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Primary Prevention Trials: Lessons Learned About Treating High-Risk Patients With Dyslipidemia Without Known Cardiovascular Disease

Posted on: Friday, 12 August 2005, 03:02 CDT

Key words: Asymptomatic patients * Cardiovascular disease * Hydroxymethylglutaryl-CoA reductase inhibitors * Hyperlipidemia * Risk factors

ABSTRACT

Cardiovascular disease (CVD) is the leading cause of death worldwide. Many serious cardiovascular (CV) events occur in individuals with no prior manifestation of the disease, and often result in death. Awareness of the contributions of various risk factors to the occurrence of CVD is growing, Asymptomatic individuals with multiple risk factors at low or moderate levels can be at greater risk for CVD than those with a single risk factor at a high level. Dyslipidemia and hypertension are two risk factors that commonly coexist and are modifiable through lifestyle changes and/ or medications. Recent trials with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated that aggressive cholesterol-lowering therapy in patients without known atherosclerotic disease, but at high risk for CVD with relatively normal low-density lipoprotein cholesterol (LDL-C) levels (< 130mg/ dL), can significantly reduce the number of coronary events experienced by these patients. This subset of at-risk patients is better served by this approach than by treatment solely based on degree of dyslipidemia.

Introduction

Cardiovascular disease (CVD) is responsible for approximately 30% of all mortality worldwide and nearly 60% of all deaths in the United States (US) annually1. Traditionally, CVD management strategies have focused on patients with clinically overt disease. The demarcation of primary versus secondary prevention in CVD is to a large extent an artificial barrier. Increasingly, guidelines such as the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the European Society of Hypertension, the European Society of Cardiology, and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure focus on the risk of CVD in the individual patient and therapy tailored to each patient's degree of risk to decrease morbidity and mortality. However, many CV events occur in individuals with risk factors for, but without diagnosis of, CVD with 80% of coronary heart disease (CHD) deaths occurring among individuals under 65 years of age during their first myocardial infarction (MI)1. Hence, the identification and treatment of the at- risk population without clinically evident disease should be important objectives of modern healthcare policies worldwide. This is especially true for adults with type 2 diabetes and some patients with marked elevation of specific risk factors. Based on epidemiologic data showing benefit from intensive therapy, the delineation of primary and secondary prevention may be deemphasized, with interest focusing on identifying and reducing risk for CVD.

Multiple risk factors and global risk

Patients commonly have multiple CVD risk factors. In one retrospective cohort study, individuals with two risk factors were more common than expected by chance (p < 0.01), and those with more than one modifiable risk factor were at greater risk for developing additional risk factors than those with no risk factors2. Hypertension and dyslipidemia are particularly comorbid conditions; hypertensive individuals are two to three times as likely to have elevated cholesterol levels than their normotensive counterparts3. Concomitant dyslipidemia and hypertension have a multiplicative effect on the risk of CHD (Figure I)4. While patients with only moderately elevated blood pressure (BP) and cholesterol levels may have a three- to four-fold increase in CVD risk3, middle-aged white men with cholesterol and systolic BP (SBP) levels in the highest quintiles have a 20-times greater risk of dying from CHD than normotensive patients with cholesterol levels in the lowest quintiles4.

The major CVD risk factors are listed in Table 1. Epidemiologic evidence indicates that race or ethnicity may influence the prevalence of risk factors, placing some populations at greater risk than others. In the Third National Health and Nutritional Examination Survey (NHANES III), after adjusting for education, black and Mexican-American women were significantly more likely to have high BP, high body mass index, a sedentary lifestyle, and diabetes mellitus than their white counterparts (p < 0.001)5. Moreover, hypertension was more common in southern blacks than in northern blacks (p < 0.02), and immigrant black women had lower rates of hypertension-related organ damage than US-born black women6. Among men, Mexican-Americans had the highest mean total cholesterol (TC) concentrations and blacks had the lowest; while among women, MexicanAmericans had the lowest mean TC concentrations7. In addition, populations in different regions of Europe have diverse CVD risk rates8. These differences, whether due to ethnicity or to modifiable differences in lifestyle and/ or culture, can help to identify asymptomatic individuals at risk for CVD. Also, factors such as physical inactivity, hypertension, cigarette smoking, and dyslipidemia should be modified to reduce risk regardless of race or ethnicity.

Figure 1. Hypercholesterolemia and hypertension interaction among nonsmokers in MRFIT (reproduced from Neaton and Wentworth4, with permission from the American Medical Association)

Guidelines for identifying and treating high-risk individuals without known CVD

Since the presence of multiple risk factors has a synergistic effect, it is important to assess a patient's absolute CVD risk based on all, rather than single, risk factors. This is necessary to determine the appropriate level of treatment. Numerous guidelines setting lipid goals relative to the CHD risk have been developed to help physicians and other health care providers manage patients with these risk factors9"12.

