• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Lipid-Modifying Therapy and Attainment of Cholesterol Goals in Europe: the Return on Expenditure Achieved for Lipid Therapy (REALITY) Study

Posted on: Saturday, 15 October 2005, 03:00 CDT

By Van Ganse, Eric; Laforest, Laurent; Alemao, Evo; Davies, Glenn; Et al

ABSTRACT

Background: Few studies have been conducted in actual clinical practice settings to evaluate the ways in which dyslipidemia is managed using lipid-modifying therapies.

Objective: To determine lipid-modifying therapy practices and their effects on low-density lipoprotein cholesterol (LDL-C) and/or total cholesterol (TC) goal attainment in Europeans based on prevailing guidelines at the time of therapy in each country.

Methods: Retrospective cohort analysis involving 58223 patients initiated on lipid-modifying therapies in 10 European countries, with a median patient follow-up on lipid-modifying therapy of 15.3 months. Data on prescriptions of lipidmodifying therapies, laboratory data including LDL-C and TC, achievement of cholesterol goals for LDL-C and/or TC, and hospitalizations were obtained from healthcare administrative databases and/or patient chart reviews.

Results: Across Europe, statin monotherapy was the initial lipid- modifying treatment in 51 786 (89.3%) of 58009 patients with available data. In addition, 38853 (89.5%) of 43410 patients with available follow-up statin potency data were initiated on statin regimens of medium or lower equipotency. Low-equipotency regimens include atorvastatin 5mg, simvastatin 10mg, and pravastatin 20mg, whereas medium-equipotency regimens include atorvastatin 10mg, simvastatin 20 mg, and pravastatin 40 mg. Regimens were adjusted to higher equipotency via either up-titration or switches to combination regimens in 16.2% of patients. On average, 40.5% of patients across Europe who were not initially at guideline recommended cholesterol goals (either LDL-C or TC) and had follow- up data attained recommended cholesterol levels, including < 30% of patients in Spain, Italy, or Hungary. In many countries, the likelihood of goal attainment was inversely associated with baseline cardiovascular risk and/or LDL-C levels.

Conclusions: Lipid management strategies in Europe during the study period were dominated by statin monotherapy. Even after prolonged follow-up on lipidmodifying therapy, approximately 60% of Europeans studied did not achieve guideline recommended cholesterol goals. Future emphasis must be placed on subsequent lipid panel monitoring, as well as the use of more efficacious, welltolerated lipid-modifying therapies such as dual cholesterol inhibitors to enable more European patients to attain their recommended cholesterol goals.

Introduction

Cardiovascular disease is a leading cause of premature death and morbidity that results annually in approximately 4 million deaths in Europe, or about 49% of all deaths and 30% of deaths in individuals younger than 65 years1-3.

Epidemiologic studies4-6 and randomized controlled trials7-18 support the clinical utility of reducing low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) using 3-hydroxy-3- methylglutaryl coenzyme A inhibitors (statins) and other therapies (e.g. fibrates, niacin) to lower the risk of coronary heart disease (CHD) and all-cause mortality. These therapies significantly reduce the risk of clinical events in patients with CHD19-20; acute coronary syndromes14,16; CHD risk equivalents, such as diabetes mellitus21,22; and other vascular risk factors, such as hypertension12. Furthermore, the Veterans Affairs HDL Intervention Trial (VA-HIT) demonstrated that raising high-density lipoprotein cholesterol (HDL-C) via treatment with a fibric-acid derivative significantly lowered recurrent coronary events23.

Recognizing these and other data, both European guidelines and US consensus panels have recommended consideration of increasingly aggressive LDL-C treatment targets, particularly in very high-risk patients1'24"26. For instance, the European Society of Cardiology and the International Atherosclerosis Society recommend a TC goal of < 4.5mmol/L (< 175mg/dL; from previous 5mmol/L) and/or an LDL-C goal of < 2.6 mmol/L (< 100 mg/dL) in patients with cardiovascular disease, diabetes, and/or 10-year absolute CHD risk > 20%, while a US consensus panel recommended consideration of an LDL-C target of < 1.75mmol/L (< 70 mg/dL) for very high risk patients1,24-26. In addition, US consensus panels have increased the threshold for HDL- C values defined as 'low'24.

Despite the reported benefits of lowering LDL-C and raising HDL- C, there is a gap between what is recommended by official evidence- based guidelines and clinical practice27,28. Although the use of lipid-modifying therapies increased as landmark statin trials were reported29-33, most patients at increased vascular risk do not achieve guideline recommended cholesterol targets when treated with lipid-modifying therapies. For instance, the European Action on secondary Prevention by Intervention to Reduce Events (EUROASPIRE II) study estimated that only 41% of patients in Europe had cholesterol under control as recommended by consensus guidelines31.

