An Economic Analysis of Stroke and Atrial Fibrillation

CHAPTER 1

An Economic Analysis of Stroke and Atrial Fibrillation ARNOLD J. GREENSPON, MD

A 67-year-old accountant is sitting at his desk, idly staring at his computer screen. He should be focusing on the balance sheet and the delay in accounts receivable. Instead, he suddenly can’t remember what day it is, what time it is. Is it morning, is it evening? In fact, he can’t remember where he is. He looks to his left and tries to speak but only garbled words come out. His coworker looks at him with alarm as he becomes more confused and disoriented. Soon, he is on the floor, as coworkers feverishly scramble and call 911 for help. He is having an acute stroke. We often measure the outcome of an acute event by analyzing the patient’s response and initial reaction to therapy, such as days in the intensive care unit or hospital. These treatment costs can be easily measured. We can also easily measure in-hospital or 30-day mortality as a measurement of outcome. With stroke, outcome measures are more difficult to define. This is partly because patients might survive their initial stroke but then go on to have significant residual disability that affects both their clinical and economic capacity. Disability incurs significant rehabilitation costs and affects the future ability of the patient to function and earn income. These effects are more difficult to measure. Atrial fibrillation (AF) is a major risk factor for ischemic stroke.1–3 Strategies to reduce the risk for stroke in AF patients involve chronic oral anticoagulation.4–6 Warfarin is the traditional oral anticoagulant given for stroke protection. It is a drug that is difficult to use because of its complex pharmacokinetics and drug interactions. Warfarin has a narrow therapeutic index that also makes it difficult to use. A target INR (international normalized ratio) of 2–3 must be achieved to protect a high-risk AF patient from stroke.7,8 An INR that is very low indicates the patient is at risk for stroke; an INR that is very high indicates the patient is at risk for bleeding. The direct oral anticoagulants (DOACs) were developed to improve outcomes in at-risk AF patients because they do not possess the disadvantages of warfarin.9,10 However, the advantages of DOACs come at higher price. The question is whether these advantages are worth the additional cost.

This chapter will review the economic costs of acute stroke and analyze the impact of AF. The economic savings of stroke prevention will be presented along with an analysis of the potential impact of the new DOAC drugs.

INTRODUCTION Stroke is one of the most significant medical problems encountered in the United States. Despite significant progress in the treatment of stroke, it remains the fifth leading cause of death in the United States and the leading cause of major disability.11,12 This is down from the third leading cause of death, likely because of advances in acute stroke care.13 Each year, approximately 795,000 people experience a stroke, 610,000 of whom have their first attack. The National Center for Health Statistics estimates that strokes are responsible for about 1 of every 20 deaths in the United States.11 The age-adjusted stroke death rate has actually fallen. Between 2003 and 2013 the stroke-related death rate declined by 33.7% while the actual number of stroke-related deaths declined by 18.2% during this period.11 This suggests that more patients are surviving their stroke. Despite improved survival, approximately 50% of these patients are left with some degree of cognitive or functional impairment. It is estimated that there are 6.6 million Americans older than 20 years of age who have survived a stroke. Using NHANES 2008–12 data, the overall stroke prevalence is estimated at 2.6%.14 Because the majority of strokes occur in the elderly population, it is assumed that the prevalence of stroke will increase dramatically over the coming years with the aging of the US population. It is projected that by 2030, an additional 3.4 million people in the United States will have had a stroke, which represents an increase of 20% from 2012.15 Some of this increase will be due to the projected improved survival from the initial stroke. Patients who survive their stroke will continue to incur medical costs associated with their rehabilitation and continuing care. 1

2

Stroke Prevention in Atrial Fibrillation

Stroke is a devastating disease. It is associated with not only significant mortality but also potentially lifealtering cognitive and motor disability. The American Heart Association estimates that the lifetime cost of ischemic stroke is $140,048.11 Any economic assessment of stroke has to take into account not only the effects of mortality but also the major impact on both cognitive and functional ability. The costs associated with the loss of productivity may be close to the cost of treating the acute stroke.16 Between 2011 and 2012, the direct cost of treating stroke was estimated at $17.2 billion while the indirect costs including lost productivity were estimated at $15.8 billion.11 Studies comparing the cost of stroke show that approximately 0.27% of gross domestic product or 3% of total national healthcare expenditures is spent on the treatment of stroke.17 Although the total annual costs associated with stroke are now estimated at between $36.5 and $65 billion, the costs associated with stroke treatment are only expected to grow so that by 2030 these costs may exceed $240 billion.15

