Journal of Clinical Lipidology (2013) 7, 642–652

Managing to low-density lipoprotein particles compared with low-density lipoprotein cholesterol: A cost-effectiveness analysis John A. Rizzo, PhD, Peter J. Mallow, PhD*, Heidi C. Waters, MS, MBA, Gregory S. Pokrywka, MD, FACP, FNLA, NCMP Stony Brook University, Stony Brook, NY, USA (Dr Rizzo); S2 Statistical Solutions, Inc, 11176 Main Street, Cincinnati, OH 45241, USA (Dr Mallow and Ms Waters); and Johns Hopkins University School of Medicine and Baltimore Lipid Center, Baltimore, MD, USA (Dr Pokrywka) KEYWORDS: Cost of drug therapy; Cost-effectiveness analysis; Cost-utility analysis; Lipoprotein; LDL-P; Statin therapy

BACKGROUND: Meta-analyses of clinical trials have shown that using statins to lower low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular events, and more intensive lowering of LDL-C further decreases the risk of occlusive vascular events. Lipoprotein studies suggest treating patients more aggressively when low-density lipoprotein particle (LDL-P) number is discordantly high in the presence of normal LDL-C levels. Failure to manage LDL-P numbers may lead to additional direct and indirect costs. OBJECTIVE: This analysis modeled direct and indirect costs associated with cardiovascular events due to suboptimal treatment resulting from discordance between LDL-C and LDL-P levels. METHODS: The analysis was conducted from the payer perspective and the employer perspective, respectively, over a 3-year time period. Clinical data were obtained from the Multi-Ethnic Study of Atherosclerosis, a community-based population study. The employer perspective included indirect costs and quality-adjusted life years in addition to the direct costs and cardiovascular disease events considered in the payer analysis. All costs are reported in 2011 dollars. RESULTS: From the payer perspective, managing LDL-C and LDL-P in comparison with LDL-C alone reduced costs ($21,212) and cardiovascular events (9 events). Similar patterns were observed for managing LDL-P alone in comparison with LDL-C. From the employer perspective, managing both LDL-P alone or in combination with LDL-C also resulted in lower costs, fewer cardiovascular disease events, and increased quality-adjusted life years in comparison with LDL-C. CONCLUSION: This analysis indicates that the benefits of additional testing to optimally manage LDL-P levels outweigh the costs of more aggressive treatment. These favorable results depended on the cost of drug therapy. Ó 2013 National Lipid Association. All rights reserved.

* Corresponding author. E-mail address: [email protected] Submitted September 28, 2012. Accepted for publication June 10, 2013.

Analyses of population risk led to the establishment of low-density lipoprotein cholesterol (LDL-C) goals, as defined in the National Cholesterol Education Program Adult Treatment Panel guidelines.1 Meta-analyses of clinical trials have indicated that lowering LDL-C with statins

1933-2874/$ - see front matter Ó 2013 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2013.06.004

Rizzo et al

Cost-effectiveness analysis of LDL-P management strategies

reduces cardiovascular disease (CVD) in many patients2,3 and that more intensive lowering of LDL-C further reduces the risk of occlusive vascular events.4 However, even when LDL-C goals are met, more than one-half of patients continue to have CVD progression and clinical events,5,6 particularly in patients with established coronary heart disease (CHD), low HDL-C, type 2 diabetes, and metabolic syndrome.5 One large study of patients hospitalized for CVD events found that 56.5% of patients with CHD and 41.5% of patients without a prior history of CHD met the National Cholesterol Education Program LDL-C target of ,100 mg/dL.7 LDL particles (LDL-Ps) contain a core of lipid, predominantly cholesterol, and some triglyceride, surrounded by a shell of phospholipids on which the major surface protein is apolipoprotein B (apoB). LDL-C measures the cholesterol content of the LDL-P. However, the LDL-C measure needs to take into account the dynamic relationship between the cholesterol and triglyceride content of LDL-Ps, which can vary widely and may change over time because of lifestyle changes and lipid-lowering therapy.8 LDL-P number was found to be a better discriminator of cardiovascular risk than LDL-C in several large epidemiologic studies, including EPIC-Norfolk,9,10 Framingham Offspring,11 Multi-Ethnic Study of Atherosclerosis (MESA),12 Women’s Health Initiative,13,14 and the Veterans Affairs High-Density Lipoprotein Intervention Trial.15 MESA examined concordant and discordant LDLC and LDL-P levels as they relate to CVD events and reported that LDL-P number was a better predictor of CVD events in discordant patients.12 Discordance between LDL-C and LDL-P levels may lead to either undertreatment or overtreatment with lipid-lowering pharmacotherapy. Patients with cholesterol-poor LDL-Ps who achieve recommended LDL-C goals may have correspondingly high LDL-P levels and therefore may remain undertreated.12 Inefficient patient management may lead to additional costs from both direct health care costs and indirect costs related to lost labor productivity. However, lipid management of patients is becoming less costly because generic statins and other lipid-lowering therapies become more widespread.16 To assess the discordance between LDL-C and LDL-P, LDL-P level can either be measured by a blood test through nuclear magnetic resonance (NMR) spectroscopy17 or through the LDL-P portion of the apoB measure. LDL-C is most commonly indirectly calculated with the Friedewald equation17 derived from a lipid panel. Clinically, a discordantly high LDL-P measure is prevalent in patients with cardiometabolic risk such as diabetes and metabolic syndrome.18 A recent editorial examined the evidence for assessing the cardiovascular risk with the use of the apoB measure or the LDL-P level.19 One of the limitations noted was the lack of economic evidence that examined the benefits of measuring LDL-P level compared with the additional costs.19 The objectives of this study are to model direct

643

and indirect costs associated with CVD events stemming from the common undertreatment scenario related to discordantly high LDL-P levels in the presence of normal LDL-C levels, to perform cost-effectiveness, and costutility analyses of managing LDL-C versus LDL-P, using data from published literature.