Cholesterol levels, CHD risk factors, the efficacy of initial lipid-modifying therapies, and compliance with regimens, as well as the ways in which these factors may change over time, might play a role in patients attaining cholesterol goals. However, most reported studies are cross-sectional or of short duration and thus cannot evaluate such temporal effects. In addition, crosssectional studies often assess cholesterol only at a single visit and are hence subject to regression dilution bias because single measures are intrinsically more variable than several measures averaged over time.

To address these issues, the Return on Expenditure Achieved for Lipid Therapy (REALITY) study evaluated prescribing patterns of lipid-modifying therapy and cholesterol goal achievement, both in patients with CHD as well as those without CHD but having multiple risk factors, in actual clinical settings representative of European primary-care practices. When determining goal attainment, targets used in the present study varied by country and were not necessarily consistent with recommendations of the US Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP).

Methods

Study setting and design

Multicenter observational studies of dyslipidemia treatment patterns were conducted with 58223 patients across 10 European countries (Table 1)34-49. Overall summary (average) results are presented; however, individual patient-level data from each country were not pooled. Adults who were initiated on lipid-modifying therapies were eligible for analysis. Longitudinal (retrospective cohort) data were collected in all 10 countries, but data collection procedures varied from country to country.

In Germany, Spain, Hungary, and Switzerland, no computerized databases were available that captured both laboratory and prescription data. Therefore, chart reviews were conducted in these countries. In other countries, such as Sweden, Italy, Norway, the Netherlands, and the United Kingdom, computerized databases were analyzed, whereas in France a combination of computerized database analysis (for lipid-modifying therapy information) and physician survey (for laboratory data) was conducted.

We analyzed retrospective data from healthcare (e.g. pharmacy, hospital, laboratory) administrative databases, chart audits, and/ or physician interviews. Results from electronic databases in France (BKLThales), Italy (Ravenna Local Health Unit), the United Kingdom (MediPlus), Scandinavian countries (Profdoc), and the Netherlands (Pharmo) were analyzed. A brief description of each database is provided below:

* BKL-Thales is a computerized network of 1200 general practitioners (GPs) who are representative of the French GP population. It includes records for > 1 million patients, of whom [asymptotically =] 100 000 were treated for dyslipidemia during the study period.

Table 1. Overview of study data by country in the Return on Expenditure Achieved for Lipid-lowering Therapy [REALITY] study

* The Ravenna Local Health Unit database comprises administrative healthcare (pharmacy) records of a northeastern Italian province of =360000 inhabitants.

* MediPlus is a proprietary (IMS Health, London, UK) computerized database comprising > 2 million patient records from = 560 GPs in the United Kingdom. It encompasses > 58 million prescription records.

* Profdoc is a proprietary (Profdoc AB, Uppsala, Sweden) electronic information system including patient-level information for primary healthcare visits, as well as laboratory and prescription records. It encompasses > 1200 primary-care practices, including 40% of the public-health sector in Sweden.

* The Pharmo database includes pharmacy, hospital, and laboratory records of = 1 million residents of 24 cities within the Netherlands and is affiliated with the pharmacoepidemiology department in the University of Utrecht; this analysis involved 97 500 residents from one of the 24 Dutch cities.

Computerized databases link patient records from distinct Healthcare settings, enabling analysis of patients' diagnoses, prescriptions, laboratory data, hospital records, and other clinical information.

In addition to the databases, structured physician interviews were conducted and patient charts reviewed by physicians in Germany, Spain, Hungary, and Switzerland. The German analysis used standardized proprietary data collectionforms (Kendle GmbH & Co., GMI KG, Munich, Germany).

The vast majority of records were drawn from a randomly selected general practice setting, with patient distributions between primary and specialty care being representative of each country or region. Data from Spain and Hungary comprised both general practices (≥ 59%) and lipid clinics ([asymptotically =] 33%), whereas data from Switzerland involved 77 (78%) general practices and 22 specialty practices. In the German analysis, 6000 general practices and 1200 cardiology practices were randomly selected from all practices. Of 237 practices agreeing to participate, 53 general practice and nine cardiology practices were randomly selected.

Data from two countries included substantial numbers of patients with CHD. In Germany, only patients with physician-documented CHD were eligible, while in Spain patients with physician diagnoses of CHD, CHD risk equivalent(s) (e.g. diabetes, carotid-artery disease, peripheral vascular disease) or ≥ 2 Framingham risk factors (e.g. smoking, hypertension) were included.

Ethics

In these non-interventional (observational), retrospective reviews, only treating physicians had access to nonanonymized data. Patient anonymity was maintained at all times, and only aggregated data regarding practice or physician characteristics, such as urban vs. rural practice location, or other regional designations, were made available.

