²⁷ Inpatient initiation is also mandated in the US Food and Drug Administration labeling for dofetilide and sotalol. ²⁷ A retrospective study using billing and discharge records to ascertain the in-hospital costs of antiarrhythmic therapy calculated the mean total inpatient costs to be $3278 per patient receiving sotalol and $3610 per patient receiving dofetilide (2007 dollars).¹⁷

COSTS ASSOCIATED WITH ATRIAL FIBRILLATION AND CARDIOVASCULAR COMORBIDITIES

According to statistics from the American Heart Association, the total cost related to stroke in the United States in 2010 was estimated to be nearly $73.7 billion,²⁸ and the estimated average lifetime cost of ischemic stroke in the United States was $140,048 per patient (1999 dollars).^28,29 However, given that stroke is usually more severe and disabling in patients with AF than in comparable patients without AF,^15,30 the costs of stroke-related care may be even higher in the AF population.

Caro and colleagues developed an economic model of stroke in AF using Medicare data from patients aged >65 years who were included in discharge databases from 7 states.³¹ According to the model, it was estimated that 96,860 strokes would occur within 1 year among patients with AF, with an associated total direct lifetime cost of nearly $8 billion.³¹ Of these costs, $2.6 billion in direct costs would be incurred during the fi rst year after the stroke.³¹ Actual costs would be even higher, given that the model did not include out-of-pocket expenses— such as costs for outpatient medications, long-term care, or patient copayments&mdash;or indirect costs from lost productivity.³¹

Lee and colleagues analyzed a random sample of 5% of all Medicare benefi ciaries, identifying 55,260 patients with AF first diagnosed during 2003 and 55,260 control patients without AF matched for age, sex, and race.³² During the first year after diagnosis, the excess costs of treating AF patients (adjusted for demographics, comorbid conditions, and baseline health costs before the diagnosis of AF) averaged $14,199 per patient (2004 dollars), which refl ected greater use of hospitalizations, physician visits, skilled nursing facilities, outpatient and home health care, durable medical equipment, and hospice care among AF patients.³² Stroke and heart failure were the 2 major complications of AF in the 1-year postindex period. The occurrence of stroke, which was nearly twice as likely among patients with AF, resulted in additional adjusted costs of $7907 per AF patient, on average, at 1 year. The occurrence of heart failure, which was tripled among patients with AF in this analysis, conferred an additional $12,117 in mean unadjusted 1-year costs.³²

Strokes in AF patients are generally associated with worse clinical outcomes—and therefore higher costs&mdash;than strokes in patients without AF. In a retrospective analysis of 1061 patients with acute ischemic stroke admitted between 1990 and 2001 to a US hospital, 216 (20.4%) had AF.³³ Nearly half of the patients with stroke and AF were bedridden (41.2%) compared with only 23.7% of those with stroke but not AF.³³ The European Community Stroke Project also found an approximate 50% higher probability of death, disability, or handicap at 3 months after a stroke among the 803 patients with AF compared with the 3659 patients who had stroke without AF.³⁴ In the Berlin Acute Stroke Study of 367 patients, the presence of AF in patients with stroke was associated with mean direct costs at 1 year that were 34% higher than those for stroke patients without AF, driven primarily by costs of the initial and subsequent hospital stays (59%) and inpatient and outpatient rehabilitation (14%).⁴ Prevention of stroke is paramount to optimize outcomes and reduce associated resource use.³²

In the FRACTAL registry of 973 US patients with AF, those who were managed with cardioversion and pharmacotherapy incurred annual AF- and cardiovascular-related healthcare costs of $4000 to $5000 (2002 dollars).¹⁹ Atrial fibrillation—related healthcare costs averaged just over $4700 per patient per year during the mean 2 years of follow-up, but annual costs varied greatly according to the AF clinical course.¹⁹ In patients who had recurrent AF, the frequency of recurrences was strongly associated with greater resource use—each recurrence increased costs by a mean of $1600 per year.¹⁹ Additionally, several cardiac baseline conditions were strongly associated with annual healthcare costs. Previous myocardial infarction, peripheral arterial disease, cardiomyopathy, and valvular disease were associated with costs of $1909, $2104, $3247, and $2211, respectively.¹⁹

In another retrospective analysis, the incremental impact of comorbid AF in the United States was evaluated. Incremental costs due to AF per hospitalization for congestive heart failure and acute myocardial infarction were $1682 and $4422, respectively, and incremental costs due to AF annually for congestive heart failure and acute myocardial infarction were $372,060,082 and $243,917,520, respectively.¹⁶

