End Points In Acute Heart Failure Syndromes
Background and Purpose Previous cost-effectiveness analyses analyzed warfarin for stroke prevention in randomized trial settings. Given the complexities of warfarin treatment, cost-effectiveness should be examined within a real-world setting.
Methods Our model followed patients with atrial fibrillation at moderate to high risk of stroke through primary and recurrent ischemic stroke, hemorrhages—intracranial and extracranial, and the resulting disability. Four scenarios were examined: (1) all patients start on warfarin with perfect control, that is, international normalized ratio (INR) values always within range; (2) all patients start on warfarin with trial-like control, where INR can fall outside the recommended range; (3) all patients start on warfarin with real-world INR control; and (4) real-world prescription (and control) of warfarin, aspirin, or neither for warfarin-eligible patients. Reported warfarin discontinuation rates were used. Main outcomes were total number of events, quality adjusted life years, and costs in a US setting.
Results The total number of primary and recurrent ischemic strokes in a 1,000-patient cohort (age 70 years, lifetime analysis) was 626, 832, 984, and 1,171 in scenarios 1 to 4, respectively. The corresponding mean quality adjusted life years per patient were 7.21, 6.92, 6.75, and 6.67 for scenarios 1 to 4, respectively. Costs per patient were $68,039, $77,764, $84,518, and $87,248 in scenarios 1 to 4, respectively. If "perfect" adherence to warfarin was assumed, except for discontinuations for clinical reasons, strokes would decrease to 503, 737, 909, and 1,120 in scenarios 1 to 4, respectively.
Conclusions Clinical and cost outcomes are strongly dependent on the quality of anticoagulation and rates of warfarin discontinuation. Clinicians should work to improve both. Policy makers should use real-world INR control and warfarin discontinuation rates when assessing cost-effectiveness.
Atrial fibrillation (AF) is a leading cause of ischemic stroke. Furthermore, stroke in a patient with AF is associated with greater mortality, morbidity, and costlier hospital stays than in stroke patients without AF. In the United States, stroke is the leading cause of long-term neurological disability and the third leading cause of death, resulting in estimated direct and indirect annual costs of $57.9 billion (2006 dollars). Thus, a crucial goal of AF patient management is stroke prevention.
Randomized controlled trials (RCTs) indicate that dose-adjusted warfarin is effective in ischemic stroke prevention. Guidelines recommend long-term anticoagulation with vitamin K antagonists, such as warfarin with an international normalized ratio (INR) target of 2.0 to 3.0. Warfarin has a variable pharmacokinetic profile and multiple drug-drug and drug-food interactions, resulting in the poor INR control frequently observed in real-world clinical practice. Patients' INRs often fall outside the recommended range, increasing the risk of ischemic stroke if INRs are too low and major bleeds, including intracranial hemorrhage (ICH), if INRs are too high. By contrast, in an RCT setting, the frequency of INR monitoring and efforts to control INR are optimized, with the result that patients remain within the target INR range longer. Persistence on warfarin is also likely to be higher in trials than in usual clinical care.
The risks and fears of warfarin therapy have limited its prescription by physicians, so that many warfarin-eligible patients with AF receive aspirin or neither warfarin nor aspirin. Although aspirin is recommended as an alternative to warfarin in low-risk patients or in those with contraindications, aspirin prevents fewer ischemic strokes than warfarin in patients at moderate to high risk. In the United States, many warfarin-eligible patients do not receive anticoagulation. Many patients with AF never start warfarin, and a sizable fraction of anticoagulated patients discontinue warfarin because of bleeding complications, risk of falls, burdens of INR testing, dose adjustment, and other factors.
Previous cost-effectiveness analyses of stroke prevention treatments have been based solely on outcomes observed within RCTs. Given the disparity between RCT results and real-world practice, such analyses provide unrealistic estimates of cost-effectiveness of stroke prevention treatments.
This study estimated the cost-effectiveness of different treatment scenarios to identify the appropriate model framework to assess warfarin and future alternative therapies. The scenarios investigated were perfect warfarin control, trial-like warfarin control, "real-world" warfarin control, and lastly, real-world prescription of warfarin, or aspirin, or neither for warfarin-eligible patients at moderate to high risk of stroke. In addition, we assessed the impact of real-world rates of warfarin discontinuation.
