Multicenter Treat-to-Target Cost-Effectiveness Evaluation of HMG-CoA Reductase Inhibitor Monotherapy

Multicenter Treat-to-Target
Cost-Effectiveness Evaluation
of HMG-CoA Reductase
Inhibitor Monotherapy

B. Daniel Lucas, Jr., PharmD^*

Cynthia A. Sanoski, PharmD^†

Matthew K. Ito, PharmD, FCCP, BCPS^§

Martha A. Aldrige, PharmD^¶

Judy W. M. Cheng, PharmD, BCPS^**

Daniel E. Hilleman, PharmD^‡

^*Director of Clinical Research, CAMC Health Education and Research Institute, Charleston, WV

^†Assistant Professor of Pharmacy Practice, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA

^§Professor of Pharmacy Practice, School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA

^¶Cardiovascular Research Fellow, School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA

^**Associate Professor of Pharmacy Practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY

^‡Professor and Chair, Department of Pharmacy Practice, School of Pharmacy and Allied Health Professions, Creighton University, Omaha, NE

KEY WORDS: statins, hypercholesterolemia, pharmacoeconomics

ABSTRACT

Purpose: HMG-CoA reductase inhibitors have become the drugs of choice for hypercholesterolemia, demonstrating a favorable side effect profile, ease of administration, and reduction of cardiovascular mortality in both primary and secondary prevention trials. Use of these agents has been suboptimal, however, possibly due to their cost. The objective of this study was to evaluate the cost-effectiveness of the five commercially available HMG-CoA reductase inhibitors in a large population of hypercholesterolemic patients using a population-based treat-to-target analysis.

Methods: Cardiac risk factors (CRFs) and lipid panels were collected for drug-naïve patients from five different regions of the United States. Risk stratification using CRFs was performed, and LDL-cholesterol (LDL-C) was based on national guidelines. Using meta-analysis to derive LDL-C lowering efficacy, each agent was modeled to achieve NCEP goals. Costing methodology was done using a third-party payer perspective. Drug costs were extracted from Medi-span, and clinic costs were based on CPT codes for office visits and lipid panels.

Results: Data were obtained for 5436 patients: high-risk (coronary artery disease [CAD]; n=1773), moderate-risk (no CAD and more than 2 CRFs; n=1318), and low-risk patients (no CAD and fewer than 2 CRFs; n=2345). High-risk, moderate-risk, and low-risk patients achieving LDL-C target with the primary agent, respectively, were: atorvastatin 100%, 100%, 100%; fluvastatin 4%, 74%, 100%; lovastatin 25%, 100%, 100%; pravastatin 25%, 95%, 100%; and simvastatin 89%, 100%, 100%. Yearly US dollar cost per patient to treat to goal LDL-C are shown in the table below:

Conclusions: The most cost-effective approach to treating a population with varying degrees of coronary heart disease risk is to individualize statin selection based on the expected LDL-C percentage required to achieve NCEP target. This approach would indicate that low-risk patients can be treated with fluvastatin and moderate-risk and high-risk patients with atorvastatin or fluvastatin. Notably, atorvastatin was the only agent achieving NCEP goals in patients in all risk groups.

INTRODUCTION

The HMG-CoA reductase inhibitors have become the drugs of choice for the treatment of hypercholesterolemia. These drugs effectively reduce LDL-cholesterol (LDL-C), have a comparatively favorable side effect profile, are easy to administer, and have been shown to reduce cardiovascular mortality in both primary and secondary prevention trials.^1–6 Despite the well-established clinical benefits of the HMG-CoA reductase inhibitors in patients with or at risk of developing coronary heart disease, these drugs are not used as often as recommended. In fact, use of lipid lowering drugs for high-risk patients has been reported as low as 25% of eligible patients.^7,8

One concern regarding HMG-CoA reductase inhibitors that possibly affects use is their cost. The average wholesale price (AWP) for HMG-CoA reductase inhibitor starting doses ranges from $1.41 per day for fluvastatin 20 mg to $2.51 per day for lovastatin 20 mg.⁹ This translates into annual drug costs ranging from $515 to $916. Higher doses of these drugs often cost incrementally more. We have previously shown that the cost of lipid lowering drugs, and more importantly, the availability of prescription insurance, are factors in the use of these agents.¹⁰