Based on these estimates, it is clear that the treatment of stroke is costly. However, some of these costs are difficult to measure. To better understand the economics of stroke, it is useful to divide these costs into three separate categories: direct costs, indirect costs, and the intangibles (Fig. 1.1). 

DIRECT COST OF STROKE The direct cost of stroke measures the direct amount of care required to treat a patient who has suffered a stroke.18 The majority of this cost relates to in-patient hospital care, including intensive care and interventional procedures. Direct cost of stroke also includes rehabilitation, nursing home care, and prescription drugs. Analyses of the direct costs associated with acute stroke include retrospective studies of in-patient databases from academic centers and larger studies of administrative databases such as the Nationwide Inpatient Sample, which sample more than one million patients. In these studies, hospitalization costs range

FIG. 1.1  The total cost of stroke care may be divided into the direct costs, the indirect costs, and the

intangible costs.

CHAPTER 1  An Economic Analysis of Stroke and Atrial Fibrillation from $8000 to $23,000 (converted to 2008 dollars) with an average hospital stay of 4.6–12.4 days.19 Studies on the cost of acute stroke care identify early critical care as a major component of hospital cost.20 In a study by Demaerschalk and Durocher, one-third of the total in-hospital costs of treating acute ischemic stroke with tissue plasminogen activator (rt-PA) were due to acute critical care.21 Other in-patient costs involve diagnostic radiology, drugs, laboratory tests, and general in-patient care. The cost of interventional vascular procedures now utilized to treat acute stroke must also be factored into the final analysis of acute cost. The majority of the direct costs associated with acute stroke treatment are attributable to the initial hospitalization.22 However, it appears that the costs associated with initial hospitalization for stroke are actually decreasing over time. In 1990 Taylor found that 70% of direct costs in the first year following an acute stroke were from the initial hospitalization.23 These costs decreased to 62% in a review of administrative claims data from 2002 to 200324 and subsequently to approximately 50% in a review of MarketScan Commercial and Medicare Database from 2009 to 2012.25 There are two explanations for this trend. Improved survival could be due to advances in interventional therapy for acute stroke and neurologic intensive care. An alternative explanation for the shifting of costs is the escalating costs and complexity of poststroke discharge care and rehabilitation. Significant costs are encountered in the year following acute stroke. Johnson and coworkers studied retrospective claims from 20,314 commercially insured and 31,037 Medicare beneficiaries in the year postadmission for acute ischemic stroke between January 2009 and December 2012. 25 Total average costs were $61,354 and $44,929, respectively. Most studies have shown that the highest costs occur in the 1–3 months following an acute stroke.26–28 This may relate to the high rate of hospital readmission postdischarge from acute stroke.25,29–31 Previous studies have shown that the 30-day readmission rate ranges from 14% to 28%. This climbs to as high as 35% at 90 days postdischarge.31 Most readmissions appear to be related to the sequelae of the acute stroke. In a study of healthcare utilization poststroke, 71.7% of 12,042 Medicare readmissions within 30 days of discharge were due to stroke-related sequelae. 25 This resulted in an average inpatient cost of $12,000 per patient or $104 million for the group. These data suggest that improvements in the management of patients

3

during their initial hospitalization for stroke may reduce the economic burden in the year post–acute stroke if hospital readmissions are targeted. 