Data extraction and analysis

In the retrospective cohort analysis, wherever possible baseline was defined as the 6- to 12-month period prior to the first (index) lipid-modifying prescription (Figure 1 ) and varied with countries depending on data availability. The index period was the interval in which the database was screened to identify all patients on lipid- modifying therapy. The study period began with the index date, which was the date of the first lipidmodifying prescription (or the first available record of a prescription), and was composed of a minimum 12 months, with varying duration across countries (i.e. in Spain it was a minimum of 3 years and in Germany a minimum of 2 years).

Figure 1. Study timeline. LMT = lipid-modifying treatment

Table 2. Dosages (mg) of individual statins, stratified by efficacy

Basic demographic, diagnostic, laboratory, and/or prescription drug data were captured. (In France, laboratory data and other patient characteristics were captured via physician survey.) We also captured patient characteristics including age; gender; cardiovascular history including cardiovascular procedures; as well as the presence of CHD or CHD risk equivalents or Framingham risk factors, such as hypertension, family history of premature CHD, current smoking or low levels of HDL-C (< 0.9mmol/L [< 35mg/ dL]). Comorbidities, such as diabetes, peripheral vascular disease, and stroke, were identified either by physician interview, records of a physician diagnosis using standardized coding methods (e.g. ICD-9- CM), or records of medication prescriptions for these conditions.

Lipid and lipoprotein levels were available in most databases and chart reviews. If more than one TC or LDL-C value was available from the 6- to 12-month period prior to the index prescription, either the most recent or the lowest value was used as the baseline cholesterol level. If no LDL-C value was available, it was computed based on the last sampling of TC, HDL-C, and triglycerides (if triglycerides were < 4.5mmol/L [< 400mg/dL] only) using the Friedewald formula50.

Lipid-modifying therapies were classified based on comparative LDL-C-lowering efficacy. Statins were assigned a drug-specific equipotency using a six-point formulation in which potency rankings of four or higher signify high-equipotency statin regimens (Table 2)51. Non-statins (niacin, fibrates, resins) were assigned an equipotent statin dose level of O. All databases included the identity and dose of the index lipid-modifying therapies, as well as subsequent prescriptions.

Outcome measures

The proportion of patients achieving LDL-C and/or TC goal was the central outcome measure (Table 1). This was computed as the number of patients achieving LDL-C or TC goal divided by the number receiving lipid-modifying therapy at the time of cholesterol measurement.

Consistent with the European Society of Cardiology guidelines in effect when data were collected, a TC goal of < 5.0mmol/L (< 193mg/ dL) and/or LDL-C < 3.0mmol/L (< 116mg/dL) were the cholesterol targets in the Netherlands, United Kingdom, Norway, Sweden, and Hungary. Cholesterol goal levels in Germany, Italy, Spain, and France were consistent with US guidelines 4.

In France, goal attainment was computed using guidelines issued by the Agence Nationale d'Accrditation et d'Evaluation en Sant (ANDEM), which are consistent with those of their US counterpart24: TC <5.2mmol/L (<200mg/dL) and LDL-C < 2.6mmol/L (< lOOmg/dL) for patients with CHD or CHD equivalents, LDL-C < 3.4mmol/L (< 130mg/ dL) for those with > 2 risk factors, and LDL-C < 4.1 mmol/L (< 160mg/ dL) for those with no risk factors or one risk factor.

Results

Patient characteristics

A total of 58223 patients were included (Table 3). The mean patient age was 63.3 (10.6) years, and 50.3% of patients were men. A total of 46.4% of patients had CHD (29.3%) or diabetes (17.1%). The mean TC level was 6.48mmol/L (250.6mg/dL), and the mean LDL-C was 4.14mmol/L (160.1mg/dL) at baseline. Most patients (88%) were over the age of 45 (male) or 55 (female) years. Other risk factors included hypertension by physician diagnosis or based on the patient receiving antihypertensive medications in 64% of participants, current smoking in 35%, a family history of premature CHD in a first- degree relative (based on chart notes) in 40%, and obesity (body mass index ≥ 30kg/m^sup 2^) in 32% (data not shown).

Lipid-modifying regimen characteristics

As shown in Table 4, 51 786 (89.3%) of 58009 patients with available data received statins as their index prescriptions (chiefly atorvastatin or simvastatin), followed by fibrates and other therapies (niacin, resins). A total of 38853 (89.5%) of 43410 patients with available data on statin potencies received statins of medium or lower equipotency. Low-equipotency statins include atorvastatin 5 mg; simvastatin 10 mg, and pravastatin 20 mg, whereas medium-equipotency statins include atorvastatin lOmg, simvastatin 20 mg, and pravastatin 40 mg (Table 2). Across all countries for which complete data were available, only 4557 (10.5%) of 43 410 patients received high-equipotency lipid-modifying therapies as their initial regimens (Table 4). Only approximately 1 % of patients received combination regimens as their starting therapies.