Given the potential for the widespread use of the HMG-CoA reductase inhibitors and their cost, we can see an obvious need for studies to define cost-effectiveness for these agents. A similar analysis on the cost-effectiveness of the HMG-CoA reductase inhibitors in a relatively small population of patients enrolled in a lipid clinic was reported previously.¹¹ The objective of the present study was to evaluate the cost-effectiveness of the five commercially available HMG-CoA reductase inhibitors in a large population of hypercholesterolemic patients using a population-based treat-to-target analysis.

METHODS

Patients

Patients screened for hypercholesterolemia at five academically affiliated medical center clinics were eligible to participate in this analysis. Baseline (receiving no lipid-lowering therapy) lipid fraction profiles and documented risk factors were obtained for each patient. Patients were included in the analysis if they met the eligibility criteria for institution of drug therapy according to the National Cholesterol Education Program Adult Treatment Panel–II (NCEP ATP-II) guidelines (Table 1). Institutional Review Board approval was obtained at respective sites.

Meta-Analysis

Efficacy estimates for each of five HMG-CoA reductase inhibitors at each of their FDA-approved dosages were based on a meta-analysis of randomized controlled trials published between January 1985 and March 2001. A MEDLINE search of the English-language literature using the key words “randomized, controlled trials,” “atorvastatin,” “fluvastatin,” “lovastatin,” “pravastatin,” and “simvastatin” was performed. Reference lists of the studies identified by the MEDLINE search were reviewed to locate additional trials.

We restricted the studies included in this analysis to those that included a placebo or active control group, randomization to treatment, a baseline dietary intervention, a minimum of 6 weeks of drug treatment prior to efficacy assessment, a minimum of 20 patients in each treatment arm, publication in an English-language peer-reviewed journal listed in Index Medicus, and reported baseline and treated LDL-C values or the percentage change in LDL-C with each treatment. The primary efficacy variable used in the meta-analysis was the percentage change in LDL-C from baseline to the final efficacy assessment in each trial. The mean percentage change and 95% confidence intervals were calculated for LDL-C for each drug and dose. The efficacy results of the individual clinical trials were weighted by the number of patients enrolled in the study. Two independent investigators accomplished data abstraction.

Cost-Effectiveness Analysis

The perspective in this analysis was that of a third party payer at risk for prescription costs and medical care.¹² Acquisition cost of the HMG-CoA reductase inhibitors was based on 2001 Price-Chek PC (MediSpan, Inc.,) average wholesale prices (AWP).⁹ Cost-effectiveness ratios for the various doses of the HMG-CoA reductase inhibitors were calculated by dividing their annual AWP acquisition cost by their respective mean percent reduction in LDL-C.

Total treatment costs for the population of patients in our database were calculated using a treat-to-target analysis. The total treatment cost was determined by calculating the percentage of patients in each cardiovascular risk stratum (Table1; low risk
< 2 risk factors; moderate risk = 2 or more risk factors; high risk = coronary heart disease) who would theoretically achieve NCEP LDL-C treatment goals with the initial dose of each HMG-CoA reductase inhibitor based on the patient’s baseline LDL-C and the meta-analysis-derived LDL-C lowering effect.

The objective of this treatment strategy was to achieve NCEP LDL-C goals in 100% of patients. When patients did not achieve NCEP goals with the initial dose of HMG-CoA reductase inhibitor, the percentage of remaining patients reaching their LDL-C goal at the next highest dose of the respective HMG-CoA reductase inhibitor was calculated. Patients requiring dose titration to achieve NCEP LDL-C goals incurred the cost of a clinic visit ($42.20) and a lipid profile analysis ($18.51). These titration costs were added for each patient requiring a subsequent dose titration. If patients did not achieve NCEP LDL-C goals at the highest available dose of the respective HMG-CoA reductase inhibitor, an alternative HMG-CoA reductase inhibitor with greater LDL-C lowering efficacy was substituted.

