Pharmacoeconomic modeling studies based on real-world data from large managed care databases have been used to describe the potential effects on both cardiovascular event reduction and healthcare costs by achieving optimal lipid values. Using baseline lipid values and product labeling information, pharmacoeconomic models estimate that lipid targets are achieved more frequently with extended-release niacin/simvastatin combination therapy than with increased statin dosage. These modeling studies also estimate that extended-release niacin/simvastatin combination therapy, which modifies all lipid parameters, would reduce direct medical costs of coronary heart disease events more effectively than would high-dose statin monotherapy.
(Am J Manag Care. 2009;15:S74-S80)
As discussed in the article in this supplement by Alagona,1 a substantial amount of residual cardiovascular disease (CVD) risk remains after high-dose statin therapy. The CTT (Cholesterol Treatment Trialists) Collaborators reported a significant 23% proportional reduction in the incidence of first major coronary heart disease (CHD) events per 1 mmol/L (39 mg/dL) low-density lipoprotein (LDL) cholesterol reduction, in which patients receiving statins had a 7.4% CHD event rate and patients receiving placebo had a 9.8% CHD event rate (95% confidence interval [CI], 0.74-0.80; P <.001).2 However, addressing the significant residual CVD risk in patients treated with statins requires addressing lipid parameters beyond LDL cholesterol. By achieving multiple lipid goals, and thereby reducing residual CVD risk, a long-term reduction in CVD events and the attendant costs may be possible. Evidence indicates that significant proportions of statin-treated patients are not reaching lipid goals, nor are enough high-risk patients receiving appropriate pharmacologic therapy.3
A recent study by Alsheikh-Ali et al3 examined lipid levels and the use of lipid-altering drugs in patients with CHD risk equivalents, mainly diabetes. On the basis of present national guidelines, the following lipid values were considered optimal for these patients: LDL cholesterol <100 mg/dL; high-density lipoprotein (HDL) cholesterol ≥40 mg/dL (men) and ≥50 mg/dL (women); and non-HDL cholesterol <130 mg/dL when triglycerides (TGs) are ≥200 mg/dL.4 Most patients with CHD risk equivalents did not meet optimal lipid targets for LDL cholesterol (67%), HDL cholesterol (66%), and non-HDL cholesterol (71%), and 88% of patients with CHD risk equivalents did not meet 1 or more of the guideline-established lipid goals.3
Statins were used by 57% of the patients, and lipid-altering drugs other than statins were rarely used.3 Specifically, in patients with low HDL cholesterol (n = 577), only 4.7% were taking niacin, 4.9% were taking a fibrate, and 0.9% were taking niacin and a fibrate. In patients with TG ≥200 mg/dL (n = 158), only 9.5% were taking a fibrate, 8.2% were taking niacin, and 1.9% were taking niacin and a fibrate. This analysis highlights the dramatic need to further improve lipid levels in a substantial proportion of high-risk patients with CHD risk equivalents,3 although current national guidelines recommend the addition of niacin or fibrates to statins to achieve multiple lipid goals after LDL cholesterol targets have been achieved.4
A retrospective database analysis recently evaluated the treatment of managed care patients who had mixed dyslipidemia and CVD risk factors.5 Mixed dyslipidemia patients were identified by any 2 nonoptimal lipid parameters set according to the NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) guidelines. The high LDL cholesterol/low HDL cholesterol group had the lowest treatment rate, whereas the low HDL cholesterol/high TG group had the highest treatment rate (). In addition, as the number of risk factors, which included age (men ≥45, women ≥55), CHD history, hypertension, and diabetes, increased, the treatment rate increased. A greater percentage of patients with 1 risk factor were treated than those patients with no risk factors; similarly, patients with 2 risk factors were more likely to be treated than those with 1 risk factor. Furthermore, more than 30% of mixed dyslipidemia patients with 3 or 4 risk factors were not treated. Interestingly, patients in the low HDL cholesterol/high TG group were treated primarily with statin monotherapy rather than combination therapy of a fibrate or niacin with a statin.5
Achieving Multiple Lipid Targets in Managed Care Populations