Table 3. Baseline patient characteristics in the REALITY study

Regimens were adjusted to higher equipotency in only 8758 (16.2%) of 53 929 patients who continued on lipid-modifying therapy.

Goal attainment

On average, 40.5% of patients who were not initially at their targets for TC or LDL-C and had available lipid data achieved these goals (Table 5). Proportions of patients meeting cholesterol goals ranged from 14.0% in Italy to 54.9% in France according to national (ANDEM) guidelines34,39. Fewer than 30% of patients in Italy, Spain, or Hungary met their cholesterol objectives39,40,48. In the Dutch study, goal attainment within the first year of treatment was higher in patients who started treatment from 1998 to 2001 (42.1%) compared with 1991 to 1997 (22.3%)47.

Table 4. Highlights of lipid management in the REALITY study

Goal attainment by baseline cholesterol level, CHD risk, and statin potency

In most countries, goal attainment was less likely with increasing cardiovascular risk. In Germany, the likelihood of CHD patients attaining the LDL-C goal of 2.6mmol/L (< 100mg/dL) was 24% (95% confidence interval [CI], 21%-27%)36. In addition, 20.2% of Spanish patients with CHD or CHD risk equivalents achieved their LDL- C targets compared with 31.4% of those having > 2 risk factors but no CHD40. In Switzerland, 30.0% of patients with CHD or CHD risk equivalents met their treatment goals compared with 45.0% of those with ≥ 2 risk factors and 47.1% with < 2 risk factors (Table 5)49. In each of these countries, goal attainment was less likely in patients with CHD or CHD risk equivalents compared with patients having only CHD risk factors.

Table 5. Cholesterol goal attainment in the REALITY study

Conversely, of 1432 French patients who did not achieve US consensus LDL-C cutpoints, 495 (34.6%) had CHD compared with 781 (54.5%) patients with ≥ 3 risk factors and 156 (10.9%) with ≤ 2 risk factors (p < 0.0001 by the Cochran-Armitage trend test52,53)34.

In addition to baseline CHD risk, cholesterol goal attainment rate was influenced by baseline cholesterol levels, in that cholesterol goal attainment was less likely with increasing cholesterol levels. For instance, 62.0% of UK residents with TC values ranging from 5.0mmol/L (193mg/dL) to 5.9mmol/L (228mg/dL) achieved their cholesterol targets in contrast to only 30.0% of those with TC ≥ 8.0mmol/L (≥ 309mg/dL)41. A logistic regression analysis of data from the Swiss study showed that patients with high baseline LDL-C levels were approximately 30% less likely to achieve LDL-C goals set by their physicians (odds ratio [OR] = 0.685; 95% CI, 0.584-0.802)49.

Although a large majority of patients did not have regimens adjusted to higher potency, regimen changes did not substantially improve goal attainment rates. In Norway, increasing lipid- modifying therapy dosages improved the likelihood of being at goal at 12 months (OR = 2.4; 95% CI, 1.3-4.7)44. On the other hand, regimen changes had more marginal benefits in Spanish, Swiss, and Hungarian patients. In Spain, 80 (12.9%) of 619 patients achieved cholesterol goals while under treatment with their index prescription, which was composed of low-to-medium equipotency statin\s in > 97% of patients receiving a statin40. After adjustments in the potency of lipid-modifying therapies, only an additional 83 (13.4%) patients met treatment targets40.

Table 6. Cholesterol goal attainment by final statin and dose in the REALITY study

Similarly, 66 (15.0%) of 440 Hungarian patients attained TC goals with their index lipid-modifying therapies, and another 50 (11.4%) did so after regimen adjustments48. In Switzerland, only 24.0% of patients whose regimens were up-titrated attained their treatment goal49. As shown in Table 6, the goal attainment rate did not usually increase with statin potency. For instance, 56.4% of patients receiving atorvastatin at a final dose of 10mg achieved their cholesterol goal as compared with 27.2% of patients receiving atorvastatin at a dose of 40mg and 6.7% of those receiving atorvastatin at a dose of 80 mg. These trends are ascribed to selection bias, in that patients prescribed high-dose statins were more likely to have higher cholesterol levels.

Discussion

Approximately 40% of patients who were newly initiated on lipid- modifying therapies achieved their LDL-C and/or TC goals according to the findings of this study involving 58223 patients in 10 European countries. These results were comparable to data from the EUROASPIRE II study, in which only 41% of all respondents and 49% of those receiving lipidmodifying therapies achieved 'therapeutic control' (TC < 5.0mmol/L)31.

