March 2009
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Effectiveness of Statins in Managing LDL and Goal Attainment in Real-World Clinical Practice
To help deliver cost-efficient health care, it is important to determine what patient risk factors are indicative of treatment failure.
By Carolyn Harley, PhD; Irwin Tran, PharmD, MS; Mike Bullano, PharmD; and Sanjay Gandhi, PhD
The NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) guidelines identify low-density lipoprotein (LDL) cholesterol as the target for lipid-lowering therapies, as it has been well established that LDL is one of the primary lipoproteins associated with atherosclerosis.1 The recommended LDL target goals for individuals are determined based on patient risk factors and the level of risk for future coronary heart disease (CHD) events. The NCEP ATP III guideline defines high-risk as the presence of clinical atherosclerotic disease or a CHD risk equivalent (type 2 diabetes, symptomatic carotid disease, or peripheral arterial disease). It is recommended that patients in the high-risk category have a target LDL goal of <100 mg/dL. Patients in the moderate- and low-risk categories have goals of <130 mg/dL and <160 mg/dL, respectively.
Based on the results of five major clinical trials, NCEP ATP III issued optional more-intensive LDL goals in 2004.2 This update created two new risk groups: moderately high risk (optional LDL goal <100 mg/dL) and very high risk (optional LDL goal <70 mg/dL). Very-high-risk patients have CHD as well as multiple poorly controlled risk factors (Table 1), including diabetes or metabolic syndrome, or a recent acute coronary syndrome event.2
STATIN COMPARATIVE EFFICACY
Statins are widely used for the treatment of hypercholesterolemia as clinical trial evidence has shown statins to be very important in reducing LDL and triglycerides, raising high-density lipoprotein (HDL), and decreasing cardiovascular events by 30% to 40% in secondary prevention.2,4-6 Comparative LDL-lowering and NCEP ATP III goal-attainment differences among statins are well documented in the controlled clinical setting. For example, rosuvastatin (Crestor, AstraZeneca) was shown to significantly reduce LDL in the STELLAR (Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin) trial, which compared the efficacy of rosuvastatin to atorvastatin (Lipitor, Pfizer), pravastatin, and simvastatin on lipid levels.7 Results from STELLAR found an 8% to 26% greater LDL reduction with rosuvastatin. Furthermore, patients treated with rosuvastatin in the STELLAR trial experienced higher rates of LDL goal attainment as per the NCEP ATP III guidelines. Although controlled clinical trials such as STELLAR are still considered the gold standard for obtaining registration approval and assisting in clinical practice decisions, comparative effectiveness studies conducted in the real-world clinical practice may be more useful for guiding evidence-based treatment decisions.
IMPORTANCE AND USE OF REAL-WORLD EFFECTIVENESS
In 2003, the Medicare Prescription Drug, Improvement, and Modernization Act charged the Agency for Healthcare Research and Quality (AHRQ) with the task of conducting specific health outcome studies to determine the safety and effectiveness of certain pharmaceuticals and to support the lack of comparative data. This task by Medicare can be regarded as a sign of the growing demand for real-world data from external stakeholders who want to see evidence of safety and effectiveness in routine clinical practice.7
Data from observational, real-world studies are designed to complement and confirm results from randomized controlled trials, the critical foundation for demonstrating a drug's efficacy and safety in a restricted setting and for gaining regulatory approval. Real-world studies typically focus on a variety of outcomes (clinical, economic, patient-reported) and employ different methodologies and data collection techniques from randomized controlled trials. The findings from these studies can strengthen a product's evidence base by providing additional insights and information that would otherwise be difficult to acquire from conventional randomized controlled trials. Benefits of real-world studies include the ability to study medications within different patient case mixes, less specialized practice settings, more typical medication compliance behavior, and specific barriers and challenges of a given health-system delivery model. Comparative effectiveness data conducted in a real-world setting may be useful to help guide clinicians' decision making.8
Several studies examining the effectiveness of statins in lowering LDL and NCEP ATP III LDL goal attainment in real-world clinical practice have been conducted in recent years.9-20
REAL-WORLD EVIDENCE OF STATINS
A retrospective longitudinal cohort study including data from a large US managed care organization compared rosuvastatin to other commercially available statins. The reported percent reductions in total cholesterol, LDL, and triglycerides, were significantly greater with rosuvastatin. For patients at moderate and high NCEP ATP III risk, LDL goal attainment was significantly higher with rosuvastatin (64%) than with all other statins (fluvastatin [34%], pravastatin [41%], lovastatin [48%], simvastatin [55%], and atorvastatin [57%]). Additionally, a greater proportion of rosuvastatin patients achieved updated very-high-risk target LDL goals as compared with patients on other statins.8
Real-world effectiveness of statins in secondary prevention. Other studies have examined the LDL-lowering and goal-attainment effects of statins in specific high-risk populations including secondary prevention (CHD or CHD risk equivalents), diabetes (a CHD high-risk equivalent), and a special population of interest: patients aged >65 years.