Neither compliance rates nor the frequency, type, and severity of adverse reactions associated with the various HMG-CoA reductase inhibitors were factored into the analysis.^2,13 Data do not suggest appreciable differences between HMG-CoA reductase inhibitors in terms of compliance and adverse reactions, making these variables unlikely to affect the analysis.

RESULTS

A total of 5436 patients with hyperlipidemia (minimum LDL-C > 130 mg/dL at baseline) were included in the study (Table 1). The low-risk group included 2345 patients, the moderate-risk group included 1318 patients, and the high-risk group included 1773 patients. The meta-analysis included 97 clinical trials with 130 cohorts with HMG-CoA reductase inhibitors.^14–109 Efficacy results based on the meta-analysis are summarized in Table 2. Cost-effectiveness based on these efficacy results and the annual AWP acquisition costs of each dose of HMG-CoA reductase inhibitor (annual $ per percent LDL-C reduction) was best for fluvastatin 40 mg and atorvastatin 10 mg.

The population-based treat-to-target economic analyses in high-risk, moderate-risk, and low-risk patients are summarized in Tables 3, 4, and 5, respectively. Among high-risk patients, atorvastatin ($1267 per patient per year) and fluvastatin ($1327 per patient per year) were significantly less expensive than lovastatin ($1840 per patient per year), pravastatin ($1803 per patient per year), and simvastatin ($1577 per patient per year). Atorvastatin was the only HMG-CoA reductase inhibitor achieving NCEP LDL-C targets in all high-risk patients without the need to substitute an alternative drug. The percentage of patients achieving NCEP LDL-C goals on the initial HMG-CoA reductase inhibitor was as follows: atorvastatin 100%; fluvastatin 4%; lovastatin 25%; pravastatin 25%; and simvastatin 89%. Atorvastatin achieved NCEP LDL-C goals in a significantly higher percentage of patients with fewer dosage adjustments than the other four agents.

Among moderate-risk patients, atorvastatin ($780 per patient per year) and fluvastatin ($772 per patient per year) were more cost-effective than lovastatin ($1622 per patient per year), pravastatin ($1640 per patient per year), and simvastatin ($1017 per patient per year). Simvastatin was less cost-effective than atorvastatin and fluvastatin, but more cost-effective than lovastatin and pravastatin. Lovastatin and pravastatin had similar cost-effectiveness, but were less cost-effective than the other agents. Fluvastatin and pravastatin required the substitution of another HMG-CoA reductase inhibitor to achieve NCEP LDL-C goals in moderate-risk patients.

Among low-risk patients, fluvastatin ($519 per patient per year) was more cost-effective than all other agents. Atorvastatin ($756 per patient per year), pravastatin, and simvastatin ($832 per patient per year) were less cost-effective than fluvastatin, but more cost-effective than lovastatin ($916 per patient per year). Lovastatin was less cost-effective than all other agents. Fluvastatin and pravastatin required dose titration to achieve NCEP LDL-C goals in low-risk patients.

Cost-effectiveness among all 5436 patients is summarized in Table 6. Overall, fluvastatin ($844 per patient per year) was more cost-effective than all other agents. Atorvastatin ($928 per patient per year) was less cost-effective than fluvastatin, but was more cost-effective than lovastatin, pravastatin, and simvastatin. Simvastatin ($1120 per patient per year) was less cost-effective than atorvastatin and fluvastatin, but was more cost-effective than lovastatin and pravastatin. Lovastatin ($1389 per patient per year) and pravastatin ($1345 per patient per year) were not significantly different from each other with regard to cost-effectiveness, but were less cost-effective than the other three agents. Across all risk strata, atorvastatin was the only agent that achieved NCEP LDL-C goals without the need to substitute another agent.

DISCUSSION

Despite the well-known clinical benefits of HMG-CoA reductase inhibitor therapy proved in both primary and secondary prevention trials, these drugs continue to be underused.^7,8 Although the reasons these drugs are underused are probably multifactorial and may not be completely understood, the acquisition cost of the HMG-CoA reductase inhibitor is substantial, and this cost may play a role.⁹ In fact, limited data indicate that the cost of these agents impacts their use.¹⁰ Therefore, studies evaluating the cost-effectiveness of individual drugs within the HMG-CoA reductase inhibitor class are needed.

