Estimating the health benefits and costs associated with ezetimibe coadministered with statin therapy compared with higher dose statin monotherapy in patients with …

Estimating the health benefits and costs associated with ezetimibe coadministered with statin therapy compared with higher dose statin monotherapy in patients with …
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  Clinical Therapeutics/Volume 30 Number 8 2008 Estimating the Health Benefits and Costs Associated with Ezetimibe Coadministered with Statin Therapy Compared with Higher Dose Statin Monotherapy in Patients with Established Cardiovascular Disease Results of a Markov Model for UK Costs Using Data Registries Roberta Ara, MScl; Abdullah Pandor MScl; Indra Tumur MScl; Suzy Paisley MA1; Alejandra Duenas PhD1; Robert Williams BScl; Anna Wilkinson MA1; Paul Durrington MD2; and Jim Chilcott MSc 1 1Health Economics and Decision Science, School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom; and 2Cardiovascular Research Group, Core Technology Facility, Manchester, United Kingdom ABSTRACT Background: Ezetimibe has been reported to im- prove lipid control in patients with established cardio- vascular disease (CVD). Objective: The aim of this study was to estimate the potential long-term impact on health status of pre- scribing ezetimibe in combination with statin therapy in patients with established CVD and evaluate its cost- effectiveness in a health economic model. Methods: A Markov model was used to compare ezetimibe and statin combination therapy with statin monotherapy. A published relationship linking chang- es in low-density lipoprotein cholesterol and cardio- vascular events was used to estimate the cardiovascu- lar events avoided through lipid-lowering therapies. The model was populated using results of extensive literature searches and a meta-analysis of clinical evi- dence. An adjustment was applied to model second- line lipid-lowering benefits. Conservative assumptions were used to extend the patient pathway beyond the clinical evidence. The analysis took the perspective of the UK Department of Health; therefore, only direct costs were included. Costs were calculated as year- 2006 British pounds. Results: For a cohort of 1000 hypothetical male patients aged 55 years, ezetimibe coadministered with current statin therapy was estimated to prevent a mean of 43 nonfatal myocardial infarctions, 7 nonfatal strokes, and 26 cardiovascular deaths over a lifetime, com- pared with doubling the current statin dose. The events avoided would provide a mean of 134 additional quality-adjusted life-years (QALYs). With a mean in- cremental cost of £3,693,000, the lifetime discounted cost per QALY gained would be £27,475 (95 CI, £27,331-£27,620) and would rise to £32,000 for men aged 75 years. Conclusions: The results suggest that, in some in- stances, ezetimibe coadministration may be cost-effective compared with statin monotherapy, but there are sev- eral limitations with this model. The economic effects of ezetimibe must be revisited when long-term effec- tiveness and safety data become available. Clin Ther. 2008;30:1508-1523) © 2008 Excerpta Medica Inc. Key words: cost, cost-effectiveness, ezetimibe, statin, cardiovascular disease. INTRODUCTION Serum cholesterol makes an important contribution to the development of atherosclerosis and is an impor- tant determinant of cardiovascular risk. It has been estimated that high cholesterol (hypercholesterolemia) causes 18 of global cerebrovascular disease and 56 of global ischemic heart disease. 1 The British Heart Foundation s and the National Heart Forum 3 suggest that about 46 of premature coronary deaths among those aged <75 years in the United Kingdom Accepted fior pubfication June 26 2008. doi:l 0.1016/j.clinthera.2008.08.002 0149-2918/ 32.00 © 2008 Excerpta Medica Inc. All rights reserved. 