Although lipid-modifying therapy has increased drug expenditures in most countries, under-treatment and failure to achieve cholesterol targets compromise treatment outcomes and are also potentially costly, in both human and financial terms54-57. Additional analyses of the German, French, and Swedish databases indicate that consistent attainment of cholesterol targets was associated with significantly lower cardiovascular morbidity and hospitalization costs34,37,46. In the German analysis of CHD patients, goal attainment within 6 months of the index prescription was associated with a reduced risk of hospitalization (p = 0.0330) and hospitalization for cardiovascular disease within 9 months (p = 0.0506)37.

The consistency, as well as the rapidity, of cholesterol goal attainment was also associated with lower coronary risk. Among French patients, 10.0% experienced at least one incident cardiovascular event, including myocardial infarction, angina, stroke, peripheral vascular disease, or heart failure. The incidence rate of cardiovascular disease was 5.5% among patients with LDL-C values at treatment objective during all 3 years of observation (TO^sup +++^ group), 10.6% in those at treatment objective during 1- 2 of 3 years (TO^sup -^ intermediate group), and 12.9% in those not at treatment objective during any year of the three (TO^sup ---^ group; one-sided p = 0.01 by Cochran-Armitage trend test). In addition, the mean LDL-C value was 2.48mmol/L (96mg/dL) in the TO^sup +++^ group, 3.33mmol/L (129mg/dL) in the TO^sup -^ intermediate group, and 4.32mmol/L (167mg/dL) in the TO^sup ---^ group34.

In Sweden the risk of major cardiovascular events was 24% lower in patients who met their treatment objectives, and this significant difference persisted after controlling for age, gender, prior cardiovascular disease, and diabetes46. Cardiovascular hospitalization costs were also significantly lower at 2-3 years among patients who achieved their cholesterol goals as compared with those who did not46.

One important finding of the REALITY study is that patients at increasing cardiovascular risk had more difficulty achieving LDL-C and TC goals (≤ 30% goal attainment rate for CHD patients). These findings echo data reported in prior clinical practice surveys58-61. In a Belgian/ Luxembourgian survey, 36% of all participants achieved European LDL-C goals: 34% of patients with CHD, peripheral vascular disease, or ≥ 2 nonlipid risk factors compared with 64% in those with no CHD, peripheral vascular disease, or any risk factors (p < 0.001)60.

Inferior goal achievement may be ascribed in large part to suboptimal use of lipid-modifying therapies. In the majority of patients with dyslipidemia in this study, statins and other regimens were initiated at medium or lower equipotent doses. However, many patients required more marked cholesterol reductions to achieve cholesterol targets. For instance, nearly half (45.6%) of Spanish patients had LDL-C values ≥ 4.91 (≥ 190mg/dL) and thus required nearly 50% LDL-C lowering to meet the ATP III goal of < 2.6mmol/L (< 100mg/dL)40. Yet only 13 (2.1%) of 619 patients received high-dose statins as their initial prescription. Similarly, 52% of Hungarian patients required > 35% reductions in TC to achieve goal, yet most (90.7%) were initiated on statins of medium or lower equipotency48.

Fewer than 20% of patients had their regimens adjusted to higher potency and even fewer received combination regimens - either initially or as subsequent therapy. Even in the small minority of patients with regimen adjustments, increasing statin doses resulted in marginal incremental benefits. Physicians may not titrate statin doses upward because they are concerned about: (1) potential adverse events; and/or (2) achieving a marginal return with increasing statin doses. Doubling the dose of a statin lowers serum LDL-C by an additional 7% and TC by an additional 5%62.

On the other hand, recent studies have demonstrated that a combination treatment involving dual cholesterol inhibition (ezetimibe-statins) and other adjunctive treatments (e.g. niacin- lovastatin) augment cholesterol goal achievement63-63. In a recent study involving 362 (58% of total patients) individuals with heterozygous familial hypercholesterolemia, 22% of patients who received ezetimibe 10mg in addition to ongoing low-dose statin therapy achieved an LDL-C goal of ≤ 2.6mmol/L (≤ 100mg/ dL) as compared with 7% of patients who received an additional dose of statin (p < 0.01), and the combination regimen was equally well tolerated as statin monotherapy, with 4% of each group discontinuing because of adverse events66. In both treatment arms, statin doses were doubled if LDL-C exceeded goal. Furthermore, in a randomized, double-blind, placebocontrolled trial involving 769 patients with primary hypercholesterolemia who were not at NCEP ATP II goal LDL- C, addition of ezetimibe 10mg to ongoing statin therapy was associated with a 72% LDL-C goal attainment rate as compared with 19% among patients receiving statins in combination with placebo (p < 0.001)67. Finally, reports have also demonstrated that intensive regimens associated with more marked reductions in LDL-C and non- lipid inflammatory markers confer protection against adverse cardiovascular outcomes and atherosclerotic progression in patients with acute coronary syndromes and angiographically documented CHD, respectively14-17.