Retrospective analyses of managed care databases have been useful for determining the efficacy of lipid therapies. In 2 recent studies, patients with laboratory values for LDL cholesterol, HDL cholesterol, and TGs, and no lipid therapy during the 6 months preindex were assessed for changes in lipid parameters and for CVD-related costs.6,7 Patients were classified as appropriately managed (AM; n = 3493) or inappropriately managed (IAM; n = 4683) using baseline lipid levels and the first post-index follow-up lipid panel and risk stratification according to NCEP ATP III guidelines. Mean LDL cholesterol, HDL cholesterol, and TG baseline levels were significantly different between AM patients and IAM patients (127 ± 35, 55 ± 15, and 131 ± 66 vs 132 ± 37, 45 ± 13, and 181 ± 81, respectively; P <.01). AM patients were 38% less likely to experience a cardiovascular event versus IAM patients (odds ratio [OR], 0.62; 95% CI, 0.48-0.80; P <.01). During follow-up, as shown in , AM patients had greater decreases in LDL cholesterol and TG levels compared with IAM patients (-12% vs -3% and -8% vs +5%; P <.01), whereas HDL cholesterol levels showed greater increases (5% vs 2%; P <.01).7 Greater reductions in CVD event risk and greater improvements in all 3 lipid parameters occurred among dyslipidemia patients managed in accordance with clinical guideline treatment recommendations in a managed care population. Moreover, during follow-up, AM patients exhibited a 10% reduction in the annual rate of cardiovascular events (95% CI, 0.81-0.99) compared with IAM patients. When considering economic concerns surrounding the appropriate or inappropriate management of lipid parameters, a 12% reduction in annual total cost attributable to CVD ($CV) (95% CI, 0.80-0.98; $696 vs $788; P = .02) was observed between groups (). Thus, comprehensive dyslipidemia management based on guideline recommendations was associated with reductions in associated annual total CVD costs in a managed care population.6
In a similar retrospective study evaluating the risk of cardiovascular events, a 1.1-million-member managed care database was analyzed to compare patients who attained combined optimal lipid values (OLVs) for LDL cholesterol, HDL cholesterol, and TGs with patients who did not attain the same optimal values.8 The patients in the study cohort (N = 30,348) were naïve to lipid therapy, had been in the plan at least 12 months, and had a mean follow-up of 27 ± 8 months. The OLVs for LDL cholesterol, HDL cholesterol, and TGs were established using the NCEP ATP III guidelines,4 and patients were placed into 1 of 4 groups: all 3 lipid parameters optimal, only 2 optimal, only 1 optimal, and none optimal at baseline.8 Although the baseline lipid values (LDL cholesterol, HDL cholesterol, TGs, and total cholesterol) did not significantly differ between groups, patients who had experienced a cardiovascular event had a greater number of abnormal lipid values. During the follow-up period, there appeared to be only moderate improvement in lipid values and, therefore, achievement of OLVs. The TG target was achieved most frequently and was stable over time at close to 75%, followed closely by achievement of HDL cholesterol at close to 65%.8 However, although TG and HDL cholesterol targets were attained with regularity, the rates did not improve during follow-up. In terms of LDL cholesterol, goal achievement improved from approximately 30% of patients to close to 40% of patients during follow-up. Even lower than LDL cholesterol goal achievement was attainment of combined lipid targets; achievement of combined OLVs occurred in approximately 13% of patients and increased to only approximately 20%. It is apparent from these results that management of all 3 major lipid levels remains a challenge.8
ORs for a cardiovascular event associated with attainment of each optimal lipid parameter were determined and 5955 events from 4059 study patients were found (). The presence of a single nonoptimal lipid value slightly increased cardiovascular event risk (OR, 1.06; 95% CI, 0.95-1.18), whereas 2 or all 3 nonoptimal lipid values significantly increased the risk of a cardiovascular event (OR, 1.22; 95% CI, 1.08-1.37; and OR, 1.45; 95% CI, 1.24-1.68, respectively; P <.05 vs all 3 OLVs). By not attaining combined OLVs, the risk of cardiovascular events was independently and significantly increased in this population during approximately 68,283 patient-years of follow-up. The combination of failing to achieve optimal LDL cholesterol with failing to achieve optimal HDL cholesterol or TG values, or both, increased the adjusted risk of cardiovascular events by 22% to 45%. These data provide further evidence for the importance of focusing therapeutic strategies upon assessment and management of multiple lipid abnormalities rather than upon a single lipid abnormality.8
