Managed Care Considerations

Supplements and Featured Publications, Secondary Prevention of Noncardioembolic Ischemic Stroke, Volume 14, Issue 7 Suppl

Stroke is the third leading cause of death in the United States and among the most costly diseases. Most strokes are categorized as ischemic, and 10% to 15% are preceded by a transient ischemic attack (TIA). Stroke survivors suffer levels of disability and handicap that range from mild to very severe, and they rarely make a complete recovery. Initial stroke patients are at considerable risk for recurrent stroke, which can compound a patient’s impairment and associated costs.

This article discusses the burden of stroke on patients and caregivers, the risk of stroke recurrence, and the pharmacoeconomics of antiplatelet therapy. Studies show that effective secondary prevention such as antiplatelet therapy can improve clinical outcomes in patients who have experienced TIA or prior stroke. Recently updated guidelines for secondary stroke prevention from the American Heart Association/American Stroke Association recommend administering antiplatelet agents rather than anticoagulants for patients who experienced an ischemic noncardioembolic stroke or TIA to reduce the risk of stroke or other cardiovascular events. The guidelines state that aspirin (ASA), ASA + extended-release dipyridamole (DP), and clopidogrel are acceptable initial treatment options for these patients.

A recent pharmacoeconomic analysis of all 3 therapies concluded that ASA and ASA + DP offer cost-effective secondary prevention for patients who have suffered a mild initial stroke. Understanding the role of antiplatelet therapy in secondary prevention can help the managed care community optimize clinical and economic outcomes, thereby reducing the overall burden of cerebrovascular disease.

(Am J Manag Care. 2008;14:S227-S237)

In the past decade, the managed care community has focused heavily on reducing cardiometabolic risk factors such as hypertension, dyslipidemia, diabetes, and smoking. Quality initiatives for cardiovascular risk reduction include pay-forperformance programs1 and improving performance using the Healthcare Effectiveness Data and Information Set (HEDIS) measures developed by the National Committee for Quality Assurance.2 Stroke prevention has been subsumed within the broader context of cardiovascular disease (CVD); however, evidence suggests that considerations unique to secondary stroke prevention—particularly antiplatelet therapy—afford managed care the opportunity to optimize clinical and economic outcomes. This article discusses the burden of stroke, the risk of stroke recurrence, and the pharmacoeconomics of antiplatelet therapy.

The Burden of Stroke


Mortality. Stroke ranks third among all causes of death, after heart disease and cancer.3 The mortality rate for patients who experience a recurrent stroke is higher than the mortality rate after an initial stroke. A study of Medicare patients noted a significantly higher 2-year survival rate following a first stroke (56.7%) as opposed to a recurrent stroke (48.3%). The disparity between survival rates became evident within 1 to 3 months poststroke and increased over time.6

Disability and Handicap. The major sequelae of stroke for survivors are disability (loss of ability to carry out activities in the usual manner) and handicap (loss of ability to fulfill one’s usual social roles), but stroke can impair virtually any human function. This includes gross and fine motor abilities, basic and instrumental activities of daily life, ambulation, language, perception, cognition, and mood.7

The levels of poststroke disability and handicap change over time, partly owing to the natural course of the disease, but also in relation to a patient’s access to rehabilitation7 and social support. Data from longitudinal and cross-sectional studies suggest that poststroke improvement is most rapid in the first month and plateaus by 3 months.7 Despite this initial period of improvement, disability and handicap remain highly prevalent 1 and 3 years poststroke.7,8 The pattern of recovery following a recurrent stroke is similar, but this is superimposed on any residual disability from the prior stroke. In a prospective observational study of 345 patients who suffered a disabling recurrent ischemic stroke, the rate of recovery was greatest during the first 6 months. Those patients who were not disabled prior to stroke recurrence and those whose disability was less severe after recurrence were most likely to recover functional independence. Patients left with moderate disability after stroke recurrence had a median recovery time of 6 months and those with severe disability required 18 months. Only 6% of patients left with very severe disability recovered by 18 months poststroke.9