The HMG-CoA reductase inhibitors effectively lower LDL-C, have simple once-a-day dosage schedules, are associated with relatively low rates of dose-limiting side effects, and reduce adverse cardiovascular events.^1–6 Despite these favorable characteristics, the HMG-CoA reductase inhibitors cannot be viewed as a homogenous group of drugs that can be used interchangeably. Significant differences in the LDL-C lowering efficacy of these drugs exist.^15,110 In addition, these agents have differing abilities to achieve NCEP LDL-C goals in various patient populations.¹¹⁰

Our study, based on a meta-analysis of published clinical trials, reaffirms the differences in LDL-C lowering efficacy among these agents. The LDL-C reductions achieved with maximal doses of these drugs vary from a high of 54% with atorvastatin 80 mg per day to a low of 30% with fluvastatin 80 mg per day (Table 2). Cost-effectiveness rates, calculated as the annual AWP drug acquisition cost divided by the percentage of LDL-C lowering with each drug dosage, were the best with atorvastatin 10 mg and fluvastatin 40 mg. These cost-effectiveness ratios are of limited practical value, however, because the actual LDL-C reduction with some of these drug doses is quite modest. For example, the drug associated with the best cost-effectiveness ratio (cost per percentage LDL-C reduction) is fluvastatin 40 mg. At this dose, fluvastatin reduces LDL-C by 26%. In our study, only 37% of moderate-risk patients and no patients in the high-risk group would achieve their LDL-C goal with this magnitude of LDL-C reduction.

Our treat-to-target economic analysis, which calculates the percentage of high-risk, moderate-risk, and low-risk patients who could reach their NCEP goal with each statin, provides an estimate of the total drug acquisition and titration costs for a population of patients in the year after drug initiation. From the health care payer perspective, this estimate is a more meaningful reflection of the costs of using different statins.

Based on treating the entire population of 5436 patients in our database, fluvastatin is the most cost-effective statin according to our treat-to-target economic analysis. Fluvastatin cost $84 less per patient per year than atorvastatin. Lovastatin, pravastatin, and simvastatin cost $545, $501, and $276 more per patient per year, respectively, than fluvastatin. Although fluvastatin was the least expensive agent overall, it was not the most cost-effective agent in all risk categories.

In low-risk patients, the majority of whom reached their LDL-C goal on the
initial dose of each agent, the drugs with the lowest acquisition cost at their respective starting doses were the most cost-effective. As a result, fluvastatin was the most cost-effective agent. In moderate-risk patients, atorvastatin and fluvastatin were the most cost-effective agents, with per patient per year costs differing by only $8. NCEP targets could be reached for most patients in this risk stratum with each statin using titrated doses. The exceptions were fluvastatin and pravastatin, with which 74% and 95% of patients, respectively, achieved the goal. These drugs required substitution of another more effective statin to bring all patients to target. With the other statins, the majority of patients reached their NCEP LDL-C targets with only one (atorvastatin) or two (lovastatin and simvastatin) dose titrations. As a result, the drugs with lower acquisition costs were also more cost-effective in patients in this risk stratum.

In high-risk patients, atorvastatin and fluvastatin were the most cost-effective drugs. Despite the similar total costs for these drugs, only 4% of fluvastatin-treated patients achieved NCEP LDL-C goals at the maximal dosage in this stratum. Atorvastatin achieved NCEP LDL-C targets in 100% of patients without the need to substitute another statin. The importance of this finding is that if only one statin was chosen to treat all patients across the entire spectrum of risk-strata, atorvastatin would be the only capable agent.