A significant percentage of people do not achieve their LDL cholesterol goals nor do they achieve goals for other lipid parameters. Although the primary focus of lipid-lowering therapy should be LDL cholesterol,4 approximately 50% of those people with known CHD do not achieve their LDL cholesterol goal. In those patients with the metabolic syndrome, the percentage of people who fail to achieve lipid goals increases to approximately 67%. To address the percentage of individuals who fail to achieve lipid goals, as well as the potential outcomes from this failure, longitudinal, retrospective analyses of administrative claims data and laboratory results from a US managed care organization were performed in 3 patient cohorts.9 In cohort 1, only LDL cholesterol was not optimal at baseline. In cohort 2, LDL cholesterol plus HDL cholesterol or TGs were not optimal at baseline. In cohort 3, all 3 lipid values, including LDL cholesterol, HDL cholesterol, and TGs, were not optimal at baseline. The analyses revealed that in cohort 1, achievement of OLV was associated with a 25% lower CVD event risk compared with those who did not (hazard ratio [HR], 0.75; P <.001).9 For patients in cohort 2, there was a large decrease in CVD event risk in patients who achieved OLVs for 2 lipid parameters (LDL cholesterol and HDL cholesterol or TGs) compared with those patients who did not (HR, 0.54; P <.001).9 Patients in cohort 3 who achieved OLVs for all 3 lipid parameters (LDL cholesterol, HDL cholesterol, and TGs) exhibited a 46% decrease in CVD event risk compared with those who did not (HR, 0.54; P = .001).9 These data emphasize the importance of achieving OLVs for all 3 lipid parameters (LDL cholesterol, HDL cholesterol, and TGs) to optimally reduce CVD events.9
A study by Simko et al10 further addresses attainment of lipid goals, and its relationship with CVD events and costs, through longitudinal, retrospective analyses conducted using administrative claims data and laboratory results. Target lipid levels were established according to the NCEP ATP III guidelines,4 and the effects of lipid goal attainment on CVD events and cost were determined.10 Between patients achieving combined OLVs (n = 10,645) for LDL cholesterol, HDL cholesterol, and TGs, and those who did not achieve all 3 combined OLVs (n = 42,133), there was a significant difference in the proportion of patients experiencing ischemic heart disease and any CVD-related event (P <.05).10 The observed incidence of peripheral arterial disease and stroke between groups was not found to be significantly different. The differences between those patients who achieve OLVs and those who do not can also be related to medical costs; patients achieving combined OLVs for LDL cholesterol, HDL cholesterol, and TGs had a 9% reduction in annual CVD-related costs per patient per year compared with patients not achieving all 3 goals (OR, 0.91; 95% CI, 0.85-0.95; P <.05). Therefore, achieving multiple OLVs was associated with a reduced risk of CVD events as well as lower associated healthcare costs. Adherence to clinical lipid treatment guidelines to reduce residual risk through achievement of multiple lipid goals benefits both the patients by reducing the risks of CVD events and the healthcare system by lowering the overall associated cost.10
Model-Based Analyses of Pharmacotherapy
Since there are not yet a great deal of data from combination lipid-modifying therapies, mathematical models have been used to predict the effects of extended-release (ER) niacin in combination with simvastatin on lipid parameters in patients enrolled in managed care plans. The estimates of patients achieving lipid goals were modeled according to individual patient baseline lipid values, as determined by a full lipid panel, and the current product labeling assuming additive effects of niacin ER and simvastatin on lipid values. Therefore, the results obtained through these models express the average change that would be expected to occur. These modeling analyses were conducted on information gathered from patients selected from a 2.1-million-patient managed care database.
