European Physicians Perspectives on Cholesterol Management and Inhibition of Cholesterol Absorption and Production

Login or register to view PDF.
Citation
European Cardiovascular Disease 2007 - Issue 1;2007:3(1):16-20
DOI
http://dx.doi.org/10.15420/ecr.2007.0.1.16

Clinical trial evidence from the past two decades has demonstrated that lowering cholesterol levels markedly impacts the occurrence of cardiovascular (CV) disease, including coronary heart disease, a leading cause of mortality and morbidity in the US and Europe.1–7 Data from these studies form the basis of national and international treatment guidelines delineating lipid thresholds and recommending treatment goals for a variety of patient types.8–11 These guidelines are an important management tool to help physicians reduce the impact of atherosclerotic-related CV disease in clinical practice.
Although 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are recommended in various guidelines, statins alone (even at higher doses) are frequently inadequate to attain low-density lipoprotein cholesterol (LDL-C) goals for many patients.12 A recent European survey reported that approximately 60% of hypercholesterolaemic patients fail to achieve cholesterol goals based on prevailing guidelines in each country.13 A principal reason for this low level of goal attainment is failure to titrate statin doses, in part because of concerns over the occurrence of adverse events at higher statin doses when only a marginal 6% reduction in LDL-C levels can be expected.13 A large gap therefore exists between what is recommended and what is actually achieved in practice. This gap will likely broaden as guidelines embrace the concept that lower LDL-C is better in light of findings from major outcome studies.14–16
An innovative approach to cholesterol management is targeting cholesterol absorption in the intestine from both biliary and dietary sources and cholesterol production in the liver,17 by administering a single tablet of ezetimibe/simvastatin or co-administering ezetimibe with a statin. Numerous studies have demonstrated that inhibiting cholesterol absorption and production produces substantially greater LDL-C lowering, and more patients attain LDL-C goals, than does doubling the initial dose of statin.18–21 The purpose of the surveys was to survey attitudes of cardiologists and general practitioners (GPs) across Europe with respect to the concept of cholesterol management, inhibiting cholesterol absorption and production, the degree to which treatment guidelines are being adopted, and potential barriers to prescribing high-dose statins for high-risk patients.

Methods

This survey was conducted among 388 practicing cardiologists in July 2005 (75 in the UK, 78 in France, 80 in Germany, 78 in Spain and 75 in The Netherlands) and 503 practising GPs and 376 cardiologists in July 2006 (177 in the UK, 175 in France, 175 in Germany, 176 in Spain and 176 in Italy).
Telephone interviews lasted approximately 12 minutes in 2005, using a Web-assisted phone interviewing approach. Eleven closed-end questions addressed objectives for treating patients with hypercholesterolaemia, the importance of meeting cholesterol targets, views on the sufficiency of statin monotherapy and ezetimibe/statin therapy, perceived benefits of inhibiting absorption and production and views on treating hypercholesterolaemia in diabetic and coronary heart disease (CHD) patients. The 2006 Internet-based survey lasted approximately six minutes and contained 10 questions addressing the percentage of patients and at-risk patients (with CHD or diabetes) with hypercholesterolaemia, guidelines for and adherence to guidelines in management of these patients, ideal LDL-C levels, benefits and sufficiency of statin therapy and high-dose statins and therapy with ezetimibe and a statin. The surveys collected information concerning gender, patients and hypercholesterolaemic patients seen in a typical week, and lipid-management activities.

Results
Demographics

In 2005, 80% of the respondents were men. Respondents had practised for 15.7 years (mean), saw 57.9 patients per week (mean) and devoted 35% of their daily routine to lipid management. In 2006, 84% were men. GPs practised mostly in the office whereas cardiologists practised in both the office and hospital. GPs saw a mean of 79 patients per month for cholesterol management, whereas cardiologists reported a mean of 69. Including new and repeat prescriptions, GPs reported a prescribing average of 92, whereas cardiologists reported prescribing 69 cholesterol-lowering agents per month. While 78% of GPs felt that <30% of patients were diagnosed with hypercholesterolaemia, 77% of cardiologists indicated that >30% were diagnosed.