Methods A decision-tree model was developed to assess the costeffectiveness of the additional drug therapy and diagnostic testing required to assess and manage LDL-P levels to reduce CVD events and to improve the quality of life for discordant patients (Fig. 1). The model compares 2 alternative management cohorts, LDL-P number alone (group P) and LDL-C in combination with LDL-P number (group C&P) with the standard care of managing LDL-C alone (group C). All model inputs are described in Table 1 and discussed below. The study incorporated sources from a ‘‘best evidence’’ literature review from peer-reviewed journals for model input values. The best evidence approach used for this study consisted of a literature search of English language articles from January 2000 to May 2012 indexed in PubMed. The inclusion criteria included studies that reported on LDL-P numbers, lipoproteins, testing for LDL-P numbers, and costs associated with cardiovascular events. The articles were ranked according to the impact factor of the journal, number of citations, and recentness of the article. A sensitivity analysis (described below) was performed to gauge the robustness of the results to alternative model input values. Direct health care costs associated with patient management and complications from CVD events, as well as indirect job absenteeism costs associated with CVD events, were modeled, and the effect on quality-adjusted life years (QALYs) was also considered. Thus, the analysis was assessed from the following 2 separate perspectives: (1) a US payer (assessing direct health care costs and CVD events) and (2) a self-insuring employer (including indirect costs and QALYs in addition to direct costs and CVD events). Results for a 3-year time horizon are presented for both of these perspectives. A 3-year time horizon was chosen to be consistent with the third-party payer perspective, which is our primary analysis of interest. Payers tend to have a relatively short time horizon because of high turnover rates in their insured populations.

Treatment groups The study computed net cost, incremental costeffectiveness analyses (CEAs), and incremental cost-utility analyses (CUAs) from the payer and self-insured employer perspectives. Both perspectives compared management of LDL-C levels alone (standard of care) with management of LDL-P levels alone or in combination with LDL-C. The 3 treatment groups modeled in this analysis were based on the

644

Journal of Clinical Lipidology, Vol 7, No 6, December 2013

Figure 1 The model compares 2 alternative management cohorts, LDL-P alone (group P) and LDL-C in combination with LDL-P (group C&P), with the standard care of managing to LDL-C alone (group C). CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particle; NMR, nuclear magnetic resonance.

MESA study population.12 Management to a LDL-P level alone would be uncommon in current clinical practice. We included it, however, to isolate the estimated effects of managing LDL-P number alone and to examine what would happen if full substitution were to occur. The MESA study population was the most appropriate study in the literature to inform our model because it presented differences in CVD event rates that could be applied to each of the 3 modeled treatment cohorts and therefore provided the most accurate event rates for use in this analysis. MESA included men and women from 4 ethnic groups (38.5% white, 27.9% black, 21.8% Hispanic, and 11.8% Chinese) in 6 different community settings who were between the ages of 45 and 84 years (mean age, 62 years). Participants in MESA self-reported to have no clinical coronary disease at the time of enrollment into the study. The participants were followed for a mean of 5.5 years and were analyzed in terms of their LDL-C and LDL-P levels. The 3 treatment groups were assumed to be the same in every respect except the way in which their LDL levels were managed and the amount of lipid-lowering treatment provided. For this model, group C included patients whose LDL-C levels were controlled to ,100 mg/dL, whereas LDL-P remained uncontrolled (standard of care). Group P included patients whose LDL-P levels were managed to a target of ,1000 nmol/L regardless of LDL-C level. Group C&P included patients whose LDL-C and LDL-P target levels were attained (,100 mg/dL and ,1000 nmol/L, respectively). These are considered to be optimal treatment goals and represent the 20th percentile from the MESA study.20 The base case modeled 1000 patients in each cohort with an average age of 62 years to be consistent with patients in the MESA study.12

CVD event rates CVD events were as defined in the MESA study12: acute myocardial infarction (MI; fatal and nonfatal), stroke (fatal

and nonfatal), angina, and other CVD death. Information on the frequency of ‘‘other CVD death’’ was not available in the literature, so rates and costs were approximated for this end point on the basis of the literature for ‘‘death from heart failure.’’ Annual CVD event rates per 1000 person-years were derived from the MESA cohort that had low LDL-C (,100 mg/dL; ,30th percentile) or equivalently low LDL-P (,1060 mg/dL; ,30th percentile).12 The event rates were 11.3 events for patients managed to LDL-C targets alone, 6.2 events for patients managed to LDL-P alone, and 8.2 events for patients managed to both LDL-P and LDL-C levels.

