Differences Between Clinical Trial Efficacy and Real-world Effectiveness

Published Online: November 01, 2006
Michael H. Davidson, MD

Aggressive lowering of low-density lipoprotein cholesterol (LDL-C) with statin therapy can reduce the incidence of morbidity and mortality from coronary heart disease (CHD) in primary and secondary prevention settings. Indeed, suboptimal statin treatment has been associated with an increased risk of CHD events. Surveys such as the Lipid Treatment Assessment Project (L-TAP) and National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II have demonstrated that patients in real-world clinical settings often fail to reach the target goals set forth by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). This failure to reach target LDL-C levels in real-world clinical practice presents a therapeutic treatment gap. There may be multiple reasons for this discrepancy: lack of patient follow-up, absence of well-defined protocols (ie, use of low-potency statins in high-risk patients), adherence controls (eg, pill counts, refill records), cost, and lack of patient motivation are a few possibilities. Several large clinical trials since ATP III have shown that these goals are achievable through aggressive statin therapy. This review sets forth compelling data that starting patients on or switching to high-efficacy LDL-C–lowering therapy enhances achievement of NCEP ATP III guidelines outside of the controlled trial setting.

(Am J Manag Care. 2006;12:S405-S411)

Extensive evidence exists that aggressive lowering of low-density lipoprotein cholesterol (LDL-C) can reduce the incidence of morbidity and mortality from coronary heart disease (CHD) in primary and secondary prevention settings. The vast majority of this evidence comes from controlled clinical trials of statins in which drug dosages are carefully titrated and/or sufficient dosages are used initially to achieve target LDL-C levels.

From these clinical data, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) established targets for LDL-C that depend on the individual risk of the patient, with the lowest LDL-C targets (<100 mg/dL) recommended for patients with CHD or other forms of vascular disease.1

Suboptimal statin treatment has been associated with an increased risk of CHD events. Among a group of 2045 postmyocardial infarction (post-MI) patients with hypercholesterolemia, 43.4% who suffered a CHD event over the next 30 months were treated with a statin but failed to achieve an LDL-C level less than 115 mg/dL.2 Suboptimal treatment was found to double the risk of nonfatal MI or CHD death compared with optimal treatment, defined in this study as attainment of an LDL-C less than 115 mg/dL.

Furthermore, landmark clinical studies such as the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)3 and Treating to New Targets (TNT)4 trials demonstrated lower rates of CHD events in patients treated to very low levels of LDL-C compared with levels that met the 2001 ATP III goals. Subsequently, the NCEP updated its recommendations to include an option to treat to an LDL-C target <70 mg/dL in certain high-risk patients.5

Undertreatment in the Real World

Evidence exists that supports the effectiveness of statins in real-world practice6-9; failure to reach target LDL-C levels outside of the clinical trial setting in real-world clinical practice presents an unmet medical need and a therapeutic treatment gap. In 2000, the Lipid Treatment Assessment Project (LTAP) demonstrated significant undertreatment of patients at risk of CHD events in clinical practice.10 Among 4888 dyslipidemic patients who had been receiving lipid-modifying therapy for at least 3 months, only 38% achieved their NCEP LDL-C targets.

Three years later, the National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II trial surveyed patients with treated dyslipidemia to assess achievement of treatment goals established by ATP III.11 Results of the survey showed that, overall, 67% of the 4885 patients achieved their LDL-C treatment goal, suggesting improved lipid management compared with previous surveys. It should be pointed out, however, that among patients in the highest risk category with triglyceride concentrations of at least 200 mg/dL, only 27% achieved their combined LDL-C and non–high-density lipoprotein cholesterol (non–HDL-C) targets, indicating that undertreatment is common in patients with hypertriglyceridemia.

In examining 367 hyperlipidemic patients in a preventive cardiology practice, Frolkis et al discovered that the mean observed LDL-C reduction (-26% ± 20%) of patients started on statins was significantly less than the expected reduction based on information in the package insert (-34% ± 7%; P <.001).12 Therefore, although some improvement in lipid management appears to be occurring, why does the treatment gap continue to persist? Lack of patient adherence, failure to titrate to an effective dose or switching to a more potent statin, inadequate patient follow-up, cost, and lack of patient motivation are some of the considerations for less-than-effective results in the clinical setting.2,12

The L-TAP data were collected before the NCEP issued its option to treat LDL-C to <70 mg/dL in the highest risk patients5; therefore, one possible assumption is that the levels of LDL-C achieved in the aggressive treatment groups in PROVE IT and TNT are attained even less often in clinical practice than the targets achieved in L-TAP. In the NEPTUNE II survey, for example, only 18% of patients classified as high risk were at optional goal of less than 70 mg/dL.11 And in a prospective managed care database analysis by Mosca et al of women at high risk of CHD, initially only 7% had reached optimal lipid levels according to American Heart Association guidelines (eg, LDL-C <100 mg/dL).13 Only one third received recommended drug therapy, again illustrating substantial undertreatment of at-risk patients.