COST-EFFECTIVENESS OF CURRENT MANAGEMENT STRATEGIES FOR ATRIAL FIBRILLATION

The effectiveness of rate versus rhythm control strategies in the management of AF was recently examined in a meta-analysis of 5 randomized trials (generally reporting results from the 1990s) directly comparing the 2 methods. ³⁵ Rate control was shown to be at least as effective as rhythm control, when combined with anticoagulation, for first-line management of patients with persistent AF or at high risk of AF recurrence.³⁵ A cost-effectiveness analysis from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study showed that the 2027 patients randomized to receive rate control used fewer resources and had lower costs (mean of $5077 lower, 2002 dollars) than did the 2033 patients randomized to receive rhythm control over a mean 3.5 years of followup. ³⁶ The largest difference in resource use between the groups was in the number of hospital days (3074 fewer days in the rate control group).³⁶

The much smaller How to Treat Chronic Atrial Fibrillation (HOT CAFE) study from Poland showed that a rate control strategy is about half as costly over the first 12 months of follow-up compared with a rhythmcontrol strategy, primarily because of reduced hospitalization rates.³⁷ Annual costs for drugs and cardioversion also were signifi cantly lower with rate control (there was no cost associated with cardioversion in the rate control group).³⁷ In the RAte Control versus Electrical cardioversion for persistent AF (RACE) study, patients who received rate control were treated with digitalis, a nondihydropyridine calcium channel blocker, a beta-blocker, or a combination of these agents. In the rhythm control group, patients underwent serial electrical cardioversion and serial antiarrhythmic drug treatment using sotalol as the first choice, followed by class IC antiarrhythmics and then amiodarone.³⁸ In a substudy of 428 patients from the RACE study, costs were higher under the rhythm control strategy due to electrical cardioversion, antiarrhythmic medication, and hospital admissions.³⁸ Thus, a rate control strategy appears to be less expensive and noninferior with respect to morbidity and mortality compared with a rhythm control strategy using these antiarrhythmic drugs.

STRATEGIES FOR THE COST-EFFECTIVE TREATMENT OF ATRIAL FIBRILLATION

Evidence suggests that hospitalizations due to AF can be avoided by shifting services from the inpatient to the outpatient setting. For example, electrical cardioversion of AF can be safely performed on an outpatient basis at a much lower average cost than on an inpatient basis.³⁹ In addition, data from the Healthcare Cost and Utilization Project indicate that roughly 60% of hospital admissions for a principal diagnosis of AF result from emergency department visits.⁴⁰ A previous single-center study, however, demonstrated a reduction in emergency department admission rates from 74% to 38% with implementation of a practice guideline for emergency management of AF emphasizing oral rate control, emergency cardioversion where appropriate, and prompt follow-up of patients in a dedicated AF clinic.⁴¹ Clearly, such results rely on the availability of outpatient programs to provide AF care, which is not possible in all areas.

Available evidence also suggests that efforts at stroke prevention among AF patients in the United States are suboptimal. Underuse of warfarin, even among AF patients known to be at high risk of stroke, has been demonstrated in numerous studies, suggesting that only 50% to 60% of patients appropriately use warfarin.^42,43 Increasing the use of and adherence to warfarin in AF patients could substantially improve clinical outcomes and reduce stroke-related costs.³¹ For patients who cannot or will not take warfarin, recent data from the Atrial fi brillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events-Aspirin (ACTIVE-A) showed that the combination of aspirin and clopidogrel is superior for stroke prevention to aspirin alone.⁴⁴

Dabigatran has been approved in the United States for the prevention of stroke and systemic embolism in patients with AF.⁴⁵ The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study showed that dabigatran (150-mg dose) compared with warfarin was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.⁴⁶ In an analysis including patients >65 years of age with AF who were at increased risk of stroke, dabigatran was a cost-effective alternative to warfarin.⁴⁷ The analysis estimated a cost of $45,372 per quality-adjusted life-year gained with high-dose dabigatran (150 mg twice daily) compared with warfarin, using an assumed daily cost for dabigatran well above its actual current US price.⁴⁷ The 2011 American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society (ACCF/AHA/HRS) guideline update recommends dabigatran as a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal-to-permanent AF, with risk factors for stroke or systemic embolization, and without a prosthetic heart valve, hemodynamically signifi cant valve disease, severe renal failure, or advanced liver disease.^27,48

The recently approved antiarrhythmic drug dronedarone may be an attractive option for improving patient outcomes and reducing healthcare resource utilization when used in appropriate patients. Dronedarone is indicated in the United States to reduce the risk of hospitalization for AF in patients with sinus rhythm with a history of paroxysmal or persistent AF.⁴⁹ Dronedarone is recommended by the 2011 ACCF/AHA/HRS guideline update in patients with AF with no or minimal heart disease, hypertension with no substantial left ventricular hypertrophy, and coronary artery disease; it is not recommended in patients with heart failure.⁴⁸ The pivotal trial leading to the approval of dronedarone (A Placebo-Controlled, Double-Blind, Parallel-Arm Trial to Assess the Effi cacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter [ATHENA]) enrolled 4628 patients with AF at 551 centers in 37 countries.⁵⁰