Healthcare utilization and cost Costs were derived from a best-evidence review of the published literature and included direct health care costs. All costs were adjusted to 2011 dollars with the use of the Medical Care Component of the Consumer Price Index. Direct costs included physician visits ($107; current procedural terminology [CPT] code 99215 physician outpatient, established patient) and the following laboratory tests: liver function ($11; CPT code 80076 hepatic function panel), serum creatinine ($9; CPT code 82550 creatine phosphokinase assay), lipid panels ($17 CPT code 80061 lipid panel), and NMR spectroscopy LDL-P ($44; CPT code 83704 lipoprotein by NMR), which were obtained from the 2011 Medicare Physician Fee Schedule and Clinical Laboratory Fee Schedule.21,22 The cost of the NMR was in addition to the cost of the lipid panels for the 2 LDL-P treatment groups. The base case model assumed that group C (managed to LDL-C only) received no NMR lipoprofiles, whereas group P (managed to LDL-P only) and group C&P (managed to both LDL-C and LDL-P targets) received both lipid panels and NMR lipoprofiles. The model assumed that a patient would first be treated in an attempt to attain the LDL-C target and then be treated to the LDL-P target with the use

Rizzo et al Table 1

Cost-effectiveness analysis of LDL-P management strategies

645

Model inputs Value*

Clinical outcomes CVD event rate/1000 person-years Management of LDL-C only Management of LDL-P only Management of LDL-C and LDL-P Distribution of CVD events (%) Nonfatal MI Fatal MI Nonfatal stroke Fatal stroke Angina Fatal other CVD Mortality rate LDL-C only LDL-P only Both LDL-C and LDL-P Utilities No complications MI Stroke Angina Health care utilization Physician visits and tests, year 1 Physician visits, n Liver function tests, n Creatine kinase tests, n Lipid panels (LDL-C, LDL-P and LDL-C&P), n NMR LipoProfile (LDL-P and LDL-C&P), n Physician visits and tests, year 2–3 Physician visits, n Liver function tests, n Creatine kinase tests, n Lipid panels (LDL-C and both), n NMR LipoProfile (LDL-P and LDL-C&P), n Employment Percentage employed, age 60–64 y, % Word days missed per CVD event, n Costs, US$ Physician visits and tests Physician visits

11.3 6.2 8.2

Otvos et al,12 2011 Otvos et al,12 2011 Otvos et al,12 2011

22.1 9.5 23.8 4.2 35.8 4.6

Roger Roger Roger Roger Roger Roger

et et et et et et

al,28 al,28 al,28 al,28 al,28 al,28

2012 2012 2012 2012 2012 2012

0.02 0.017 0.016

CDC,31 2006; Otvos et al,12 2011 CDC,31 2006; Otvos et al,12 2011 CDC,31 2006; Otvos et al,12 2011

0.85 0.67 0.57 0.67

Choudhury et al,36 2011 Dyer et al,37 2010 Dyer et al,37 2010 Dyer et al,37 2010

3 2 2 2 2

Benner et al,23 2005 Benner et al,23 2005 Benner et al,23 2005 Assumption Assumption

1 1 1 1 1

Assumption Assumption Assumption Assumption Assumption

46.5 6.8

107

Liver function tests

11

Creatine kinase tests

9

Lipid panels

17

NMR LipoProfile

44

Statin cost (annual) CVD events Nonfatal MI, year 1 Nonfatal MI, year 2–3 (per year) Fatal MI Nonfatal stroke, year 1

Reference

48 23,326 10,858 20,914 28,887

Purcell,33 2009 Goetzel et al,35 2004

2011 Physician Fee Schedule national payment amount for HCPCS code 99215 (physician outpatient, established patient) 2011 Clinical Laboratory Fee Schedule national average for HCPCS code 80076 (hepatic function panel) 2011 Clinical Laboratory Fee Schedule national average for HCPCS code 82550 2011 Clinical Laboratory Fee Schedule national average for HCPCS code 80061 (lipid panel) 2011 Clinical Laboratory Fee Schedule national average for HCPCS code 83704 (lipoprotein by NMR) Lazar et al,16 2011 Cherry et al,26 2009 Cherry et al,26 2009 HCUP,27 2004 Cherry et al,26 2009 (continued on next page)

646

Journal of Clinical Lipidology, Vol 7, No 6, December 2013

Table 1

(continued )

Nonfatal stroke, year 2–3 (per year) Fatal stroke Angina Fatal other CVD Lost wages and benefits (per day) Discount rate, %

Value*

Reference

20,339 15,480 5,293 12,135 240 3

Cherry et al,26 2009 Chan et al,25 2007 HCUP,27 2004 HCUP,27 2004; Chan et al,25 2007 US Bureau of Labor Statistics34 Lazar et al,16 2011; Cherry et al,26 2009

CVD, cardiovascular disease; HCPCS, Healthcare Common Procedure Coding System; LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particle number; MI, myocardial infarction; NMR, nuclear magnetic resonance spectroscopy. *All costs have been adjusted to 2011 dollars.

of sequential testing for group C&P. The base case assumed 3 physician visits and 2 of each laboratory test in year 1, with 1 physician visit and 1 of each laboratory test in subsequent years to account for annual visits and testing. Cost of lipid-lowering therapy was estimated according to the literature at $4 per patient per month, equivalent to generic statin use.16 The literature suggests that managing to LDL-P requires treating at doses between 22% and 27% higher than managing to LDL-C alone.23,24 Therefore, this study assumed a statin dose increase of 25%.