A retrospective claims data study estimated the clinical effectiveness of rosuvastatin compared to atorvastatin and simvastatin among NCEP ATP III high-risk patients treated in routine clinical practice.15 This study examined patients with a history of CHD who were newly started on statin treatment with one of these three statins. Primary outcome variables included percent LDL reduction and achievement of NCEP ATP III LDL goals. After adjustment for baseline differences, a regression model demonstrated that rosuvastatin was significantly more effective in percent LDL reduction (37% vs 28% or 27% for atorvastatin or simvastatin, respectively) and percentage LDL ATP III goal attainment (70% vs 55% or 51% for atorvastatin or simvastatin, respectively). This study provided evidence that rosuvastatin was more effective in lowering LDL and attaining LDL goal levels in a secondary prevention population compared to other statins.
Diabetes. Randomized controlled trials have repeatedly shown statins to reduce all-cause mortality and major cardiovascular events in patients with diabetes.20-30 A retrospective longitudinal cohort study used an electronic medical record database (General Electric Medical Systems database) to compare rosuvastatin to other statins in achieving NCEP ATP LDL goals among patients with type 1 or type 2 diabetes.16 This study found that a greater proportion of high-risk (patients with diabetes) and very high risk (patients with diabetes and additional risk factors) individuals reached their target LDL goal on rosuvastatin compared with other statins (P<.05) (Table 2). A similar study was conducted using data from a large national US managed care database.17 Again, patients with type 1 and type 2 diabetes receiving rosuvastatin had the greatest percent LDL reduction compared with other statins, and rosuvastatin patients were significantly more likely to attain LDL goals compared to patients taking other statins (Table 2).
Special population of interest. NCEP ATP III guidelines identify age (men ≥45 years; women ≥55 years) as a major CHD risk factor. Older patients may have additional cardiovascular risk factors or concomitant conditions that can heighten their NCEP ATP III risk status and necessitate more aggressive lipid goals. Understanding statin effectiveness in LDL reduction and goal attainment may help physicians select the most appropriate statin agent for their older patients aged ≥65 years, a population that may have greater access to statin therapy due to Medicare Part D pharmacy benefits.
A retrospective study compared change in LDL and goal attainment in a population of patients aged ≥65 years newly treated with rosuvastatin versus other statins in routine clinical practice. Primary endpoints included percent change in LDL from baseline and NCEP ATP III goal attainment among patients who were not at LDL goal prior to starting statin therapy. After controlling for covariates, patients treated with rosuvastatin had significantly greater reductions in LDL from baseline compared with atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin (35.8% vs 29.3%, 21.9%, 22.5%, 22.0%, and 24.9%, respectively). Compared with patients receiving atorvastatin, fluvastatin, lovastatin, and pravastatin, patients receiving rosuvastatin treatment were more likely to attain LDL goal (P<.0001).18
IDENTIFICATION OF PATIENTS AT RISK FOR NOT ACHIEVING NCEP ATP III LDL GOALS
The lower overall NCEP ATP LDL goal rates (eg, 34%–64%)8 observed in the real-world setting compared with rates reported from controlled clinical trials (53%–80%)8 suggest there may be disparities in statin treatment-related endpoints between patients treated in these different settings. There are numerous reasons for this disparity, which are discussed briefly here and in more detail elsewhere.9 Such findings foster a need to further investigate factors that may help identify patient groups likely to obtain the most benefit from various statin treatment strategies. Additionally, the ability to identify patients most likely to fail accepted statin treatment endpoints may help provide guidance to evidence-based decision makers on which patients are most likely to benefit from highly efficacious statin therapy. This effort is well aligned to and supportive of cost-effective health care policy decisions.