The achievement of OLVs and CVD event reduction were examined as a consequence of various pharmacologic interventions, including niacin ER/simvastatin and simvastatin/ezetimibe combination therapies, as well as niacin ER, simvastatin, and ezetimibe monotherapies.11 In this model, CVD risk and cardiovascular events were identified for each patient (N = 44,351) and the population CVD event rate during the follow-up (30 ± 12 months) was calculated to be 15.2% (OR, 0.69; 95% CI, 0.61-0.81), which places these patients at high risk according to Framingham score prediction. Achievement of OLVs (18% of patients) versus nonachievement of OLVs (82%) was used to estimate the CVD event rates associated with OLV achievement.11 In this model, niacin ER/simvastatin combination therapy yielded a significantly greater percentage of patients (66.2%) who could be expected to achieve OLVs as compared with other treatments in the model (P <.05, compared with simvastatin/ezetimibe, niacin ER, and simvastatin) due to the additive beneficial effects expected with the combination of niacin ER with simvastatin.11 Additionally, relative risk reductions were calculated for each of the different modeled therapies. Under baseline conditions, the CVD event rate was estimated to be 15.2%, whereas a relative risk reduction was found across all of the interventions studied. The largest risk reduction (38%) occurred with niacin ER/simvastatin treatment; the 15.2% baseline event rate was reduced to 9.4%, which was significantly different from the CVD event reductions calculated for the other treatment conditions (P <.05 compared with simvastatin/ezetimibe, niacin ER, and simvastatin).
In a more recent managed care database analysis, the effects of simvastatin monotherapy, simvastatin/ezetimibe, and niacin ER/simvastatin were modeled to estimate the achievement of OLVs in untreated managed care patients with CHD or CHD risk equivalents. The primary outcome measure was percentage of patients with nonoptimal values.12 The analysis included 20,948 lipid therapy-naïve patients at baseline, nonoptimal values occurred in 79% of patients for LDL cholesterol, 43% for HDL cholesterol, 42% for TGs, 77% for non-HDL cholesterol, and 92% for combined lipid values.12 As shown in , all of the modeled therapies decreased the nonoptimal value frequencies. The least beneficial treatment was simvastatin monotherapy, whereas the greatest effects were estimated to occur in a dose-dependent fashion with niacin ER/simvastatin combination therapy. In this managed care population, nonoptimal lipid values persisted after modeled simvastatin 40 mg and modeled niacin ER/simvastatin reduced residual dyslipidemia and nonoptimal lipid values to a greater extent than did simvastatin/ezetimibe.12
A recent retrospective analysis of a real-world managed care population compared annual CVD-related healthcare utilization and costs in patients with prior CVD and either initiating simvastatin monotherapy (n = 25,499) or niacin ER/simvastatin combination therapy (n = 552). Mean annual healthcare resource utilization and costs were compared and consisted of CVD-attributable inpatient, emergency department, and outpatient visits.13 Patients treated with niacin ER/simvastatin combination therapy tended to have more outpatient visits (4.3 ± 4.9 vs 3.4 ± 6.0) and emergency department visits (0.5 ± 0.2 vs 0.1 ± 0.3) compared with statin monotherapy patients, although these differences did not reach statistical significance. Conversely, inpatient visits were significantly greater among the statin monotherapy patients (0.3 ± 0.6 vs 0.2 ± 0.5; P = .0078) than in niacin ER/simvastatin-treated patients (). Therefore, high-risk patients with prior CVD and treated with niacin ER/simvastatin had lower CVD-attributable inpatient resource utilization compared with simvastatin monotherapy patients.13 Moreover, mean unadjusted total CVD costs were greater among statin monotherapy patients than for niacin ER/simvastatin patients ($4544 ± $16,471 vs $3517 ± $7871; P = .0035). After adjusting for baseline cost drivers, niacin ER/simvastatin patients showed an 18% reduction in annual CVD costs compared with statin monotherapy patients (; P = .0325). Thus, in addition to the difference in healthcare utilization, high-risk patients with prior CVD and treated with niacin ER/simvastatin combination therapy had lower total annual CVD-attributable costs compared with simvastatin monotherapy patients. Further studies examining the clinical and economic impact of a comprehensive lipid treatment approach targeting lipid fractions other than LDL cholesterol are warranted.13
Statins are the initial pharmaceutical intervention for reducing LDL cholesterol and CVD event risk, and usage of statins in managed care populations will help to reduce the long-term costs associated with cardiovascular events. However, as demonstrated in the article by Alagona,1 residual CVD risk still remains after statin therapy, which can be linked to elevated TGs and non-HDL cholesterol as well as low HDL cholesterol. Studies assessing the attainment of multiple lipid targets in managed care populations have demonstrated that the achievement of combined OLVs, rather than simply achieving a goal for LDL cholesterol reduction, is associated with a reduced risk of cardiovascular events and lower healthcare costs. In addition, the number of lipid targets achieved or, conversely, the number of existing lipid abnormalities, are associated with cardiovascular event risk; the greater the number of lipid abnormalities not at OLV, the greater the cardiovascular risk. Modeling studies also estimated that OLVs would be more frequently achieved in managed care organization populations with niacin ER/simvastatin combination therapy than with other high-potency agents and, subsequently, would provide significant reductions in projected CVD event rates. Moreover, models indicated that lipid-modifying therapy with a niacin ER/simvastatin combination would be expected to reduce inpatient hospital visits and direct medical costs of CHD events more effectively than simvastatin monotherapy. These studies further reinforce the importance of considering combination lipid therapy to produce the largest benefits in both patient outcomes and potential cost savings.