CVD-related costs Costs for each CVD event were derived from the literature25–27 and multiplied by the relative frequencies of each type of event (22.1% nonfatal MI, 9.5% fatal MI, 23.8% nonfatal stroke, 4.2% fatal stroke, 35.8% angina, 4.6% fatal other CVD event)28 to obtain weighted average costs of CVD events for each cohort. Costs were estimated for each year the patient stayed in the model, accounting for the acute phase of the CVD event as well as costs incurred in later years.

Mortality Annual mortality rates were obtained from life table data for men and women aged 60 to 64 years,29 which corresponded with the age of patients in MESA.12 Death from heart disease was estimated on the basis of CVD death rates specific to each treatment group.30–32 Mortality rates were calculated as 0.02 for group C, 0.017 for group P, and 0.016 for group C&P, using life table data and CVD event rates from MESA.12 Because CVD death rates were highest in group C, these patients had a higher annual mortality than did patients in the other 2 groups. As patients died, they dropped out of the model. For the self-insured employer perspective, indirect costs included job absenteeism. A separate CUA assessed cost per QALY for the employer perspective as well.

Job absenteeism costs Indirect costs were measured as the value of lost wages from job absenteeism due to a CVD event, and assumptions

were based on literature and data from the US Bureau of Labor Statistics.34 One might also wish to consider on-thejob productivity losses, often referred to as ‘‘presenteeism.’’ Data on worker productivity are quite challenging to obtain, however, given the heterogeneity of jobs and the difficulty in measuring on-the-job productivity. Thus, we are only able to measure the absenteeism cost dimension. The base case model assumed that 46.5% of the cohort was employed with the use of data from the US Census Bureau and Congressional Research Services,33 lost wages and benefits amounted to $240 per lost work day,34 and 6.8 work days per annum were lost because of CVD events.35 Employment data were only available in 5-year age increments, and the midpoint of the applicable increment was chosen for these analyses. These costs were added to the direct health care costs above to provide an estimate of total CVD-related costs from the self-insured employer perspective.

QALYs Quality-of-life estimates were taken from the literature and included quality of life for no complications (0.85),36 nonfatal MI (0.67), nonfatal stroke (0.57), and angina (0.67).37 This information was combined with estimated life years to obtain QALYs for each cohort.

Discounting and sensitivity analysis Because the analysis extends beyond a 1-year time horizon, a standard discount rate of 3% was applied to compute costs and clinical end points in net present value terms.16,26 To gauge robustness of the results, sensitivity analyses were performed, varying each model input to high and low values relative to baseline and recomputing CEA and CUA ratios. Cost measures were varied 625% from baseline values, and alternative discount rates of 1% and 5% were examined. The ranges chosen for the sensitivity analysis were determined to explore the robustness of the results over a wide range of scenarios.38 With respect to the statin therapy, to be consistent with cost patterns observed at different chain stores, generic statin therapy costs were also varied 625% from baseline.39

Rizzo et al

Cost-effectiveness analysis of LDL-P management strategies

Calculating CEAs and CUAs Once CVD events, QALYs, and costs were calculated for each cohort, CEAs were calculated from both the payer and self-insured employer perspectives, and CUAs were calculated for the self-insured employer perspective. The standard approach is to compare the differences in costs between alternative treatments with the differences in their effectiveness. Thus, incremental cost-effectiveness ratios for group P vs group C and group C&P vs group C, respectively, were computed. These ratios were calculated for the CEAs as follows: Let Cc denote the costs for group C and Cp the costs for group P, and let CVDc denote the number of CVD events occurring in group C, and CVDp the number occurring in group P. Then the incremental cost effectiveness of treating group P compared with group C is: CEAPC 5 CP 2CC = CVDc 2CVDp




647

events in the denominator of equations 1 and 2. The net cost analyses computed the incremental costs of group P and group C&P relative to group C (standard of care), respectively.

Results The base case model showed 33 CVD events in group C, 18 in group P, and 24 in group C&P for the 3-year time horizon. Costs of lipid-lowering agents were higher for groups P and C&P than for group C because higher lipidlowering doses were required to reach LDL-P targets than LDL-C targets. Laboratory costs were also higher, because of the additional testing required for LDL-P management. However, lowering LDL-P to target level reduced CVD events relative to group C, leading to cost savings.

Payer perspective ð1Þ

The numerator in equation (1) shows the additional costs of treating group P relative to group C patients. The denominator shows the reduction in CVD events in group P relative to group C. Thus, equation (1) calculates the incremental costs of treating group P per additional case of CVD avoided. A similar equation shows the incremental cost of treating patients in group C&P relative to group C:

Both managing LDL-P alone and in combination with LDL-C resulted in lower overall costs and fewer CVD events (Table 2). The total direct health care costs included cost of care, medication costs, and costs of CVD-related events are summarized in Table 1. Results for group P vs group C indicated 15 fewer CVD events and a direct cost savings of $237,728, whereas group C&P had 9 fewer CVD events than group C, with a direct cost savings of $21,212 (Table 2).