Goal Attainment

In 2005, cardiologists in all countries generally agreed (mean 77%) that the objective of treating hypercholesterolaemia patients is both to lower LDL-C and total cholesterol and to prevent the occurrence of primary or secondary cardiovascular events (see Table 1). Markedly fewer cardiologists believed that lowering cholesterol alone or preventing cardiovascular events alone was the primary goal, although cardiologists in Germany and UK were more likely to believe that preventing cardiovascular events should be the primary objective than those in France and The Netherlands. Most cardiologists (88%) believed that it is extremely or very important to help patients with diabetes or CHD reach the LDL-C targets put forth in their respective countries.
The majority of all physicians (7 of 10) in 2006 estimated that half or fewer of at-risk patients had reached their LDL-C goal, with LDL-C level <2.5mmol/l named as the ideal level (see Figure 1). There was no agreement about ideal level for at-risk patients, with most physicians indicating that the ideal goal was <1.8 or 1.8–2.0mmol/l (see Table 2). GPs were more likely to feel unaware of the ideal LDL-C levels for at-risk patients, with 12–13% unaware versus 5–6% of cardiologists.

Sufficiency of Statin Monotherapy and Inhibiting Cholesterol Absorption and Production

Two-thirds of cardiologists in 2005 believed that many high-risk hypercholesterolaemia patients were insufficiently treated by statin monotherapy (see Table 1), as did 72% of all physicians in 2006. However, approximately 50% of cardiologists in Germany and The Netherlands thought this was true. In 2006, 48% of physicians believed that doubling the statin dose achieved an additional 6% LDL-C reduction while one-third believed that this dose could achieve an extra 25% reduction in LDL-C.
Eighty-five per cent of cardiologists surveyed in 2005 (see Table 1) and 92% in 2006, as well as GPs surveyed in 2006 (82%), agreed that inhibiting cholesterol absorption and production achieves greater LDL-C reduction than treating one source with statins (see Table 1). Four identifiable viewpoints were discernable in 2005 with respect to whether cardiologists believed that statin monotherapy was insufficient and whether ezetimibe/statin therapy was likely to achieve greater reductions in LDL-C.

Seven per cent believed that monotherapy is insufficient but were unconvinced that inhibiting absorption and production would achieve greater cholesterol reductions; 7% believed that monotherapy is sufficient and that inhibiting cholesterol absorption and production would not achieve greater reductions; and 25% believed that monotherapy may be sufficient but greater results would be achieved by inhibiting cholesterol absorption and production. The vast majority (60%) believed that monotherapy was insufficient and that greater reductions would be achieved by utilising therapy that inhibits cholesterol absorption and production.

Benefits of Inhibiting Cholesterol Absorption and Production

At least six out of 10 cardiologists surveyed in 2005 thought that the benefits of inhibiting cholesterol absorption and production were: better efficacy (68%), better overall results (65%), reaching goal more quickly (61%) and fewer side effects than high-dose statins (61%) (see Figure 2). Similarly, nearly half also believed that fewer safety concerns were beneficial, with more than seven out of 10 preferring a more tolerable treatment than a high-dose statin. A similar percentage of cardiologists believed that better overall results would be achieved by inhibiting cholesterol absorption and production, independent of whether they believed it would produce greater LDL-C reductions (65% versus 61%, respectively).

Treating Diabetic and Coronary Heart Disease Patients

For at-risk patients with uncontrolled LDL-C and diabetes or CHD, more than eight out of 10 cardiologists surveyed in 2005 believed that cholesterol management is better achieved with treatment of both cholesterol absorption and production (see Table 1). A large number surveyed felt that it was more important to treat biliary cholesterol than dietary cholesterol when choosing a treatment method for inhibiting cholesterol absorption in patients with CHD or diabetes (see Table 1). German cardiologists were less likely to agree with the priority of treating biliary cholesterol than their Dutch, British and Spanish counterparts. GPs (61%) and cardiologists (68%) surveyed in 2006 expressed reluctance to prescribe high-dose statins to patients with risk factors due to safety and side effects, and lack of efficacy at high doses (28% and 21%, respectively).