INDIRECT COST OF STROKE Indirect cost of stroke measures the value of loss of productivity due to disability, as well as the costs of caregiving by unpaid family members. Indirect costs may sometimes exceed the direct costs of treating the acute stroke. In the study by Taylor in 1996, indirect costs accounted for $23.6 billion or 58% of the total lifetime stroke-related costs.23 Subsequently, Joo and coworkers summarized the results of 31 studies between 1990 and 2012 evaluating the indirect cost of stroke.32 They highlighted the difficulty in precisely establishing the true indirect cost of stroke. This difficulty is due to the range of study methods, types of data, and the definitions of indirect costs. In their review, indirect costs, depending on the definition, represented a median of 32% of the total cost of treating stroke. Two examples highlight the difficulty in precisely measuring the indirect cost of stroke. First, the cost of informal caregiving by family members following acute stroke is difficult to quantify. Although many studies mention the importance of informal caregiving in the rehabilitation of a stroke patient, there is no accepted method to measure the cost of lost wages or productivity by involved family members. A second area where measurement may be inexact is estimating the true cost of lost productivity due to illness and disability. This is a particularly difficult area to analyze since many stroke patients are older than 65 years and, while not in full-time positions, are still contributing to the workforce on a part-time or volunteer basis. Therefore, because there is no consensus on how to measure indirect cost, further study is necessary to better understand and assess the impact of indirect costs. But, there can be no doubt that indirect costs represent a substantial proportion of the total economic burden of stroke. 

INTANGIBLE COSTS These costs might include items that are generally not considered in the evaluation of disease states such as the cost of pain and suffering of the victim or his/her family members. Intangible costs might also include disruption in a family member’s ability to be fully employed or fully productive. Lost time and lost wages are difficult to track. Intangible costs

Stroke Prevention in Atrial Fibrillation

4

are difficult, if not impossible, to accurately measure. Nonetheless, they have an important impact on the true cost of stroke. 

IMPACT OF ATRIAL FIBRILLATION ON STROKE-RELATED COSTS AF is associated with strokes that are larger and more severe, resulting in more prolonged hospital stays and higher mortality.33 Stroke severity is measured using various clinical tools such as the Scandinavian Stroke Scale and the National Institute of Health Stroke Scale. Multiple studies show that patients with AF are three to four times more likely to have severe strokes and higher degrees of functional impairment.34–37 These strokes are associated with higher in-hospital, 30-day, and 1-year mortality. In a study of 1185 acute stroke patients, Jørgensen and coworkers found that AF patients had a higher in-hospital mortality (odds ratio = 1.84) and more prolonged hospital stays (50.4 vs. 39.8 days, P < .001).38 Twelve studies compared the 30-day mortality in acute stroke patients with and without AF34–36,38–46 (Table 1.1). These studies show that, on average, mortality in AF patients was approximately two times higher than their counterparts without AF (30-day AF mortality 11.3%–27% vs. no AF mortality 3.4%–12.2%). The higher mortality rate in AF patients extended 1 year post–hospital discharge (AF mortality 31.7%–63% vs. no AF mortality 13.7%–34%).

The costs associated with the care of AF stroke patients are also higher. Ali and coworkers evaluated the direct medical costs associated with acute stroke care in consecutive patients.47 Direct medical costs were 50% greater for those patients with AF compared with those in sinus rhythm (£9083 vs. £5729, P < .001). Multivariate analysis in this study confirmed that AF is an independent predictor of acute care costs. Other studies have confirmed these findings including a MarketScan analysis of the medical treatment of 160,456 stroke patients for 1 year. In their analysis, Sussman et al. found that adjusted mean incremental costs (index plus 12-month postindex) for AF patients were $4726 higher than those for non-AF, a difference of approximately 20%.48 These data provide further evidence of the impact of AF on stroke-related healthcare costs. Targeting AF patients could, therefore, have a major economic impact on the costs associated with overall stroke care. 

COST-EFFECTIVENESS OF TREATMENTS FOR STROKE PREVENTION IN ATRIAL FIBRILLATION AF is the most common arrhythmia encountered in clinical practice. Its prevalence ranges from 0.4% to 1.1% of the United States population.49 The presence of AF increases with age, affecting approximately 10% of patients over the age of 80 years.50 The risk for

TABLE 1.1

Influence of Atrial Fibrillation (AF) on Stroke Survival SAMPLE SIZE

Study

30-DAY MORTALITY (%)

1-YEAR MORTALITY (%)

AF

No AF

AF

No AF

Sig.