Stroke and Overall Health. Comorbidities commonly associated with stroke include coronary heart disease (CHD) and peripheral arterial disease (PAD), which share some of stroke’s risk factors. Direct sequelae of stroke include seizures,10,11 complications related to immobility (eg, pressure sores, deep vein thrombosis, and pulmonary embolism), infections (eg, urinary tract and chest infections), pain,10,11 aspiration,12 and psychological dysfunction (especially depression).11,13 As a result of chronic inactivity, stroke survivors sometimes develop long-term sequelae. Poor cardiorespiratory fitness increases a patient’s risk for CVD and recurrent stroke.14 Bone loss beyond that which is associated with normal aging has been observed in stroke patients and could lead to the development of osteoporosis.15

Quality of Life (QOL). A large US population survey found that stroke patients report significantly poorer QOL than individuals who have not suffered strokes.16 A patient’s levels of functional status and disability following a stroke are said to be important predictors of QOL.17-19 Although higher functional status generally is associated with better QOL, patients with similar levels of disability might have very different perceptions about their QOL.20 Poststroke depression is consistently tied to diminished QOL.17,18,21-23 Other poststroke factors thought to correlate with QOL include fatigue,22 cognitive impairment,17 handicap or decreased participation,24-26 social support,19 and comorbidities.27

Impact of Stroke on the Caregiver

Stroke is one of the most expensive diseases in the United States. For noninstitutionalized US adults in 1997, cerebrovascular disease constituted the eighth most costly condition (after heart disease, cancer, trauma, mental disorders, pulmonary disease, diabetes, and hypertension) in terms of total annual direct expenditures. It was the most costly condition in terms of mean annual expenditure per patient.30 In 1991, the estimated mean lifetime cost (including direct and indirect costs) for a patient who suffered an ischemic stroke was $90,981,31 which translates to $140,048 in 1999 dollars.3 In 2008, the estimated annual direct and indirect costs of stroke in the United States totaled $65.5 billion.3 Another study projected that the total direct and indirect costs of stroke from 2005 to 2050 would exceed $2.2 trillion (2005 dollars).32

Hospital care spending contributes significantly to the direct cost of stroke. The number of inpatients discharged from short-stay hospitals who received a primary diagnosis of stroke increased 20% from 1979 to 2005.3 According to Nationwide Inpatient Survey data, hospital admissions for cerebrovascular diseases rose 12.8% in the decade between 1990-1991 and 2000-2001.33 Although the mean length of the patient’s hospital stay declined in this time period (eg, from 9.5 to 5.3 days for ischemic stroke), mean hospital charges per patient greatly increased (eg, jumping from $10,500 up to $16,200 for ischemic stroke). In-hospital stroke mortality rates decreased (eg, relative risk reduction was 36% for ischemic stroke), but the incremental cost for each survivor was $204,964.33

One study determined that the greatest cost drivers for incident stroke are acute hospitalization and inpatient rehabilitation, totaling $12,423 and $25,968 annually per person, respectively; the greatest cost drivers for prevalent stroke are nursing home care and lost earnings, at $33,636 and $22,880 annually per person, respectively. These estimates (in 2005 dollars) exclude strokes in people under 45 years of age and do not consider caregivers’ lost earnings.32

Costs for recurrent stroke versus first stroke were compared using historical data from a random sample of Medicare patients hospitalized for stroke in 1991. Patients in the 2 groups had similar costs for their initial hospitalization and for poststroke months 1 to 3, but in months 4 to 24, total direct medical costs averaged $375 per month more for patients in the recurrent stroke group, even though they had a higher mortality rate. This difference was largely attributable to nursing home care and acute rehospitalization—consistent with recurrent stroke’s propensity for causing more severe disability than initial stroke.6

Resource Use and Risk of Recurrent Events

After an initial stroke, survivors have a substantial risk of recurrence. Pooled data from several US population-based studies found that for initial stroke patients aged 40 to 69 years, the risk of suffering a recurrent stroke within 5 years was 13% for men and 22% for women. For patients ≥70 years, the 5-year risk of recurrent stroke was 23% for men and 28% for women.3 An estimated 10% to 15% of first ischemic strokes are preceded by a transient ischemic attack (TIA).3,34,35 Prospective community studies in the United Kingdom have found that ~12% of people who experience a TIA will have a stroke within the first year, and 30% will have one within 5 years.35 These data suggest that the risk of stroke after a TIA is roughly similar to the risk of recurrence after an initial stroke.