Guidelines

The 2006 survey found that GPs (39%) were more likely to be unaware of guidelines for ensuring optimal cardiovascular outcomes than cardiologists (16%). More cardiologists than GPs were aware of National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III, European Society of Cardiology (ESC) or American Heart Association guidelines (31% versus 5%). Local country guidelines were the most closely followed by GPs (54%) and cardiologists (30%). Two-thirds of cardiologists and one-quarter of GPs followed international guidelines. Overall, 77% of physicians believed that guidelines for management of hypercholesterolaemia in at-risk patients were not adequately followed in their country. Cost, reimbursement restrictions, local guidelines encouraging use of low-dose statins and the perspective that attainment of LDL-C goal was sufficient were the key reasons cited for not following guidelines. GPs were more likely to feel that the risks associated with high-dose statins caused guidelines not to be followed (44% versus 33% of cardiologists), while more cardiologists felt that the time involved in titrating a statin was an obstacle (37% versus 22% of GPs).

Discussion

The majority of physicians surveyed believed that statin therapy alone may be insufficient to treat hypercholesterolaemia in patients with CV risk and also believed that inhibiting cholesterol absorption and production achieves greater LDL-C reduction than treating only one source. That is, treating both absorption of cholesterol by the intestine and production by the liver is likely to produce superior cholesterol lowering compared with treating production with statins alone. This view is consistent with abundant clinical trial evidence indicating that inhibiting cholesterol absorption and production provides consistently superior LDL-C lowering efficacy with improved LDL-C goal attainment.18,20–26 The majority of physicians expected inhibiting cholesterol absorption and production to achieve better efficacy more quickly and with fewer side effects compared with using high-dose statins. Most physicians preferred to use cholesterol-lowering treatments that were more tolerable than high-dose statins for patients with CV risk factors, with concern about side effects driving physicians’ reluctance to prescribe high-dose statins rather than concerns about lack of efficacy.

Many cardiologists felt it was more important to treat biliary cholesterol than dietary cholesterol when choosing a treatment method for inhibiting absorption in patients with CHD or diabetes, highlighting the growing awareness of the impact of biliary cholesterol on LDL-C levels. Cholesterol in the body originates from absorption of both biliary and dietary cholesterol in the intestine and production in the liver and peripheral tissues, with approximately two-thirds of intestinal cholesterol deriving from biliary sources. Inhibiting the absorption of biliary cholesterol represents an important therapeutic target because, unlike dietary cholesterol, the amount of cholesterol in bile is largely unaffected by dietary modification or agents such as statins, fibrates or nicotinic acid.
Almost all physicians agreed that their main objective was lowering LDL-C and total cholesterol. More than 80% agreed that their objective was preventing a primary or secondary CV event, as well as lowering LDL-C and total cholesterol, and also saw the importance of helping patients with diabetes or CHD reach LDL-C goals. Still, only a fraction of physicians were aware of the ideal LDL-C levels for patients with CHD or diabetes, and most thought that no more than half of all of their patients had reached target LDL-C levels. Nearly half of physicians were not aware of the effect of doubling the dose of a statin on LDL-C reduction. GPs in particular were unaware of important international guidelines for at-risk patients and tended to follow local country guidelines. Most physicians agreed that guidelines are not adequately followed, often due to budgetary constraints.
In conclusion, the findings of the 2005 and 2006 surveys reflect the growing belief among practitioners in Europe that many patients with hypercholesterolaemia need a more advanced cholesterol-lowering therapy to reach LDL-C goals. To achieve greater LDL-C control (particularly in patients with CV risk factors), many practitioners are relying more on inhibiting both cholesterol absorption in the intestine and cholesterol production in the liver. It is now widely accepted that lowering LDL-C to goal results in better patient outcomes. Our results suggest that many physicians are uncomfortable reaching these goals through increasing statin dose. Co-administration of a cholesterol absorption inhibitor with a statin achieves better LDL-C control without an increase in statin dose. Ôûá

Acknowledgements

Writing assistance for this paper was provided by Jan S Redfern, PhD, and Wendy Horn, PhD, and funding was provided by Merck & Co., Inc., Whitehouse Station, New Jersey.