CEAC&P 5ðCC&P 2CC Þ=ðCVDC 2CVDC&P Þ

Self-insuring employer perspective

ð2Þ

Only direct health care costs were included when calculating the CEA for the payer perspective, but indirect costs related to job absenteeism were also added for the self-insured employer perspective. A similar procedure was followed for the CUA, but with QALYs replacing CVD

Table 2

The results of the CEA indicated that both group P and group C&P had lower overall costs and fewer CVD events compared to group C (Table 2). Total days absent from work over the 3-year time horizon were 102, 56.4, and 74.1 for groups C, P, and C&P, respectively. The indirect costs over the 3-year time horizon were, respectively,

CEA and CUA: employer perspective 3-Year base case

CEA payer Group P vs Group C Group C&P vs Group C CEA self-insuring employer Group P vs Group C Group C&P vs Group C CUA Group P vs Group C Group C&P vs Group C

ICER

No. of CVD events avoided*

Cost savings, US$

No. of QALYs gained

Dominant Dominant

15 9

237,728 21,212

NA NA

Dominant Dominant

15 9

248,739 27,858

NA NA

Dominant Dominant

NA NA

248,739 27,858

10.2 11.4

CEA, cost-effectiveness analysis; CUA, cost-utility analysis; CVD, cardiovascular disease; ICER, incremental cost-effectiveness ratio; group C, managed to low-density lipoprotein cholesterol only; group P, managed to low-density lipoprotein particle number only; group C&P, managed to both low-density lipoprotein cholesterol and low-density lipoprotein particle number; NA, not available; QALY, quality-adjusted life year. *CVD events have been rounded up to the nearest whole number.

648

Journal of Clinical Lipidology, Vol 7, No 6, December 2013

$24,488 (group C), $13,476 (group P), and $17,841 (group C&P). Thus, when added to the direct health care costs, total costs were $1,667,805 (group C), $1,419,065 (group P), and $1,639,947 (group C&P). Results for group P vs group C indicated 15 fewer CVD events and a total cost savings of $248,739, whereas group C&P had 9 fewer CVD events than group C, with a total cost savings of $27,858. The average quality of life for a person with a CVD event was 0.6 for each cohort, with total QALYs gained of 2421.5 for group C, 2431.7 for group P, and 2432.9 for group C&P. The results of the CUA indicated that both group P and group C&P were dominant in comparison with group C. Group P had 10.2 more QALYs gained than group C, whereas group C&P had an additional 11.4 QALYs gained compared with group C (Table 2).

the lone exception was for group C&P when the CVD event rate was lowered, which resulted in an ICER of $11,216. Likewise, when performing sensitivity analysis for the CUA, the results also found group P and group C&P to decrease overall costs and to decrease the number of CVD events in most scenarios. The lone exception was for group C&P when the CVD event rate was lowered, which resulted in an ICER of $2816 (Table 4).

Sensitivity analyses Sensitivity analyses that varied model inputs by 25% in either direction supported the base case findings in terms of cost-effectiveness (Table 3). In nearly every case, both group P and group C&P resulted in lower overall costs and fewer CVD events than group C. The only exceptions in the sensitivity analyses were from the payer perspective in group C&P when lowering the CVD event rate (incremental cost-effectiveness ratio [ICER] 5 $12,208), CVD costs (ICER 5 $2472), raising the annual health care costs for year 1 (ICER 5 $261), and in years 2 to 3 (ICER 5 $384) (Table 3). For the self-insuring employer perspective,

Table 3

Discussion On the basis of the results of this analysis, managing patients to LDL-P targets, either alone or in combination with LDL-C, are cost-effective alternatives to managing to LDL-C targets alone. Although managing to LDL-P adds costs (NMR lipoprotein test and additional pharmacotherapy), LDL-P management prevents more CVD events, which more than offset the costs of testing and pharmacotherapy. From a payer perspective in which direct medical costs were assessed, managing LDL-P either alone or in combination with LDL-C proved less expensive and more effective than managing LDL-C alone. This analysis also included the perspective of a selfinsured employer, which took into account indirect job absenteeism costs. However, these absenteeism costs did not have a large effect on the results, with the LDL-P cohorts remaining dominant. These indirect costs applied only to employed persons. However, if a greater percentage of the population were employed, additional cost savings

CEA: cost/CVD avoided CEA ICERs Group P vs Group C

Input varied Payer sensitivity analysis Annual mortality rate CVD event rate Annual health care costs, year 1 Annual health care costs, years 2 and 3 Drug costs CVD costs Discount rate Self-insuring employer sensitivity analysis Annual mortality rate CVD event rate Annual health care costs, year 1 Annual health care costs, years 2 and 3 Drug costs CVD costs Job absenteeism costs Discount rate

CEA ICERs Group C&P vs Group C

High

Low

High

Low

216,316 218,313 215,239 215,091 215,774 222,892 216,219

216,436 213,147 217,513 217,661 216,978 29,860 216,536

21,354 24,315 261 384 2859 25,394 21,333

21,556 12,208 23,183 23,307 22,063 2,472 21,592

217,075 219,072 215,998 215,849 216,532 223,650 217,324 216,977

217,194 213,906 218,271 218,420 217,737 210,619 216,376 217,295

22,994 27,907 2326 2122 22,182 29,694 23,369 22,966

23,362 11,216 26,032 26,236 24,176 3,336 22,989 23,396

CEA, cost-effectiveness analysis; CUA, cost-utility analysis; CVD, cardiovascular disease; group C, managed to low-density lipoprotein cholesterol only; group P, managed to low-density lipoprotein particle number only; group C&P, managed to both low-density lipoprotein cholesterol and low-density lipoprotein particle number; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. All values are in US$.