It is encouraging to note that Dutch patients in the present study who initiated lipid-modifying therapies from 1998 through 2001 had enhanced cholesterol goal attainment compared with those beginning treatment before these dates47. Similar temporal trends toward enhanced use of lipid-modifying therapies and cholesterol control were also observed in the EUROASPIRE study31.

Limitations of the present study include its retrospective design and observational, rather than interventional, nature. The use of patient charts and other clinical records does not enable assessment of actual patient behaviors, such as filling a prescription or taking prescribed medications. Although medication persistence was not captured in all REALITY countries, available data show that patients included in these analyses had prolonged treatment with lipid lowering. For instance, in Norway patients had valid lipid prescriptions for 81% of 991 days (2.7 years) and in Sweden this proportion was 70% of 1000 days. In the United Kingdom, independent predictors of high prescribing persistency (≥ 80%) in the first year of therapy included higher baseline TC (OR= 1.38; 95% CI, 1.20-1.56) and prior CHD (OR = 1.51; 95% CI, 1.42-1.60) or CHD- equivalent (OR = 1.41; 95% CI, 1.30-1.52) status. The setting of the present study is also a potential strength because it may be more consistent than controlled trials with 'realworld' clinical practice.

One limitation of the present study is the heterogeneity of methods used to collect data, which was dictated by differing healthcare information systems in each country. Analyses of both treatment patterns and goal attainment were conducted separately for each country (though overall results were combined). The impact of heterogeneity across countries was not evaluated. Analyses of additional variables not captured in all countries of the REALITY study, including diet, exercise, and patient attitudes toward lipid- modifying therapies, would have been necessary to evaluate heterogeneity. Consensus cholesterol goals have become increasingly stringent in Europe and the United States. However, the present analysis was confined to the prevailing LDL-C and TC goals at the time the data were collected and based on practices in each country. Most countries, such as France, prefer to use their own national standards (i.e. ANDEM), which may or may not agree with the European Society of Cardiology guidelines. No attempt was made to vary the cholesterol goals (as in a sensitivity analysis) to determine the effects on goal attainment rates.

Because of its limited baseline period, this analysis probably underestimated the number of patients with CHD and other comorbidities occurring > 6 months before the index prescription date. The analysis was confined to achievement of LDL-C and TC goals and did not evaluate effects of lipid-modifying therapies on other potentially atherothrombotic surrogate end points, including HDL-C, the ratio of TC or LDL-C to HDL-C, triglycrides, or C-reactive protein. The an\alysis did not subdivide numbers (%) of patients receiving specific non-statin therapies (fibrates, niacin, resins).

Conclusions

Lipid management strategies in Europe during the study period were dominated by statin monotherapy. Even after prolonged follow- up on lipid-modifying therapy, approximately 60% of Europeans did not achieve guideline recommended cholesterol goals, with a range of goals in different countries. Future emphasis must be placed on subsequent lipid panel monitoring, as well as the use of more efficacious, well-tolerated lipidmodifying therapies such as dual cholesterol inhibitors to enable more European patients to attain their recommended cholesterol goals.

Acknowledgment

The REALITY study was funded by Merck/Schering Plough LLC (Singapore).

References

1. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: Third Joint Task Force of European and other societies on cardiovascular disease prevention and clinical practice. Eur J Cardiovasc Prev Rehabil 2003;10(Suppl l):Sl-78

2. European Heart Network. Statistical data about cardiovascular disease in Europe. Available from http://www.ehnheart.org/files/ statistics%202005-09271 lA.pdf [Accessed 6 July 2005]

3. World Health Organization. World Health Report 2003. Available from http://www.who.int/entity/whr/2003/en/index.html [Accessed 6 July 2005]

4. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986)256:2823-8

5. Martin MJ, Hulley SB, Browner WS, et al. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361 662 men. Lancet 1986;2:933-6

6. Stason WB. Costs and benefits of risk factor reduction for coronary heart disease: insights from screening and treatment of serum cholesterol. Am Heart J 1990;119:718-24

7. 4S Investigators. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9

8. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7

9. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9

10. LIPID Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57

11. Collins R. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22

12. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003)361:1149-58

13. Collins R, Armitage J, Parish S, et al. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004)363:757-67

14. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504

15. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004)291:1071-80

16. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005)352:20- 8

17. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005)352:29-38

18. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998)279:161522

19. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 19868:1245-55

20. Canner PL, Furberg CD, Terrin ML, et al. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol 2005)95:254-7

21. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003)361:2005-16

22. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004)364:685- 96

23. Rubins HB, Robbins SR, Collins D, et al. Gemfibrozil for secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. Veterans Affairs HDL Intervention Trial Study Group. N Engl J Med 1999)341:410-18