Limitations do exist in the present study. Economic modeling of morbid and mortal outcomes was not performed. However, formulary decisions are often made without accounting for these outcomes. Furthermore, recent data demonstrated that treating patients to target LDL-C reduces overall costs.¹¹¹ Treating to target LDL-C avoided $218,000 in costs in a study including 341 patients with CHD. This estimate was based on avoidance of 39 hospitalizations or emergency room visits (21 unstable angina, 7 strokes, 5 nonfatal MI, 4 angioplasties, 2 PVD).

Alternative cost-cutting means have also been employed. Tablet cutting has been used in the Veterans Affairs Hospitals and managed-care environments. Alternate-day statin dosing has been reported by others.¹¹² These measures were not modeled and are not generally accepted by the medical community as appropriate ways to reduce costs.

In conclusion, these data indicate that the most cost-effective approach to treating a patient population with varying degrees of risk for CHD is to individualize statin therapy selection based on the expected percentage reduction in LDL-C required to achieve NCEP target with the lowest acquisition cost. This approach would indicate that treatment of low-risk patients be accomplished with fluvastatin; whereas treatment of moderate-risk and high-risk patients be achieved with atorvastatin or fluvastatin. Worth noting is the fact that only atorvastatin achieved NCEP LDL-C goals in 100% of high-risk patients.

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Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin

High-Risk 1267 1327 1840 1803 1577

Moderate-Risk 780 772 1622 1640 1017

Low-Risk 756 519 916 832 832

All patients 928 844 1389 1345 1120

Table 1. Baseline LDL-cholesterol and NCEP-II treatment goals for the 5436 study patients

High-Risk Patients^*

Baseline LDL-C Patients in Patients in Reduction

(n=1773) each stratum (%) each stratum (n) needed^† (%)

≥ 200 to ≤ 210 4 71 51–52

≥ 190 to ≤ 199 7 124 48–50

≥ 180 to ≤ 189 11 195 45–47

≥ 170 to ≤ 179 28 496 42–44

≥ 160 to ≤ 169 25 443 38–41

≥ 150 to ≤ 159 16 284 34–37

≥ 140 to ≤ 149 5 89 29–33

≥ 130 to ≤ 139 4 71 23–28

Moderate-Risk Patients^§

Baseline LDL-C Patients in Patients in Reduction

(n=1318) each stratum (%) each stratum (n) needed^¶ (%)

≥ 200 to ≤ 210 5 66 36-39

≥ 190 to ≤ 199 7 91 32–35

≥ 180 to ≤ 189 14 185 28–31

≥ 170 to ≤ 179 37 488 24–27

≥ 160 to ≤ 169 37 488 19–23

Low-Risk Patients**

Baseline LDL-C Patients in Patients in Reduction

(n=2345) each stratum (%) each stratum (n) needed^‡ (%)

≥ 200 to ≤ 210 6 139 20–24

≥ 190 to ≤ 199 94 2206 16–19

*Defined as having coronary artery disease (CAD).

^†Reduction needed to achieve NCEP-II LDL-C goal of ≤ 100 mg/dL.

§Defined as patients without CAD with 2 or more risk factors.

¶Reduction needed to achieve NCEP-II LDL-C goal of < 130 mg/dL.

**Defined as patients without CAD and with fewer than 2 risk factors.

^‡Reduction needed to achieve NCEP-II LDL-C goal of < 160 mg/dL.

Table 6. Population-based treat-to-target cost analysis for 5436 patients with hypercholesterolemia

Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin

Low-risk group (n=2345)

Cost per patient per year ($) 756 519 916 832 832

Cost for all patients in group ($) 1,772,820 1,217,055 2,148,020 1,951,040 1,951,040

Moderate-risk group (n=1318)

Cost per patient per year ($) 780 772 1,622 1,640 1,017

Cost for all patients in group ($) 1,028,040 1,017,496 2,137,796 2,161,520 1,340,406

High-risk group (n=1773)

Cost per patient per year ($) 1,267 1,327 1,840 1,803 1,577

Cost for all patients in group ($) 2,246,391 2,352,771 3,262,320 3,196,719 2,796,021

Total (n=5436)

Cost per patient per year ($) 928 844 1,389 1,345 1,120

Cost for all patients in group ($) 5,047,251 4,587,322 7,548,136 7,309,279 6,087,467