1508 Volume 30 Number 8  R Ara et al are attributable to raised serum cholesterol. The UK population also has one of the highest mean serum cholesterol levels in the world, with -70 of the population with levels >5.0 mmol/L. 4 Hypercholesterolemia is the largest modifiable risk factor for coronary heart disease (CHD). e,3 Lifestyle factors, including diet, obesity, smoking, and lack of physical activity, are important in the prevention of CHD, but in many cases, pharmaceutical lipid- regulating interventions are also required. Statins in- hibit the hepatic synthesis of cholesterol and are the recommended first-line pharmaceutical approach.5 Com- bination treatment may be an option for patients whose cholesterol levels are not adequately reduced with the maximum tolerated or highest licensed statin dose. Ezetimibe is a comparatively new cholesterol- lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol and of plant sterols. Although the evidence base is limited, some short- term clinical data suggest that the combination of ezetimibe and statin therapy may provide an addi- tional low-density lipoprotein cholesterol (LDL-C) reduction compared with statin monotherapy. Long- term clinical data demonstrating a reduction in car- diovascular risk corresponding to the observed ezetimibe-induced cholesterol reduction are awaited. However, based on the evidence currently available, ezetimibe coadministered with a statin is approved for use in the European Union as an adjunct therapy to diet for primary hypercholesterolemia in patients whose cholesterol levels are not sufficiently controlled with a statin alone. 6 In 2003, when ezetimibe became available in Eng- land and Wales, 3854 patients received prescrip- tions for the drug. 7 In 2004, the number had risen to 24,651 patients; an additional 32,309 patients re- ceived ezetimibe in 2005, representing a year-over- year growth rate of 55 . 8,9 The 740,000 prescriptions dispensed in 2005 represented a cost of approximately £26 million 8,9 to the National Health Service in Eng- land and Wales. Based on the limited number of eco- nomic evaluations of ezetimibe, the cost-effectiveness of this treatment in the United Kingdom is open to question. This paper describes an economic evaluation commissioned by the National Institute for Clinical Excellence (NICE) to inform the recent appraisal of ezetimibe for the treatment of primary hypercholester- olemia in the United Kingdom. 1° The aim of this study was to estimate the potential long-term impact on health status of prescribing ezetimibe in combination with statin therapy in patients with established cardio- vascular disease (CVD) and evaluate its cost-effectiveness in a health economic model. M ETHODS Overview We adapted an existing CVD model reported in 20075 to estimate the potential costs and health out- comes associated with ezetimibe coadministered with statin therapy compared with statin monotherapy in patients whose cholesterol levels are not appropriately controlled with a statin alone. The model (constructed in Microsoft Excel 2003) synthesizes the best available evidence on the costs and consequences resulting from the use of ezetimibe combination therapy. The result of a meta-analysis of clinical evidence 1° was used to populate the model, supported by published evidence from extensive literature searches. An adjustment was applied to model second-line lipid-lowering benefits in patients who do not experience adequate lipid control on maximum tolerated statin doses. The relative risks of events were estimated using a published relationship linking changes in LDL-C and CVD events.ll Transi- tions to subsequent events were derived from UK reg- istries; health-state costs and quality-of-life data were obtained from published literature. The uncertainty in input parameters was characterized by probability distributions, and Monte Carlo simulations were used to replicate this uncertainty in the results. Conservative assumptions were employed to extend the patient pathway beyond the clinical evidence. A more detailed description is provided in the following section. omparison of Treatment Regimens UK guidelines for statin treatment recommend ini- tial therapy with a drug that has a low acquisition cost (taking into account required daily dose and product price per dose). 5 Prescribing data suggest this recommendation is generally followed, with almost 50 of patient-days of statin treatment in England being provided with generic simvastatin, le If ezeti- mibe is to be added to the maximum tolerated statin dose, there are several possible treatment regimens. We report in detail the costs and benefits associated with ezetimibe coadministered with currently pre- scribed statin versus currently prescribed statin titrated by 1 dose increment. Results for several other treat- ment comparisons are summarized in Table I. August 2008 1509  Clinical Therapeutics q_ 08 ¢,1 ,~ -- ~1 > ~- E c - 13 0 0 > 0 m ~ ~ I:m ~ e- ._~ 0 .N o ~ ~ o 2 r- -E~ z ~7. e- e- ~ -~ ~- ~ N u o > m 0 4-- ~ °-g8 ~ E-~ -.2 ~J O0 000 O0 ~o ~ ~ ~. O0 O0 O0 ~ ~ ~ ~ .