24. Adult Treatment Panel. 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)106:3143-421

25. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;! 10:227-39

26. International Atherosclerosis Society. Harmonized clinical guidelines on prevention of atherosclerotic vascular disease: executive summary. Available from http://www.athero.org/download/ guidelines.pdf [Accessed 10 May 2005]

27. Frolkis JP, Pearce GL, Nambi V, et al. Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice. Am J Med 2002)113:625-9

28. Sacks FM. Adherence to statin therapy: why aren't we doing better? Am J Med 2002; 113:685-6

29. de Velasco JA, Cosin J, Lopez Sendon JL, et al. [Secondary prevention of myocardial infarction in Spain. The PREVERSE study]. Rev Esp Cardiol 1997;50:406-15

30. Velasco JA. After 4S, CARE and LIPID - is evidence-based medicine being practised? Atherosclerosis 1999;147(Suppl 1):S39-44

31. EUROASPIRE I and II Group. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. EUROASPIRE I and II Group. European Action on secondary Prevention by Intervention to Reduce Events. Lancet 2001;357:995- 1001

32. EUROASPIRE Study Group. EUROASPIRE. A European Society of Cardiology survey of secondary prevention of coronary heart disease: principal results. EUROASPIRE Study Group. European Action on secondary Prevention through Intervention to Reduce Events. Eur Heart J 1997; 18:1 569-82

33. EUROASPIRE II Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J 2001 ;22:554-72

34. Van Ganse E, Souchet T, Laforest L, et al. Effectiveness of lipidlowering therapy. Br J Clin Pharmacol 2005;59:456-63

35. Van Ganse E, Souchet T, Laforest L, et al. Long-term achievement of therapeutic objectives of lipid-lowering agents in primary prevention patients and cardiovascular outcomes: an observational study. Atherosclerosis 2005 July 19 [Epub ahead of print]

36. Krobot KJ, Yin DD, Alemao E, et al. Real-world effectiveness of lipid-lowering therapy in male and female outpatients with coronary heart disease: relation to pre-treatment lowdensity lipoprotein-cholesterol, pre-treatment coronary heart disease risk, and other factors. Eur J Cardiovasc Prev Rehabil 2005;12:37-45

37. Rajagopalan S, Alemao E, Krobot K, et al. LDL-C goal attainment and cardiovascular hospitalization among CHD patients in Germany. Presented at European Atherosclerosis Society. Prague, Czech Republic (April 23-26, 2005)

38. Esposti ED, Melilli LE, Alemao E, et al. A population-based crosssectional study on treatment patterns for hypercholesterolemia in Ravenna, Italy. Session Pl 12. Presented at the 5th International Congress on Coronary Artery Disease - From Prevention to Intervention. Florence, Italy (October 19-22, 2003)

39. Esposti ED, Melilli LE, Alemao E, et al. Lipid testing and results in patients receiving lipid-lowering therapy in a northern region in Italy. Session P228. Presented at the 5th International Congress on Coronary Artery Disease - From Prevention to Intervention. Florence, Italy (October 19-22, 2003)

40. Garca Ruiz FJ, Ibanez AM, Prez-Jimnez F, et al. and the REALITY Study Group. Current lipid management and low cholesterol goal attainment in common daily practice in Spain: the REALITY Study. PharmacoEconomics 2004;22(Suppl 3): 1-14

41. Melilli LE, Alemao E, Yin, DD. Factors associated with cholesterol goal attainment in the United Kingdom: patient characteristics and management practices. Session 305 P2999. Presented at the European Society of Cardiology. Vienna, Austria (August 30-September 3, 2003)

42. Yin DD, Melilli LE, Alemao E. Trends in management of hypercholesterolemia in the United Kingdom: primary care practice from 1998 to 2001. Session 301 P633. Presented at the 5th International \Congress on Coronary Artery Disease - From Prevention to Intervention. Florence, Italy (October 19-22, 2003)

43. Melilli LE, Alemao E, Yin DD. Persistency of lipid-lowering therapy in United Kingdom: primary care practices and associated factors. Session 305 P2998. Presented at the European Society of Cardiology. Vienna, Austria (August 30-September 3, 2003)

44. Ose L, Skjeldestad FE, Bakken IJ, et al. Current management of hyperlipidemia in Norway and factors associated with cholesterol goal attainment. Presented at European Atherosclerosis Society. Seville, Spain (April 17-20, 2004)