Table 1

Table 2

Recently published claims analyses provide additional real-world data on secondary events after a stroke. Vickrey et al36 used administrative data from several large US managed care organizations, including commercial (employer-based) and Medicare plans, to identify patients who had stroke, acute myocardial infarction (MI), or PAD during 1995-1998. Vickrey et al estimated the occurrences of subsequent vascular events based on an observation period of up to 3 years after the index event (). In the stroke cohort, more than 75% of secondary events were strokes; in the acute MI cohort, more than 75% of secondary events were MIs; and in the PAD cohort, secondary events were somewhat more likely to be MIs than strokes.36 Caro et al37 analyzed poststroke hospitalization rates using administrative data from 18,695 patients who received a diagnosis of ischemic stroke (first or recurrent) in Canada during 1990-1995. In a mean follow-up period of 4.6 years, 72.7% of patients were hospitalized at least once. The mean time to first hospitalization was 1.59 years, and the mean length of stay was 13.9 days. Of the 12.5% of patients hospitalized for any reason in the first month after the index stroke, recurrent stroke accounted for 32.8% of hospitalizations and TIA for 5.8%. Rates of hospitalization for recurrent stroke and TIA subsequently decreased, stabilizing in the second year ().37 Hospitalization costs were highest in the first year after the index stroke, attributable primarily to recurrent stroke and TIA. In successive years, hospitalization costs for recurrent stroke and TIA decreased substantially, whereas hospitalization costs for other CVD and bleeds remained about the same. The investigators noted that secondary prevention after the index event was suboptimal; with respect to antiplatelet therapy, only 36.0% of patients filled at least 1 prescription for aspirin (ASA), 4.5% for ticlopidine, 1.1% for clopidogrel, and less than 1% for dipyridamole.37

These data suggest that TIA and stroke are important risk factors for subsequent stroke and both are indications for secondary prevention. The Canadian study37 demonstrates that the need for secondary prevention may be greatest in the first 6 to 12 months after an index stroke.

Treatment Persistence and Recurrent Events Shaya et al38 used claims data from Medicaid managed care organizations in Maryland to identify patients who had a stroke in 2001-2003. The study included 925 stroke patients who received antithrombotic therapy (ASA, clopidogrel, or warfarin). Patients were considered to have discontinued therapy if they stopped taking the initial drug prescribed (switching to a different drug was classified as discontinuation). A mean follow-up period of 208 days observed that patients who persisted with initial therapy were 1.57 times more likely to avoid a recurrent stroke compared with patients who were nonpersistent (P <.001).38

Pharmacoeconomics of Antiplatelet Therapy for Secondary Stroke Prevention

Antiplatelet Options

&#8226; In WARSS, 2206 patients were randomized to 2 years of warfarin (INR, 1.4-2.8) or ASA (325 mg/day). Warfarin was associated with an increased risk of minor bleeding compared with ASA, but there was no significant difference between the groups in regard to major bleeding. The investigators concluded that both agents are reasonable alternatives in the doses used but that warfarin is more costly and patients receiving warfarin require close monitoring.40

Efficacy, Safety, and Tolerability of Antiplatelet Therapy

&#8226; MATCH (Management of Atherothrombosis with Clopidogrel in High-risk Patients). For high-risk patients who recently experienced ischemic stroke or TIA, adding ASA (75 mg/day) to clopidogrel did not significantly reduce the composite outcome of ischemic stroke, MI, vascular death, or rehospitalization for an acute ischemic event; nor did it reduce the individual outcome of ischemic stroke. However, ASA + clopidogrel significantly increased the risk of major&#8212;and even life-threatening&#8212;bleeding.43