Author Affiliations: From Research Development and Operations, HealthCore, Inc, Wilmington, DE; Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, PA.
Funding Source: This work was supported by an educational grant from Solvay Pharmaceuticals and Abbott.
Author Disclosure: Grant support (on behalf of HealthCore, Inc): Abbott, AstraZeneca, Bristol-Myers Squibb, Pfizer.
Authorship Information: Concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; and supervision.
Address correspondence to: Mark J. Cziraky, PharmD, CLS, FAHA, HealthCore, Inc, 800 Delaware Ave, Fifth Fl, Wilmington, DE 19801. E-mail: email@example.com.
1. Alagona P Jr. Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy. Am J Manag Care. 2009;15:S65-S73.
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(9493):1267-1278.
3. Alsheikh-Ali AA, Lin JL, Abourjaily P, Ahearn D, Kuvin JT, Karas RH. Extent to which accepted serum lipid goals are achieved in a contemporary general medical population with coronary heart disease risk equivalents. Am J Cardiol. 2006;98(9):1231-1233.
4. 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(25):3143-3421.
5. Burge R, Laitinen D, Shetty S. Lipid therapy utilization rates in a mixed dyslipidemia managed care population. J Clin Lipidol. 2008;2(3):228.
6. Balu S, Simko RJ, Burge RT, Quimbo R, Cziraky MJ. Impact of adhering to lipid management national guideline recommendations on cardiovascular events and costs in a managed care population. Value Health. 2008;11(3):A4.
7. Simko RJ, Balu S, Burge RT, Quimbo R, Cziraky MJ. Improvements in cardiovascular disease outcomes in managed care patients managed according to national lipid treatment guidelines. Value Health. 2008;11(3):A193.
8. Stanek EJ, Sarawate C, Willey VJ, Charland SL, Cziraky MJ. Risk of cardiovascular events in patients at optimal values for combined lipid parameters. Curr Med Res Opin. 2007;23(3):553-563.
9. Charland SL, Cziraky MJ, Quimbo R, et al. Achieving optimal lipid values in patients with dyslipidemia is associated with reduced risk of cardiovascular events. J Clin Lipidol. 2008;2:343-353.
10. Simko RJ, Cziraky MJ, Quimbo R, Sarawate C, Burge RT. The effects of multiple lipid goal attainment on cardiovascular events and costs. Presented at: National Lipid Association Annual Meeting; Scottsdale, AZ; 2007.
11. Charland SL, Quimbo R, Cziraky MJ, Weathermon RA, Stanek EJ. Modeled achievement of optimal lipid values and associated cardiovascular event rates with extended-release niacin/simvastatin, ezetimibe/simvastatin, and individual agents in a managed care population. Value Health. 2007;10:A56.
12. Stanek E, Charland SL. Residual dyslipidemia on simvastatin: population modeling of optimal lipid value achievement with added extended-release niacin versus ezetimibe. Value Health. 2008;11(3):A191.
13. Balu S, Burge RT, Simko RJ, Quimbo R, Cziraky MJ. Comparison of health care resource utilization and cost between statin monotherapy and simvastatin plus niacin combination therapy patients with prior cardiovascular disease in a managed care setting. American Heart Association Quality of Care and Outcomes Research. Baltimore, MD; 2008.