Rizzo et al Table 4

Cost-effectiveness analysis of LDL-P management strategies

649

CUA: cost/QALYs gained CUA ICERs Group P vs Group C

CUA ICERs Group C&P vs Group C

Inputs varied

High

Low

High

Low

Sensitivity analysis Annual mortality rate CVD event rate Quality of life Annual health care costs, year 1 Annual health care costs, years 2 and 3 Drug costs CVD costs Job absenteeism costs Discount rate

220,564 231,494 219,452 222,702 –22,491 223,460 233,561 224,584 224,319

229,656 215,986 232,420 225,928 –26,139 225,169 215,069 224,046 224,310

21,890 27,287 21,834 2250 –94 21,673 27,433 22,583 22,300

23,275 2,816 23,056 –4,625 24,782 23,203 2,558 22,292 22,575

CEA, cost-effectiveness analysis; CUA, cost-utility analysis; CVD, cardiovascular disease; group C, managed to low-density lipoprotein cholesterol only; group P, managed to low-density lipoprotein particle number only; group C&P, managed to both low-density lipoprotein cholesterol and low-density lipoprotein particle number; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. All values are in US$.

for the LDL-P and the LDL-C&P group would have been realized because of fewer missed work days related to CVD events. The cost-utility results were consistent with the CEAs. In particular, the LDL-P and the LDL-C&P management strategies remain dominant, indicating lower costs and increased QALYs. Sensitivity analyses, which varied model inputs by 25% from base case, indicated that the model was sensitive to increased drug costs. In terms of cost of lipid-lowering therapy, the base case model assumed a cost of $4 per patient per month, which represented a generic drug cost.16 If nongeneric drug costs had been modeled, the results would have been more favorable to managing LDL-C alone. However, as this analysis indicates, as statins become less costly because of the expansion of generics, managing patients to their LDL-P levels becomes more cost effective. This analysis is consistent with an earlier costeffectiveness study of generic statin therapy, which showed that as generic statins become cheaper there may be more cost-effective uses of statin therapy.16 This analysis has several limitations. The MESA study was used to estimate differences in CVD event risk between managing LDL-C only versus a strategy that involved managing LDL-P. MESA is a primary prevention study with a population free of cardiovascular events at baseline and approximately 20% of the population was treated with lipid-lowering drugs over the 5.5-year follow-up period. The low baseline risk of the MESA population is an important limitation. However, few treatment studies in higher risk populations can address the ability of LDL-P to be a better discriminator of CVD event risk than LDL-C. For example, the lipid and lipoprotein analysis recently published from the Heart Protection Study, which represented a high-risk population with a large number of CVD events, only reported population analyses and did not

perform subgroup discordant analyses.40 MESA was the only study in the literature, other than a smaller analysis published from the Framingham Offspring Study,11 that included differences in CVD event rates that could be applied to the 3 modeled cohorts; therefore, it provided a more accurate base case, because actual end points are preferable to imputed end points in economic modeling.41 An issue of concern was the CVD event rate in the LDLP–only management cohort. Patients in the MESA study managed to LDL-P only incurred 6.2 CVD events, which seemed counterintuitive because lowering both LDL-C and LDL-P to target levels should yield fewer CVD events than managing to LDL-P alone. However, the LDL-P–only results in MESA were based on 18 CVD events, whereas the other groups had 33 and 50 CVD events. Therefore, these results may be less reliable and generalizable. To account for this, further sensitivity analysis changed the event rate for the LDL-P–only cohort to 8.5 events/1000 person-years, because evidence suggests that controlling LDL-P alone is approximately 25% more effective in lowering CVD risk than controlling LDL-C alone.11 Even when using this revised, more conservative approach, managing to LDL-P alone proved to be dominant in comparison with managing to LDL-C alone. This study assumed that the number of physician visits and laboratory tests for the 2 LDL-P treatment arms were equal to the LDL-C–only management treatment arm. This assumption was made on the basis of expert opinion and recent guidance from the Food and Drug Administration to indicate that monitoring of liver function tests is no longer necessary.42 However, the increased statin doses necessary to manage to the LDL-P goal could cause more intolerance to statins and therefore require additional testing. An additional limitation was the fact that the analysis primarily addressed the scenario in which patients require more lipid-lowering therapy (undertreatment) and did not