Patients at Risk: Identification and Intervention. An examination of administrative claims data found that in a group of patients receiving a statin other than rosuvastatin patients who required a =15% reduction in LDL-C to meet their ATP III goal were less likely to reach their goal than those who needed a <15% reduction (P <.05).9 Patients not taking rosuvastatin who were defined as moderate or high risk by NCEP criteria were also less likely to achieve their LDL-C goal than those at low risk of future CHD events.

Clinicians would benefit from guidance in identifying patients at high risk of failure to reach NCEP ATP III LDL-C goals while receiving statins and in selecting therapies and choosing strategies to help these high-risk patients attain their treatment goals.

Lack of Goal Attainment: Comparative Data on Lipid-lowering Efficacy

Multiple reasons may explain the failure to attain lipid treatment goals in the real-world setting: lack of patient follow-up, absence of well-defined treatment protocols, adherence issues, cost, and lack of patient motivation are all possibilities. More specifically, 3 reasons have a major impact on ability to attain treatment goals: (1) lack of statin dose titration; (2) initiation of low-potency statins inadequate for achieving major reductions in LDL-C; (3) underuse of supplemental (ie, combination or add-on) lipid-lowering therapies.

Dose Titration. Lack of dose titration is a cause of failure to reach LDL-C goal in clinical practice. Foley et al found that of the 52% of high-risk (diabetes or CHD) patients who did not reach goal initially, less than half had their dose titrated once; only 14% attained goal by 6 months, in part due to inadequate titration.14 The investigators report that true titration and goal attainment rates may be even lower than represented in the study.

Statin Efficacy: High Potency for High Risk. The various marketed statins have been compared in their ability to reduce LDL-C levels and achieve NCEP LDL-C targets compared with other statin monotherapies in clinical trials. In these studies, rosuvastatin has proved superior to other commonly used statins.15



A 12-week study of 516 hypercholesterolemic patients found that LDL-C reductions were 40% with rosuvastatin 5 mg, 43% with rosuvastatin 10 mg, and 35% with atorvastatin 10 mg (P <.01 and P <.05 for pairwise comparisons with atorvastatin).16 ATP III treatment goals were achieved more often with rosuvastatin 5 and 10 mg than with atorvastatin 10 mg (84%, 82%, and 72%, respectively). Similarly, in a 52-week study of 412 hypercholesterolemic patients, whose dosages could be titrated at 12 weeks, rosuvastatin 5 or 10 mg was again superior to atorvastatin 10 mg in reducing levels of LDL-C (47% and 53% vs 44%; P <.05 and P <.001, respectively) and in achieving LDLC goals (98% for rosuvastatin 10 mg vs 87% for atorvastatin 10 mg).17

In the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR), in which 2431 adults with hypercholesterolemia were randomized to 1 of 15 open-label treatment arms for 6 weeks, rosuvastatin 10 to 40 mg/day reduced LDL-C by 46% to 55%, compared with 37% to 51% for atorvastatin 10 to 80 mg/day, 28% to 46% for simvastatin 10 to 80 mg/day, and 20% to 30% for pravastatin 10 to 40 mg/day.18 The analysis also showed that 89% of the rosuvastatin 20- and 40-mg/day groups reached NCEP LDL-C goals, the highest proportion of the trial groups (Figure).



Emerging data from recent presentations validate the use of rosuvastatin outside of the clinical trial setting as an effective agent to achieve treatment goals in those at greatest risk for treatment failure.6-9

Supplementing Statin Monotherapy. Not all patients will respond to aggressive statin dosing or high-potency therapy and will require a combination regimen to attain treatment goals.19,20 The addition of an intestinal absorption inhibitor to the blunting of endogenous cholesterol production by a statin has proved to be an effective treatment alternative.21-24 Substantial additional reductions in LDL-C were reported for simvastatin/ezetimibe versus placebo when added to a stable statin regimen.21 Another study of ezetimibe demonstrated the ability of such add-on therapy to improve goal adherence: 71.5% reached goal with ezetimibe versus 18.9% for placebo (P <.001).22



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