Candelise40

1991

221

837

27

14

<0.05

Britton39

1985

92

196

26

5

<0.05

Broderick41

1992

318

1064

23

8

<0.001

Sandercock42

1992

115

560

23

8

<0.05

Lin34

1996

103

398

25

14

<0.05

Jørgensen38

1996

968

217

33

17

<0.001

Lamassa35

2001

803

3659

19

12

<0.001

Kimura43

2005

3335

12,496

11

3

<0.001

Ghatnekar44

2008

1619

4992

13

7

<0.01

Thygesen45

2009

741

3108

15

6

<0.05

Hannon36

2010

177

391

15

12

NS

Saposnik46

2013

2185

10,501

22

10

<0.001

AF

No AF

Sig.

44

18

<0.001

63

34

<0.05

32

14

<0.05

37

20

<0.01

CHAPTER 1  An Economic Analysis of Stroke and Atrial Fibrillation embolic stroke is estimated to be at least five times higher in those patients with AF compared with the general population.1 In addition to age, clinical risk factors, such as diabetes, hypertension, congestive heart failure, vascular disease, and history of prior stroke or transient ischemic attack (TIA), identify those patients with AF who are at higher risk for stroke. The CHADS2-Vasc score was validated as a useful clinical tool to identify those patients most likely to benefit from anticoagulation.51 Randomized clinical trials have shown that the vitamin K antagonist warfarin significantly reduces strokes in high-risk AF patients. Hart and coworkers performed a metaanalysis on data from 16 randomized trials testing warfarin to prevent stroke in AF.4 Warfarin was associated with a 62% relative risk reduction (95% CI 48%–72%) when compared with placebo. The major limitation of warfarin is bleeding, with intracranial bleeding being the most serious potential complication.52 When compared with aspirin, warfarin almost doubles the risk of major bleeding (2.2 vs. 1.3 events per 100 patient-years).53 Any economic evaluation of anticoagulant therapy in stroke prevention must consider the benefit of anticoagulation therapy against the risk of bleeding. 

ECONOMIC ANALYSIS OF ANTICOAGULATION FOR STROKE PREVENTION Economic analyses have validated the cost-effectiveness of warfarin in preventing stroke. Any economic analysis has to take into account the potential health gain of a therapy and balance it against the cost and potential adverse events associated with that therapy. Health gain may be measured by determining the response to treatment and subtracting the adverse events. There are several ways in which these effects can be evaluated: cost reduction studies, cost-effectiveness studies, and finally, cost utility studies. Cost reduction studies compare the direct costs of treatment. As previously described, direct costs include hospitalizations, medications, and overall medical resources. In a study of the economic impact of warfarin on stroke prevention, Caro and coworkers found that warfarin was associated with lower direct medical costs as compared with no therapy ($2599 per patientyear vs. $4113 per patient-year).54 These findings were based on the assumption that warfarin reduced the rate of thromboembolic stroke by 69%, an estimated stroke rate of 14.3/1000 warfarin patients versus 46.7/1000 patients not anticoagulated.