References
  1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994;344:1383–9.
    Crossref | PubMed
  2. 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.
    Crossref | PubMed
  3. 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;279:1615–22.
    Crossref | PubMed
  4. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial, Lancet, 2002;360:7–22.
    Crossref | PubMed
  5. LaRosa JC, He J, Vupputuri S, Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials, JAMA, 1999;282:2340–46.
    Crossref | PubMed
  6. Law MR, Wald NJ, Rudnicka AR, Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis, BMJ, 2003;326:1423–9.
    Crossref | PubMed
  7. 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;366:1267–78.
    Crossref | PubMed
  8. Executive Summary of The 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), JAMA, 2001;285:2486–97.
    Crossref | PubMed
  9. 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 in Clinical Practice, Eur Heart J, 2003;24:1601–10.
    Crossref | PubMed
  10. 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;110:227–39.
    Crossref | PubMed
  11. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary, Eur Heart J, 2007;28:88–136.
    Crossref | PubMed
  12. Goettsch WG, Yin DD, Alemao E, et al., Statins are less effective in common daily practice among patients with hypercholesterolemia: the REALITY-PHARMO study, Curr Med Res Opin, 2004;20:1025–33.
    Crossref | PubMed
  13. Van Ganse E, Laforest L, Alemao E, et al., Lipid-modifying therapy and attainment of cholesterol goals in Europe: the Return on Expenditure Achieved for Lipid Therapy (REALITY) study, Curr Med Res Opin, 2005;21:1389–99.
    Crossref | PubMed
  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;350:1495–1504.
    Crossref | PubMed
  15. Koren MJ, Hunninghake DB, Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study, J Am Coll Cardiol, 2004;44:1772–9.
    Crossref | PubMed
  16. LaRosa JC, Grundy SM, Waters DD, et al., Intensive lipid lowering with atorvastatin in patients with stable coronary disease, N Engl J Med, 2005;352:1425–35.
    Crossref | PubMed
  17. Leitersdorf E, Cholesterol absorption inhibition: filling an unmet need in lipid-lowering management, Eur Heart J Suppl, 2001;3(Suppl E):E17-E23.
    Crossref 
  18. Ballantyne C, Abate N, Zhong Y, et al., Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia. the Vytorin Versus Atorvastatin (VYVA) Study. (abstract), Am Heart J, 2005;149:1464–73.
    Crossref | PubMed
  19. Barrios V, Amabile N, Paganelli F, et al., Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin 10/20 mg/day compared to doubling the dose of atorvastatin in hypercholesterolaemic patients with atherosclerosis or coronary heart disease, Int J Clin Pract, 2005;59:1377–86.
    Crossref | PubMed
  20. Feldman T, Koren M, Insull W, Jr, et al., Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals, Am J Cardiol, 2004;93:1481–6.
    Crossref | PubMed
  21. Goldberg RB, Guyton JR, Mazzone T, et al., Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study, Mayo Clin Proc, 2006;81:1579–88
    Crossref | PubMed
  22. Ballantyne CM, Houri J, Notarbartolo A, et al., Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial, Circulation, 2003;20;107:2409–15.
    Crossref | PubMed
  23. Ballantyne CM, Blazing MA, King TR, et al., Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia, Am J Cardiol, 2004;93:1487–94.
    Crossref | PubMed
  24. Melani L, Mills R, Hassman D, et al., Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial, Eur Heart J, 2003;24:717–28.
    Crossref | PubMed
  25. Gagne C, Bays HE, Weiss SR, et al., Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia, Am J Cardiol, 2002;90:1084–91.
    Crossref | PubMed
  26. Kerzner B, Corbelli J, Sharp S, et al., Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia, Am J Cardiol, 2003;91:418–24.
    Crossref | PubMed