~ oo ooo oo ° IIII II 0000 O0 0000 O0 4~ E< 2(:7 c -'~ ~4 k,O c- ~o o 0 c-4 L3 O0 000 O0 O0 000 O0 O0 000 O0 0000 O0 O0 0000 O0 O0 ~o oo oo ~00~ ~ ~ 02 co~ > ~~ .2.2 E co ~ co ._ kO ~-, ~D ~ 3 >t. > t. ~j 44~-~ ~ ~ 00 ~: ~ ~~-~aE~._ ~ ~~ ....... ~ ~_~_ ~S~ ~ ~ ~ ~ ~ ~ co.~ ~_~ co c- < 0 0 ~ o.4 ~ c~ o4 c f f cO c',l ~'3 £',1 co co r- c- ~o~ oo ~, m 1510 Volume 30 Number 8  R. Ara et al. ~q kO ~o 0 0 U • 20' n ~. G._ O o4 I O O 0 0 o4 o4 0 Oh c'~ I 0 0 ',,0 cO t'C o4 0 0 0 0 0 0 0 0 0 0 c~ u') u') ',,0 CO CO u') o ~ ~ I I I I I I ~- CY~ ~ 3 ~ I I I o ~ ~ ~ ~ ~ ~ o o o o o o o o o o o o o o o o o o o o o o o c-,i c~ c~ u,.) ',,o ',,o ~ co c~ E< LJ r- o ) o ) o ) o ) o ) o ) o ) o ) o ) o ) o ) o ) -'~ ~q t- E~ o ,~u ,' cg _= >~ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ',,0 I'~ I'~ I'~ u') CO c~ CO -i e- .m e- O m m > E < O T O u'3 ~ b0 b0 b0 b0 b0 b0 b0 b0 b0 E E E E E E E E E E 0 0 0 0 ~ 0 ~ 04 0 0 0 0 0 C C C i ,u ~.__E ,~ ~',u - - - ~.__E - • ,~ b0 ,~ .- ~.- b0 m m E ~ ~ ~ &,~ '~ ~ '~ ~-': ~ ...... • ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ • ~ ~ ,~ ,~ ~ ,~ ~ ,~ ,~ ~ ,~ ~ ,~ ~ ,~ ~ ~ LJJ LJJ LJJ LJJ LJJ LJJ LJJ LJJ LJJ LJJ m 0 c 4~ 2o = o> C~- ~_ o o m 73 -U U ,.'S u f~ ._ j m m cg 73 ~_ cg 12 <~ (7* August 2008 1511   linical Therapeutics Disease Treatment athway Markov models are useful for conditions that involve events that can occur more than once, proba- bilities that change according to the time since a pre- vious event, and risks that continue or increase over time. 13 Because CVD satisfies these requisites, a Markov model was chosen to represent the patients clinical pathway; Figure 1 illustrates the health states included. These health states are representative of the main cardiovascular events and were governed by the evidence available to populate effectiveness and transitions. Commencing in one of the postevent health states, an annual cycle was used for the probability of mov- ing to a subsequent event. In accordance with recom- mendations for conditions associated with fatal events, a lifetime horizon was used to capture the potential long-term consequences of the disease. 14 Age- and sex-specific prevalence data published by the British Heart Foundation were used to distribute patients to initial health states. 15 First- and subsequent- year transitions to CVD events were also age related (Table II). For patients with a history of a CHD event, the probability of subsequent nonfatal myocardial in- farctions (MIs), nonfatal strokes, and cardiovascular deaths were derived from patients in the Nottingham Heart Attack Register. 16 For patients with a history of a stroke, probabilities of subsequent events were derived from patients in the South London Stroke Register. 17 The transitions from transient ischemic attack and sta- ble angina were taken from the existing CVD model. 5 Ezetimibe Effectiveness Data We undertook a systematic review of the evidence relating to the effectiveness of ezetimibe (coadminis- tered with a statin) compared with statin monothera- After stable angina After unstable angina ew unstable angina After M I ~Z~ After TIA ~Z~ After stroke New ~ Death nonfatal MI 3 health states) ew nonfatal stroke Figure 1. Health states modeled in 10,000 Monte Carlo simulations in a Markov model to estimate the cost- effectiveness of ezetimibe plus statin combination therapy compared with doubling current statin close alone to treat hypercholesterolemia in a theoretical cohort of 1000 men aged SS years in the United Kingdom, based on registry data. In each cycle, all individuals were at risk of entering the absorbing health state, death, which included health states: Fatal coronary heart disease, Fatal stroke, or death through other causes. Transitions from new-event health states used First-year event rates, whereas transitions from postevent health states used subsequent-year event rates. MI = myo- cardial infarction; TIA = transient ischemic attack. 1512 Volume 30 Number 8
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