5

Cost-effectiveness studies are another method to evaluate the economic impact of an intervention. These studies are often reported as the cost per unit of outcome such as dollars per year of life saved or cost of preventing one stroke. The cost-effectiveness of anticoagulation in nonrheumatic AF was modeled utilizing the costs from a UK anticoagulation clinic, meta-analyses from clinical trial data of anticoagulation such as the Boston Area Anticoagulation Trial for Atrial Fibrillation, and UK National Health data.55 The discounted cost of anticoagulation for one subject over 10 years was £4760 compared with £17,820 for the treatment of stroke for one subject over 10 years. This translated into a cost per year of life gained of £1751–£13,221, depending on the case scenario. Cost utility studies measure the effectiveness of a therapy over a time horizon in the target population. This is usually expressed by using the term qualityadjusted life year (QALY). The health gain obtained by anticoagulation is, therefore, the benefit of stroke prevention minus the costs associated with bleeding. Economists have used various methods to determine whether a therapy is cost-effective. The incremental cost-effectiveness ratio (ICER) is expressed as the difference in cost between two therapies divided by the difference in health gain or QALY. An ICER less than $50,000/QALY is felt to be cost-effective. Gage and coworkers used decision analysis to model the effects of anticoagulation on patient outcomes in nonvalvular AF.56 Stroke prevention was considered in the context of clinical variables along with adverse outcomes such as major hemorrhage. In patients over 65 years of age with one additional risk factor for stroke (hypertension, diabetes mellitus, heart disease, or prior stroke/TIA) who are considered at medium risk for stroke, warfarin costs $8000 per QALY saved. However, if one considered anticoagulation in a 65-year-old with nonvalvular atrial fibrillation (NVAF) and no risk factors, the QALY saved rose to $370,000. Other investigators have modeled the cost-effectiveness of warfarin depending on the clinical scenario of warfarin monitoring.57 They found that the economic benefit of warfarin declined as INR control became less optimal as compared with clinical trials. This type of analysis allows one to conclude that warfarin therapy is most cost-effective when it is dosed appropriately in those at high risk for stroke. 

LIMITATIONS OF COST ANALYSIS STUDIES It is always problematic to extrapolate the results of carefully conducted clinical trials to real-world experience. The efficacy of warfarin in reducing stroke in

6

Stroke Prevention in Atrial Fibrillation

nonvalvular AF is well established. However, economic analysis relies on a number of assumptions that may not apply in clinical practice. First, the number of AF patients at risk for stroke who are actually treated with anticoagulation is low. In a 2011 study of Medicare patients, only 41.5% of nonvalvular AF patients were on warfarin.58 Second, patient adherence is low. Fang and colleagues found that 26.3% of Medicare patients discontinued warfarin treatment despite a low risk for hemorrhage.59 Third, warfarin is a difficult drug because of differences in bioavailability, drug and food interactions, and a narrow therapeutic index. Patients must achieve an INR of 2–3 to achieve therapeutic efficacy.60 Patients are often unable to maintain a therapeutic INR. In a study of 138,319 AF patients undergoing INR monitoring, the time in therapeutic range (TTR) averaged 53.7%.61 Similarly, in ORBIT, a registry of AF patients, only 59% of the INR measurements were between 2 and 3, with a median TTR of 68%.62 Previous studies have shown that a high TTR correlates with improved outcomes.63 Therefore, some of these limitations will influence the assumptions used in the economic models and affect the precision of any cost analysis. 

COST-EFFECTIVENESS OF THE NEW ANTICOAGULANTS Cost analysis has been applied to the newer DOACs, dabigatran, rivaroxaban, apixaban, and edoxaban. Clinical trials have shown that these agents are at least as effective as warfarin in reducing stroke in NVAF.9 These new drugs, however, come at a higher cost than warfarin, which is relatively inexpensive. On the other hand, the DOACs do not incur the expense of routine laboratory monitoring. The question is whether these newer agents are worth the cost. The cost-effectiveness of these agents compared with the standard therapy of warfarin anticoagulation has been evaluated in numerous studies64–66 (Table 1.2). These economic evaluations utilize Markov modeling to simulate clinical outcomes based on the input of a number of variables. These variables include the expected efficacy of a DOAC, based on the results of clinical trials, the expected TTR for the warfarin group, and baseline stroke risk factors, generally derived from the CHADS2-Vasc score. Other factors, such as patient age, the expected time horizon for therapy, and drug cost may be entered into these models. In addition, the negative impact of significant hemorrhage is factored into the results. Although warfarin