&#8226; ESPS-2 (European Stroke Prevention Study 2). In patients who recently suffered ischemic stroke or TIA, the risk of stroke (fatal or nonfatal) was significantly reduced by administering either ASA (25 mg twice daily) or modified-release DP, or a combination of the two, compared with placebo. The combination was significantly more effective than either agent alone. ASA-containing regimens significantly increased bleeding frequency, and bleeding was more often severe. Headaches were notably more frequent in patients using ASA-containing regimens and more likely to cause discontinuation than DP-containing regimens.45

&#8226; PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes). The results of this randomized controlled trial were announced in May 2008 at the XVII European Stroke Conference. In patients who recently suffered ischemic stroke, rates of recurrent stroke (any type) were not significantly different in patients receiving ASA + ER-DP (25/200 mg twice daily) compared with those taking clopidogrel (75 mg/day). Ischemic strokes were less frequent in the ASA + ER-DP group, while hemorrhagic strokes were less frequent in the clopidogrel group. The benefit-risk ratio in terms of the combination of recurrent stroke and major hemorrhage did not vary significantly between the 2 treatments.47

Guidelines Based largely on the previously mentioned trials, the 2008 update48 of the 2006 American Heart Association (AHA)/American Stroke Association guidelines for secondary stroke prevention49 includes the following recommendations for patients who suffer ischemic noncardioembolic stroke or TIA:

&#8226; Antiplatelet agents are recommended instead of anticoagulants to reduce the risk of stroke and other cardiovascular events (Class I, Level of Evidence A).

&#8226; Based on comparative trials, the combination of ASA + ER-DP is recommended over ASA alone (Class I, Level of Evidence B).

&#8226; Adding ASA to clopidogrel increases the risk of hemorrhage. Combination ASA + clopidogrel is not routinely recommended for ischemic stroke and TIA patients unless they have a specific indication, such as acute coronary syndrome (ACS) or a coronary stent

&#8226; There is no evidence that increasing the ASA dose can provide additional benefit to patients who suffer a stroke while receiving ASA. Other antiplatelet agents are often considered, but no single agent or combination has been well studied for this patient category.

Investigational Agents

&#8226; Cangrelor is an intravenous, reversible, nonthienopyridine P2Y12 antagonist that has shown promise in patients who have ACS or are undergoing PCI. The CHAMPION-PCI and CHAMPION-PLATFORM are 2 ongoing phase 3 trials that are evaluating cangrelor.50 Results of cangrelor use in patients with prior stroke have not been reported. As an intravenous agent, cangrelor would not be suitable for long-term secondary prevention but potentially could be used in cases of acute stroke.

Multiple cost-effectiveness analyses have been reported from various countries,53-62 including 4 from the perspective of a US payer.54,58-60 Of the 4 US studies,54,59,60 3 compared all of the AHA/ American Stroke Association&#8211;recommended antiplatelet regimens. Matchar et al conducted the most recent of these studies, using the Duke Stroke Policy Model (DSPM), a peer-reviewed simulation model of the natural history of stroke and the impact of prevention strategies.54 Matchar et al compared the cost-effectiveness of ASA, ASA + DP, clopidogrel, and placebo. Using outcomes data from ESPS- 2 and CAPRIE, recurrent stroke risk ratios were calculated for ASA versus placebo, ASA + DP versus placebo, and clopidogrel versus placebo (the latter derived from ratios for clopidogrel vs ASA and ASA vs placebo). Stroke care cost estimates were based on Medicare claims data, and quality-adjusted life-years (QALYs) were estimated according to the results of a large survey of patients at risk for stroke. The following drug costs were based on 2005 prices from a wholesale pharmacy Web site: ASA, $1 per month; clopidogrel, $120 per month; ASA + DP, $120 per month. The target population consisted of 70-year-old men who had suffered a mild stroke.54