Abstract and Introduction
Abstract
Background and Purpose Previous cost-effectiveness analyses analyzed warfarin for stroke prevention in randomized trial settings. Given the complexities of warfarin treatment, cost-effectiveness should be examined within a real-world setting.
Methods Our model followed patients with atrial fibrillation at moderate to high risk of stroke through primary and recurrent ischemic stroke, hemorrhages—intracranial and extracranial, and the resulting disability. Four scenarios were examined: (1) all patients start on warfarin with perfect control, that is, international normalized ratio (INR) values always within range; (2) all patients start on warfarin with trial-like control, where INR can fall outside the recommended range; (3) all patients start on warfarin with real-world INR control; and (4) real-world prescription (and control) of warfarin, aspirin, or neither for warfarin-eligible patients. Reported warfarin discontinuation rates were used. Main outcomes were total number of events, quality adjusted life years, and costs in a US setting.
Results The total number of primary and recurrent ischemic strokes in a 1,000-patient cohort (age 70 years, lifetime analysis) was 626, 832, 984, and 1,171 in scenarios 1 to 4, respectively. The corresponding mean quality adjusted life years per patient were 7.21, 6.92, 6.75, and 6.67 for scenarios 1 to 4, respectively. Costs per patient were $68,039, $77,764, $84,518, and $87,248 in scenarios 1 to 4, respectively. If "perfect" adherence to warfarin was assumed, except for discontinuations for clinical reasons, strokes would decrease to 503, 737, 909, and 1,120 in scenarios 1 to 4, respectively.
Conclusions Clinical and cost outcomes are strongly dependent on the quality of anticoagulation and rates of warfarin discontinuation. Clinicians should work to improve both. Policy makers should use real-world INR control and warfarin discontinuation rates when assessing cost-effectiveness.
Introduction
Atrial fibrillation (AF) is a leading cause of ischemic stroke. Furthermore, stroke in a patient with AF is associated with greater mortality, morbidity, and costlier hospital stays than in stroke patients without AF. In the United States, stroke is the leading cause of long-term neurological disability and the third leading cause of death, resulting in estimated direct and indirect annual costs of $57.9 billion (2006 dollars). Thus, a crucial goal of AF patient management is stroke prevention.
Randomized controlled trials (RCTs) indicate that dose-adjusted warfarin is effective in ischemic stroke prevention. Guidelines recommend long-term anticoagulation with vitamin K antagonists, such as warfarin with an international normalized ratio (INR) target of 2.0 to 3.0. Warfarin has a variable pharmacokinetic profile and multiple drug-drug and drug-food interactions, resulting in the poor INR control frequently observed in real-world clinical practice. Patients' INRs often fall outside the recommended range, increasing the risk of ischemic stroke if INRs are too low and major bleeds, including intracranial hemorrhage (ICH), if INRs are too high. By contrast, in an RCT setting, the frequency of INR monitoring and efforts to control INR are optimized, with the result that patients remain within the target INR range longer. Persistence on warfarin is also likely to be higher in trials than in usual clinical care.
The risks and fears of warfarin therapy have limited its prescription by physicians, so that many warfarin-eligible patients with AF receive aspirin or neither warfarin nor aspirin. Although aspirin is recommended as an alternative to warfarin in low-risk patients or in those with contraindications, aspirin prevents fewer ischemic strokes than warfarin in patients at moderate to high risk. In the United States, many warfarin-eligible patients do not receive anticoagulation. Many patients with AF never start warfarin, and a sizable fraction of anticoagulated patients discontinue warfarin because of bleeding complications, risk of falls, burdens of INR testing, dose adjustment, and other factors.
Previous cost-effectiveness analyses of stroke prevention treatments have been based solely on outcomes observed within RCTs. Given the disparity between RCT results and real-world practice, such analyses provide unrealistic estimates of cost-effectiveness of stroke prevention treatments.
This study estimated the cost-effectiveness of different treatment scenarios to identify the appropriate model framework to assess warfarin and future alternative therapies. The scenarios investigated were perfect warfarin control, trial-like warfarin control, "real-world" warfarin control, and lastly, real-world prescription of warfarin, or aspirin, or neither for warfarin-eligible patients at moderate to high risk of stroke. In addition, we assessed the impact of real-world rates of warfarin discontinuation.
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