Two such studies were conducted to identify patient risk factors associated with the failure to attain NCEP ATP III LDL goals in routine clinical practice. The effectiveness of all statins was evaluated in such patients with at least one risk factor for not achieving LDL goals.13 The first retrospective longitudinal cohort study used administrative claims data from a large health plan and included adults newly initiated on statin therapy. Accepted multivariate logistic modeling techniques yielded results that demonstrated patients requiring ≥15% reduction in LDL to reach goal, or being at high or moderate risk for future CHD events (per NCEP ATP III), had increased risk for not achieving LDL goals compared to patients who needed <15% LDL reduction and were at low CHD risk. Moreover, patients who required ≥30% reduction in LDL to reach goal were at even higher risk of not achieving LDL goals compared to either patients requiring 15% to 30% or <15% LDL reduction.
A subanalysis of patients with at least one of these risk factors for not achieving LDL goal (requiring ≥15% LDL reduction to reach goal or being of a moderate or high CHD risk status) yielded that rosuvastatin was more effective at getting these patients to LDL goal than any other statin (Table 3). Rosuvastatin had a significantly lower failure rate compared with all other statins (31.8% vs 38.2%, 42.4%, 55.8%, 57.6%, and 50.1% for atorvastatin, simvastatin, pravastatin, fluvastatin, and lovastatin, respectively). Of note, no significant differences in LDL goal rates were observed across statins among patients needing <15% LDL reduction and patients at low CHD risk.
A second study was conducted using a large data set from a geographically diverse managed care organization.19 Similar methodology was employed and included patients who were not at LDL goal prior to initiating statin treatment. This study validated the findings from the first study. First, needing ≥5% reduction in LDL to reach goal, or being at moderate or high NCEP ATP III risk status, were associated with increased risk of not achieving LDL targets (comparison groups same as Kamat described previously). Second, patients taking rosuvastatin were statistically less likely to fail to achieve such goals (Table 3). Third, no differences were observed in the probability for attaining LDL goal among patients at low CHD risk taking rosuvastatin compared with atorvastatin or simvastatin.
Both of these studies provide evidence that patients who need ≥15% reduction in LDL, or are at moderate or high risk for CHD, are at greater risk for failing to achieve LDL goals. It was demonstrated that these patients may be more likely to attain LDL goal with rosuvastatin compared to other statins. Conversely, patients at low risk for goal attainment failure are suitable candidates for initiation on most statins and may consider simvastatin, which currently has a generic form available. Physicians could potentially use these results to help them identify patients who are at higher risk of goal attainment failure and may therefore be candidates for rosuvastatin therapy.
SUMMARY
Statins have been shown to help reduce LDL and reduce overall risk of primary and secondary prevention of cardiovascular events. Evaluating statins in the real world complements traditional randomized controlled trials by providing evidence of a product's effectiveness across a broader segment of patients in a less controlled practice environment. Numerous real-world data studies conducted in various patient populations have shown that rosuvastatin is the monotherapy statin associated with the highest percentage of LDL reduction and the largest percentage of patients with NCEP ATP III goal attainment. To help deliver cost-efficient health care (maximum clinical benefit relative to cost), it is important to determine what patient risk factors indicate treatment failure. Patients who are at elevated risk of future CHD events or who need ≥15% LDL reduction are more likely to achieve target with rosuvastatin, whereas other statins may provide similar goal attainment benefits as rosuvastatin in low-risk patients who need <15% LDL reduction.
Carolyn Harley, PhD, is Vice President, Health Economics and Outcomes, i3 Innovus in Palo Alto, Calif. Irwin Tran, PharmD, MS, is a fellow in the Pharmacoeconomics, Outcomes Research, and Policy Department, at the University of Southern California, Los Angeles. Mike Bullano, PharmD, and Sanjay Gandhi, PhD, are in the Department of Health Economics and Outcomes Research at AstraZeneca Pharmaceuticals, Wilmington. Dr. Harley may be reached at Carolyn.Harley@i3Innovus.com; or phone: 650-858-6805.
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