In the base-case analysis, DSPM was run for 10,000 simulated patients for each treatment strategy. To examine the impact of sampling variability (&#8220;probabilistic sensitivity analysis&#8221;), this procedure was executed 100 times. To evaluate the robustness of the base-case analysis, several conventional sensitivity analyses were performed: (1) using different risk ratio estimates for ASA from 2 published metaanalyses, (2) using drug costs based on the Federal Supply Schedule (ASA, $0.21/month; ASA + DP, $48/month; clopidogrel, $61/month), (3) assuming that treatment was effective for only 2 years, and (4) incorporating risk ratios for MI (based on clinical trial data).54

Table 3

Any 2 strategies can be compared in terms of their incremental cost-effectiveness ratio (ie, the incremental cost divided by the incremental QALYs). A strategy is considered preferable if it improves outcomes at a reasonable cost. The benchmark or threshold for reasonable cost is commonly considered to be $50,000 per QALY; in this study, the benchmark varied between $10,000 and $100,000.54 Results of the base-case analysis () indicated that (1) ASA was cost-effective compared with placebo, largely because of its low cost; (2) ASA + DP improved outcomes, but at an increased cost; and (3) clopidogrel was dominated.54

In the probabilistic sensitivity analysis, clopidogrel was rarely preferred. In the conventional sensitivity analyses, reducing medication cost estimates based on the Federal Supply Schedule made ASA + DP more cost-effective and clopidogrel less so. Assuming that treatment was effective for only 2 years moved both clopidogrel and ASA + DP out of the cost-effective range. The other 2 sensitivity analyses had no substantive impact.54 The investigators concluded that both ASA and ASA + DP appeared to provide good value compared with placebo, with no clear preference for either one. The more one is willing to pay for improved outcomes, the more likely that ASA + DP will be preferred.54

Current 2008 prices for ASA + DP and clopidogrel are somewhat higher than the 2005 values used in the analyses by Matchar et al. In 2008, the average wholesale price for a month&#8217;s supply of ASA + DP was $167 and $156 for clopidogrel.63 The current costs of other aspects of stroke care may also differ from the 2005 estimates. Also, the analyses by Matchar et al did not take into account outcomes from ESPRIT, which had not yet been published. A more recent pharmacoeconomic analysis from the United Kingdom that incorporated ESPRIT outcomes concluded that ASA + DP is the preferred treatment for secondary stroke prevention (up to a maximum of 5 years, the treatment duration for patients in ESPRIT).53 However, this result may not be applicable to the United States because of differences between the 2 countries&#8217; healthcare systems.

The analyses by Matchar et al targeted patients who suffered a mild stroke.54 There may be other relevant considerations for different patient populations. For example, for patients who experienced a more severe initial stroke, preventing recurrence may be less beneficial in terms of QALYs. Thus, it has been suggested that ASA may be the most costeffective therapy for patients afflicted with substantial disability after an initial stroke.64

For some subgroups of stroke patients, clopidogrel may prove more cost-effective. Analysis of the predefined subgroups in CAPRIE suggests that stroke patients with coexisting PAD may derive more benefit from clopidogrel than from ASA.42,64 Post-hoc subgroup analyses of CAPRIE further suggest that the absolute benefit of clopidogrel compared with ASA is amplified in patients who are at particularly high risk for ischemic events. This includes patients who have diabetes (especially insulin-dependent diabetes),65 a history of coronary bypass surgery,66 or who have already experienced recurrent ischemic events.67 These subgroups were not predefined, however, and CAPRIE may not have been adequately powered for them.64 Additional research is needed to determine the costeffectiveness of clopidogrel in subgroups

of very high-risk stroke patients.


Author Affiliation: SelectHealth.

Funding Source: This supplement was supported by Boehringer Ingelheim.

Author Disclosure: The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept, design, and drafting of the manuscript and critical revision of the manuscript for important intellectual content.

Address Correspondence to: Jeffrey D. Dunn, PharmD, MBA, SelectHealth, 9502 Carriage Chase Ln, Sandy, UT 04092. E-mail:

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