45. Lindgren P, Borgstrm F, Stlhammar J, et al. Association between achieving treatment goals for lipid-lowering and cardiovascular events in real clinical practice. Eur J Cardiovasc Prev Rehabil 2005 [in press]

46. Carlsson A, Borgstrom F, Stlhammar J, et al. Costs of care for patients treated with lipid-lowering drugs. PharmacoEconomics 2004;22(Suppl 3):25-35

47. Goettsch WG, Yin DD, Alemao E, et al. Statins are less effective in common daily practice among patients with hypercholesterolemia: the REALITY-PHAPJvIO study. Curr Med Res Opin 2004;20:1025-33

48. Mrk L, Zmolyi K, Alemao E, et al. Cholesterol goal attainment among patients treated with lipid lowering drugs in Hungary. Session PCV32. Presented at EURO ISPOR Meeting 2004. Hamburg, Germany (October 24-26, 2004)

49. Darioli R, Alemao E, Davies G, et al. Lipid management and cholesterol goal attainment in Switzerland: the Swiss review of Return on Expenditure Achieved for Lipid Therapy (REALITY] study. Presented at European Atherosclerosis Society. Seville, Spain (April 17-20, 2004)

50. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502

51. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207-13

52. Cochran WG. Some methods for strengthening the common chisquare tests. Biometrics 1954; 10:417-51

53. Armitage P. Tests for linear trends in proportions and frequencies. Biometrics 1955;11:375-85

54. Cramer JA. Effect of partial compliance on cardiovascular medication effectiveness. Heart 2002;88:203-6

55. Ito MK, Delucca GM, Aldridge MA. The relationship between lowdensity lipoprotein cholesterol goal attainment and prevention of coronary heart disease-related events. J Cardiovasc Pharmacol Ther 2001;6:129-35

56. Stein EA. Managing dyslipidemia in the high-risk patient. Am J Cardiol 2002;89:50C-7C

57. McDermott MM, Schmitt B, Wallner E. Impact of medication nonadherence on coronary heart disease outcomes. A critical review. Arch Intern Med 1997; 157:1921 -9

58. Pearson TA, Laurora I, Chu H, et al. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000; 160:459-67

59. Olson KL, Tsuyuki RT. Patients' achievement of cholesterol targets: a cross-sectional evaluation. Am J Prev Med 2003;25:339-42

60. Muls E, De Backer G, De Bacquer D, et al. LIPI-WATCH, a BelgianLuxembourg survey on achievement of European Atherosclerosis Society lipid goals. Clin Drug Invest 2000;19:219-29

61. Eagle KA, Kline-Rogers E, Goodman SG, et al. Adherence to evidence-based therapies after discharge for acute coronary syndromes: an ongoing prospective, observational study. Am J Med 2004;117:73-81

62. Roberts WC. The rule of 5 and the rule of 7 in lipid- lowering by statin drugs. Am J Cardiol 1997;80:106-7

63. Denke MA. Coadministration of multidrug therapy to achieve lipid goals. J Am Osteopath Assoc 2004; 104:17-22

64. Pearson T, Denke M, McBride P, et al. Ezetimibe added to statin therapy reduces LDL-C and improves goal attainment in patients with hypercholesterolemia. Abstract presented at 2004 Scientific Session of the American College of Cardiology. New Orleans, La (March 7-10, 2004)

65. Kashyap ML, McGovern ME, Berra K, et al. Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol 2002;89:672-8

66. Stein E, Stender S, Mata P, et al. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J 2004;148:447-55

67. Gagn C, Bays HE, Weiss SR, et al. Efficiency and safety of ezetimibe added to on-going statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1084-91

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3102_5, Accepted for publication: 14 July 2005

Published Online: 10 August 2005

doi:10.1185/030079905X59139

Eric Van Ganse(a), Laurent Laforest(a), Evo Alemao(b), Glenn Davies(c), Stephen Gutkin(d) and Don Yin(b)

a Pharmacoepidemiology EA 3091 Centre Hospitalier Lyon-Sud, France

b Outcomes Research, Merck and Co, Inc., Whitehouse Station, NJ, USA

c Health Economic Statistics, Merck Research Laboratories, Blue Bell, PA, USA

d Rete Biomedical Communications Corp., Ridgewood, NJ, USA

Address for correspondence: Eric Van Ganse, MD, PhD, Centre Hospitalier Lyon-Sud (Ste Eugnie, 5F) F-69495 Pierre Bnite Cedex, France. Tl.: +33-472-666438; Fax: +33-472-666444; email: eric.van- ganse@chu-lyon.fr

Key words: Coronary disease * Hydroxymethylglutaryl CoA reductase inhibitors * Hypercholesterolemia * Prevention and control * Statins

Copyright Librapharm Sep 2005

Source: Current Medical Research and Opinion

More News in this Category