650

Journal of Clinical Lipidology, Vol 7, No 6, December 2013

focus on patients with adequately low LDL-P but LDL-C levels above treatment goals. The undertreatment scenario was chosen because it is the primary scenario in which there can be an improvement in pharmacotherapy and a reduction of cardiac events. In addition, the overtreatment scenario is less costly, given the plethora of generic lipidlowering drugs. Caution must be exercised in interpreting the generalizability of these results. Although the MESA database used for the key clinical outcomes in this study was taken from 6 large communities in the United States and is ethnically diverse, it is not a nationally representative sample. Although both LDL-C and LDL-P have been shown to be associated with risk of major cardiovascular events, non–HDL-C and apoB have been shown to be associated with these risks as well. Moreover, non–HDL-C can be easily calculated from lipid levels already measured in a standard lipid profile. Furthermore, a National Lipid Association Expert Panel suggested that both LDL-C and non–HDL-C measures should first be managed to their respective goals before LDL-P is assessed to guide management.43 Sniderman et al44 performed an analysis that compared non–HDL-C and apoB with LDL-C management, finding evidence that apoB management is a valuable guide for treatment. However, LDL-P discordance has been separately documented with LDL-C, non–HDL-C, and apoB in the literature, whereby LDL-P is discordantly high, especially in the presence of insulin-resistant dyslipidemia.45–47 Further, NMR testing measures a variety of additional lipoprotein parameters, possibly leading to management decisions that are based on the detection of other aspects of the atherosclerotic process.19,48 Despite these limitations, this study provides insight into improved testing and treatment of patients at risk for CVD events. The current standard of care is to manage to LDL-C goals; however, prior studies have shown that even when LDL-C goals are met, greater than 50% of patients continue to have CVD events,5–7 particularly in subpopulations of patients with prior CHD, type 2 diabetes, and metabolic syndrome.5 The American Diabetes Association and the American College of Cardiology Foundation noted in a joint consensus statement that LDL-C underestimates the burden of atherogenic, cholesterol-carrying lipoproteins in patients with cardiometabolic risk and that measurements of LDL-P or apoB may more closely quantitate the atherogenic lipoprotein load.18 The National Lipid Association has also recommended that measurement of LDL-P is reasonable for many patients at intermediate and high risk treated to LDL-C and non–HDL-C goals.43 Therefore, managing to LDL-P targets may be even more cost saving in higher risk subpopulations. Further research on this issue is warranted. NMR testing is available in the United States and is reimbursed by Medicare under the Clinical and Laboratory Fee Schedule. However, third-party payers may have different approaches about whether to reimburse for this test and the level of reimbursement, which may result in

access issues for patients. Because LDL-C remains the standard of care, it seems prudent to first control LDL-C levels and then perform NMR testing to determine whether LDL-P management is warranted.

Conclusion This study examines the cost-effectiveness of a strategy that manages to LDL goals, which can lead to the avoidance of more CVD events and can address residual CVD risk. The analysis indicated that suboptimal LDL management can lead to additional direct and indirect costs related to increased CVD events. The results of this study suggest CVD-related costs may outweigh the additional costs of LDL-P testing and increased lipid-lowering drug therapy to manage more aggressively to LDL-P levels. Proper management of both LDL-C and LDL-P shows a substantial reduction in CVD event risk. Therefore, health insurance plans and self-insured employers may wish to consider ensuring patient access to this type of testing.

Acknowledgments We thank Dr. Peter Neumann of Tufts Medical Center Institute for Clinical Research and Health Policy Studies for helpful comments and suggestions.

Financial disclosures The study was funded by LipoScience, Inc. John Rizzo is a paid consultant to S2 Statistical Solutions, Inc. Peter Mallow is an employee of and Heidi Waters was an employee of S2 Statistical Solutions, Inc., a paid consultant to LipoScience, Inc. Gregory S. Pokrywka is an unpaid advisor to LipoScience, Inc.

References 1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. 2. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278. 3. Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterollowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–125. 4. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376: 1670–1681. 5. Fruchart JC, Sacks FM, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res. 2008;5:319–335. 6. Kones R. Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey. Drug Des Devel Ther. 2011; 5:325–380.

Rizzo et al

Cost-effectiveness analysis of LDL-P management strategies

7. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J. 2009;157: 111–117.e2. 8. Rosenson RS, Davidson MH, Pourfarzib R. Underappreciated opportunities for low-density lipoprotein management in patients with cardiometabolic residual risk. Atherosclerosis. 2010;213:1–7. 9. Arsenault BJ, Despres JP, Stroes ES, et al. Lipid assessment, metabolic syndrome and coronary heart disease risk. Eur J Clin Invest. 2010;40: 1081–1093. 10. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49:547–553. 11. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study implications for LDL management. J Clin Lipidol. 2007;1:583–592. 12. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between lowdensity lipoprotein cholesterol and particle number. J Clin Lipidol. 2011;5:105–113. 13. Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930–1937. 14. Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation. 2009;119:931–939. 15. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006; 113:1556–1563. 16. Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L. Cost-effectiveness of statin therapy for primary prevention in a lowcost statin era. Circulation. 2011;124:146–153. 17. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006; 26:847–870. 18. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811–822. 19. Master SR, Rader DJ. Beyond LDL cholesterol in assessing cardiovascular risk: apo B or LDL-P? Clin Chem. 2013;59:723–725. 20. Contois JH, McConnell JP, Sethi AA, et al. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 2009;55:407–419. 21. Centers for Medicare and Medicaid Services. 2011 Physician fee schedule. Available at: https://www.cms.gov/apps/physician-fee-schedule/ overview.aspx. Accessed February 15, 2012. 22. Centers for Medicare and Medicaid Services. 2011 Clinical laboratory fee schedule. Available at: https://www.cms.gov/ClinicalLabFeeSched/ 02_clinlab.asp#TopOfPage. Accessed February 15, 2012. 23. Benner JS, Smith TW, Klingman D, et al. Cost-effectiveness of rosuvastatin compared with other statins from a managed care perspective. Value Health. 2005;8:618–628. 24. Sniderman AD. Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice. J Clin Lipidol. 2008;2:36–42. 25. Chan PS, Nallamothu BK, Gurm HS, Hayward RA, Vijan S. Incremental benefit and cost-effectiveness of high-dose statin therapy in high-risk patients with coronary artery disease. Circulation. 2007; 115:2398–2409. 26. Cherry SB, Benner JS, Hussein MA, Tang SS, Nichol MB. The clinical and economic burden of nonadherence with antihypertensive and