Over the median 22 months of follow-up, the primary outcome event (fi rst hospitalization for cardiovascular events or all-cause mortality) occurred in 31.9% of patients randomized to dronedarone and in 39.4% of those randomized to placebo (hazard ratio, 0.76; 95% confi dence interval, 0.69-0.84; P <.001).⁵⁰ The incidence of most other clinical outcomes was also reduced with dronedarone, and the incidence of serious adverse events did not differ signifi cantly between groups.⁵⁰ Addition ally, a post hoc analysis of the ATHENA trial demonstrated that dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (P = .027).⁵¹ Thus, in contrast to the antiarrhythmic drugs tested in the AFFIRM trial, dronedarone, as demonstrated in the ATHENA trial, reduced cardiovascular morbidity and prevented hospitalizations. Dronedarone is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or New York Heart Association (NHYA) class IV heart failure and in patients with AF who will not or cannot be cardioverted into normal sinus rhythm. In patients with severe heart failure and left ventricular systolic dysfunction, use of dronedarone was associated with increased early mortality related to the worsening of heart failure.⁵²

Naccarelli and colleagues analyzed the incidence and direct costs of ATHENA-type outcomes in 15,552 patients with AF who were covered by employer-sponsored Medicare supplemental insurance from 2004 to 2007.⁵³ In this retrospective analysis, AF patients were similar to those recruited in the ATHENA trial.^50,53 During the fi rst year after initial hospitalization for AF, 54% of patients were hospitalized for cardiovascular causes. The 10,547 hospitalizations among these patients cost an average of $11,085 each, resulting in total costs of $117 million. Another 3.4% of the patients died from cardiovascular causes, at a mean cost of $17,486 each, resulting in total costs of $9.4 million. Mean costs of outcomes varied widely among the cohort, from $7476 (mean cost per hospitalization for AF/supraventricular rhythm disorder [primary diagnosis, nonfatal]) to $37,067 (mean hospitalization cost per death, cardiovascular transcutaneous intervention procedure, or cardiovascular surgical intervention) per patient. Given the 24% relative reduction in hospitalizations noted with its use in the ATHENA trial,⁵⁰ dronedarone has the potential to reduce the costs associated with the use of these resources in patients with AF.

COST AND COST-EFFECTIVENESS OF CATHETER ABLATION

For AF patients whose symptoms are not well controlled with pharmacologic therapy, catheter ablation has emerged as another important treatment option.⁴⁸ Catheter ablation successfully treats paroxysmal AF in 41% to 94% of patients, with recent studies reporting success rates of >80%.⁵⁴ Randomized studies have found ablation to be more effective than antiarrhythmic drugs when used as a second-line strategy.^55-58 A recent meta-analysis of catheter ablation trials reported a signifi cant reduction in hospitalizations in patients receiving ablation after failure of antiarrhythmic drugs.⁵⁹

A US cost-effectiveness model of AF ablation versus rate control or antiarrhythmic drugs based on published literature and Medicare data compared lifetime costs in 55-year-old and 65-year-old patient cohorts at moderate or low risk of stroke.⁶⁰ The model assumed that amiodarone would be used for rhythm control and a combination of digoxin and atenolol would be used for rate control. Lifetime costs were calculated and ranged from $43,036 to $59,380 for ablation, compared with ranges of $24,540 to $50,509 for rate control and $38,425 to $55,795 for amiodarone (2004 US dollars), based on varying assumptions about the potential for AF ablation to reduce the risk of stroke.⁶⁰

A Canadian study estimated costs of AF catheter ablation compared with the cost of rate control or antiarrhythmic drug treatment based on cost data from the Canadian Atrial Fibrillation registry, government fee schedules, and published data. The authors projected that annual AF costs would be signifi cantly lower after ablation ($1597 to $2132 in 2005 Canadian dollars) compared with medical therapy ($4176 to $5060). Using these estimates, it was concluded that costs of ablation and antiarrhythmic drug therapy would be the same after 3.2 to 8.4 years of follow-up, or after 4.5 to 10.8 years of follow-up with 3% discounting applied to future costs.⁶¹

Cost-effectiveness of AF catheter ablation is difficult to determine, as differences exist in the experience level of each center, use of technology, and rates of reimbursement, which affect cost calculations⁵⁴; however, 3 studies that evaluated the cost-effectiveness of AF ablation compared with rhythm control or antiarrhythmic drug strategies in specifi c AF populations showed that ablation treatment results in improved quality-adjusted life expectancy at a higher cost. Thus, AF ablation may be a cost-effective treatment option for appropriately selected patients.^60,62,63 In analyses conducted to date, incremental cost-effectiveness ratios for AF ablation in selected populations were close to $50,000 per quality-adjusted life-year.^60,64

Conclusions

With an aging population and improved survival among patients with cardiovascular disease, the prevalence of AF in the United States is likely to increase significantly. This will impose on society an even greater burden of morbidity and mortality from stroke and heart failure, which will in turn increase resource use and associated healthcare costs. More effective ways of delivering care (including more optimal use of proven therapies such as anticoagulation), as well as the use of new and emerging strategies with the potential to decrease healthcare costs, can help to address and manage the predicted rise in AF and its associated events.