is consistently found to be the least costly drug, all of the newer agents are more cost-effective than doseadjusted warfarin. Healthcare professionals and payers need to evaluate any new therapy when it becomes available. Is the new therapy, which often comes at a higher acquisition cost, associated with better outcomes? In simple terms, is the new therapy worthwhile? When reviewing the results of the economic analyses of the DOACs, it is apparent that there are variable outcome measurements. In addition, the outcome of these models must be kept in perspective because the QALY difference between apixaban, the best performer, and rivaroxaban, the weakest performer, is only 50 days. The QALY, overall cost, and ICER vary from study to study. This is because each model is based on different assumptions. The model tested assumes different patient characteristics, drug compliance or TTR if the patient is on warfarin, and the rate of bleeding or significant hemorrhage. The outcome of the model will be significantly affected if the assumptions are changed. It is clear from previous studies on the cost-effectiveness of warfarin that the target population must have a significant risk for stroke in order for the treatment to be cost-effective.56 Therefore, any model can only approximate what will happen in the “real world” when patients are not selected for a clinical trial or their risk factors are not carefully screened and drug pricing is not rigidly controlled. The cost-effectiveness of the DOACs will also depend on the effectiveness of warfarin control in a given population. However, it must be emphasized that the consistent message of these economic analyses is the superiority of the DOACs for stroke prevention. Improved pricing will only improve the economic advantage. The question then becomes, which of the DOACs is the most cost-effective? In the most recent analysis, Shah and coworkers developed a Markov model for the five available oral anticoagulants—warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban.66 The model utilized a US commercial population and modeled the cost-effectiveness of treatment over a lifetime horizon. Similar to previous studies, they found that warfarin costs were the lowest ($46,241, 95% CI $44,499–47,874) and rivaroxaban costs were the highest ($58,889, 95% CI $57,467–60,444). Of the agents studied, apixaban had the highest QALY (9.38, 95% CI, 9.24–9.48), which corresponds to an ICER of $25,816/ QALY when compared with warfarin. This study demonstrates that apixaban is cost-effective given an ICER of less than $50,000, which is generally the accepted value for a favorable effect. 

CHAPTER 1  An Economic Analysis of Stroke and Atrial Fibrillation

7

TABLE 1.2

Cost-effectiveness of Direct Oral Anticoagulants Compared With Warfarin Study Freeman67 $US 2008

Shah68

Year 2011

2011

Gonzalez-Juanatey70

2012

Kamel71

2012

Lee72

2012

$US 2011 Kamel73

2012

Harrington64

2013

Shah66 $US 2015

2016

110 mg bid

10.70

164,576

51,229

150 mg bid

10.84

168,398

45,372

8.40

44,300

_______

110 mg bid

8.54

43,700

150,000

150 mg bid

6.68

40,169

86,000

6.82

44,379

_______

110 mg bid

6.86

41,324

29,994

150 mg bid

7.08

42,946

9041

8.45

10,343

_______

8.73

15,195

17,581

150 mg bid

3.91

_______

DAB

4.19

25,000

WAR 20 mg daily

WAR APIX

$US 2013

QALY

WAR

RIVA

$US 2011

_______

WAR DAB

$US 2011

ICER/QALY

143,193

WAR DAB

€ 2012

Cost

10.28

WAR DAB

2011

Dose

WAR DAB

$US 2010

Sorenson69 $CAN 2010

Drug

5 mg bid

WAR

9.81

88,544

_______

10.03

94,456

27,498

3.91

378,000

_______

4.19

381,700

11,4000

7.97

77,813

_______

DAB

150 mg bid

8.41

82,719

11,150

RIVA

20 mg daily

8.26

78,738

3190

APIX

5 mg bid

8.47

85,326

15,026

46,241

_______

DAB

150 mg bid

9.35

56,425

31,435

RIVA

20 mg daily

9.24

58,879

57,434

APIX

5 mg bid

9.38

55,455

25,816

EDOX

60 mg daily

9.31

54,159

27,643

WAR

APIX, apixaban; DAB, dabigatran; EDOX, edoxaban; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; RIVA, rivaroxaban; WAR, warfarin.

CONCLUSION

REFERENCES

Stroke remains a devastating disease with high morbidity and mortality. This chapter has pointed out that the economic impact of stroke is profound, but difficult to quantitate. Anticoagulation can significantly reduce the risk for stroke. Economic analysis has shown that warfarin is highly cost-effective despite problems with compliance and achieving an adequate TTR. The newer agents offer the promise of reducing stroke and being cost-effective.

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