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

651

lipid-lowering therapy in hypertensive patients. Value Health. 2009; 12:489–497. Russo CA, Ho K, Elixhauser A. Hospital stays for circulatory diseases, 2004. Healthcare Cost and Utilization Project. HCUP Statistical Brief #26. Washington, DC: Agency for Healthcare Research and Quality; 2007 Available at , http://www.hcup-us.ahrq.gov/reports/statbriefs/sb26. pdf; 2007 Accessed April 4, 2012. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220. Centers for Disease Control and Prevention. Number of deaths and death rates, by age, race, and sex: United States, 2005. Available at: http://www.disastercenter.com/cdc/Death%20rates%202005.html. Accessed April 4, 2012. Stroke statistics. The University Hospital, University of Medicine & Dentistry of New Jersey. Available at: http://www.theuniversityhospital.com/ stroke/stats.htm. Accessed April 4, 2012. Division for Heart Disease and Stroke Prevention. Centers for Disease Control and Prevention. Heart failure death rates among adults aged 65 years and older, by state, 2006. Available at:http://www.cdc.gov/ dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm. Accessed April 4, 2012. Zafari AM, Afonso LC, Aggarwal K, et al. Myocardial infarction. Medscape Ref. Available at , http://emedicine.medscape.com/ article/155919-overview#aw2aab6b2b6aa; 2012 Accessed April 4, 2012. Purcell P. Older workers: employment and retirement trends. Federal Publications. Paper 655. 2009. Available at: http://digitalcommons. ilr.cornell.edu/key_workplace/655. Accessed January 29, 2012. US Bureau of Labor Statistics. Overview of BLS wage data by area and occupation. Available at: http://www.bls.gov/bls/blswage.htm. Accessed January 31, 2012. Goetzel RZ, Long SR, Ozminkowski RJ, Hawkins K, Wang S, Lynch W. Health, absence, disability, and presenteeism cost estimates of certain physical and mental health conditions affecting U.S. employers. J Occup Environ Med. 2004;46:398–412. Choudhry NK, Patrick AR, Glynn RJ, Avorn J. The costeffectiveness of C-reactive protein testing and rosuvastatin treatment for patients with normal cholesterol levels. J Am Coll Cardiol. 2011;57:784–791. Dyer MT, Goldsmith KA, Sharples LS, Buxton MJ. A review of health utilities using the EQ-5D in studies of cardiovascular disease. Health Qual Life Outcomes. 2010;8:13. Weinstein MC, O’Brien B, Hornberger J, et al. Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on Good Research Practices–Modeling Studies. Value Health. 2003;6:9–17. Consumer Reports. Best buy drugs: statins drugs to treat high cholesterol and heart disease. 2012. Available at: http://www.consumerreports.org/ health/best-buy-drugs/index.htm. Accessed August 30, 2012. Parish S, Offer A, Clarke R, et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation. 2012;125:2469–2478. Farahani P. A perspective on principles of comparative costeffectiveness studies for pharmacotherapy of chronic diseases. Clin Diabetes. 2012;30:54–60. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. February 28, 2012. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed May 24, 2013. Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5: 338–367. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337–345.

652

Journal of Clinical Lipidology, Vol 7, No 6, December 2013

45. Cole TG, Contois JH, Csako G, et al. Association of apolipoprotein B and nuclear magnetic resonance spectroscopy-derived LDL particle number with outcomes in 25 clinical studies: assessment by the AACC Lipoprotein and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 2013;59:752–770. 46. Cromwell WC, Otvos JD. Heterogeneity of low-density lipoprotein particle number in patients with type 2 diabetes mellitus and lowdensity lipoprotein cholesterol ,100 mg/dl. Am J Cardiol. 2006;98: 1599–1602.

47. Degoma EM, Davis MD, Dunbar RL, Mohler ER III, Greenland P, French B. Discordance between non-HDL-cholesterol and LDLparticle measurements: results from the Multi-Ethnic Study of Atherosclerosis [e-pub ahead of print March 26, 2013]. Atherosclerosis. doi: 10.1016/j.atherosclerosis.2013.03.012. 48. Nasir K, Martin SS, Virani S. Discordance: can we capitalize on it to better personalize atherosclerosis treatment? [e-pub ahead of print April 20, 2013]. Atherosclerosis. http://dx.doi.org/10.1016/j.atherosclerosis.2013.04.018.