Recommendations for cholesterol goals vary slightly between published guidelines. In the US, NCEP ATP III recommends a low- density lipoprotein cholesterol (LDL-C) goal of < 160mg/dL for patients free of CHD with less than or equal to one risk factor for CHD (Table 1) and a LDL-C goal of < 130mg/dL for patients with two or more risk factors without known coronary artery disease (CAD). More recently, an LDL-C goal of < 1OO mg/dL, with an option of < 70 mg/dL, is recommended for individuals with diabetes mellitus and those with > 20% 10-year CHD risk12. The Third Joint Task Force European guideline10 uses charts based on sex, age, smoking status, SBP, and TC to estimate the 10-year risk for fatal CVD for any combination of these factors. Goals of < 190 mg/dL TC and < 115 mg/ dL LDL-C are recommended for all patients, and goals of < 175mg/ dL TC and < 100 mg/dL LDL-C are recommended for high-risk patients with moderately elevated cholesterol levels without diagnosed CVD. The European Society of Hypertension guidelines use charts based on BP levels and additional risk factors and recommend goals of < 135mg/ dL TC and < 77mg/dL LDL-C for primary prevention in patients with a 10-year CVD risk ≥ 20%". While there are no specific published guidelines that set goals for triglycerides (TG) or high-density lipoprotein cholesterol (HDL-C), NCEP ATP III recommends that the non-HDL-C goal be set at 30 mg/dL above the LDL-C goals, especially for those individuals with TG levels ≥ 200mg/dL. It is conceivable that guidelines for these lipid parameters will also be forthcoming once the evidence on methods to manage these lipids, either through lifestyle changes or medical intervention, becomes available.

Table 1. Major risk factors for cardiovascular disease

Although published recommendations have divergent means of identifying and specifying cholesterol goals, the trend is toward increasingly lower LDL-C targets. All CVD management guidelines recommend lifestyle changes, including smoking cessation, regular physical exercise, and dietary modifications (reduced salt, saturated fat, and cholesterol intake; increased fruit, vegetable, and whole grain ingestion; and moderate alcohol consumption) as a central strategy for achieving cholesterol and BP goals. However, lifestyle changes, even when fully implemented, are frequently insufficient to lower LDL-C levels to the required goal. Patient compliance with these changes can be improved, albeit with limited success, with additional help from a dietician13. Consequently, many individuals require pharmacologie assistance to achieve their goals. Thus, standard clinical practices recommend the use of lipid- modifying medications, especially statins, at the appropriate dose, to treat dyslipidemia14. Furthermore, thiazide-type diuretics, supplemented by an angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, β-blocker, or a calcium channel blocker, if necessary, should be used to treat hypertension". Clinical trials have demonstrated that diuretics are effective and economical in the treatment of hypertension and in reducing CVD risk15'16. Attainment of lipid and BP targets is particularly crucial for risk management in the asymptomatic patient.

Statin efficacy on primary coronary event prevention in high- risk patients without known CVD

Large-scale, prospective, randomized trials (Table 2) have demonstrated that intensive statin therapy significantly reduces lipid levels and the incidence o\f coronary events in individuals without known CVD with low or average cholesterol levels17"21. Since guidelines focus on treatment of the symptomatic patient, the benefits of treating high-risk individuals without known CVD may largely go unnoticed and may inadvertently result in under treatment of this population.

In the West of Scotland Coronary Prevention Study (WOSCOPS)17, pravastatin 40mg/day reduced primary CV events by 31% (p < 0.001) over 4.9 years compared with placebo in hypercholesterolemic men without a history of MI. Furthermore, there were significant reductions in nonfatal MI (31%, p < 0.001) and death from all CV causes (32%, p = 0.033). In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)18 lovastatin 20- 40mg/ day reduced the risk for the first acute major coronary event by 37% (p < 0.001) over 5.2 years compared with placebo in individuals with average TC and LDL-C levels and below average HDL- C levels and without overt CVD. In addition, lovastatin treatment reduced the risk for MI (40%, p = 0.002), unstable angina (32%, p = 0.02), coronary events (25%, p = 0.006), CV events (25%, p = 0.003), and the need for coronary revascularization procedures (33%, p = 0.001).

Although the Heart Protection Study (HPS) was not exclusively a primary prevention trial, 35% of the participants were free of CHD and qualified for inclusion in this analysis19. In this group, simvastatin 40mg/day reduced major vascular events by 22% compared with placebo (p = 0.0006) in the patient subpopulation without elevated LDL-C levels at baseline (< 100mg/dL). In patients with diabetes and no history of coronary or occlusive arterial disease, simvastatin reduced the incidence of major coronary events, strokes, and revascularizations by 22% (p < 0.0001) and the proportion of first major vascular events by 33% (p = 0.0003)22. More recently, the Collaborative Atorvastatin Diabetes Study (CARDS) observed that a daily dose of 10 mg atorvastatin caused a 37% rate reduction in at least one major CV event (p = 0.001) and reduced the death rate by 27% (p = 0.059)23 compared with placebo. The risk reduction was similar in patients with no CAD to those with CAD. These data further emphasize the value of this new and emerging concept of treating patients based on overall risk, especially those with type 2 diabetes.

In stark contrast to other trials, pravastatin 2040mg/day, given in addition to an antihypertensive drug regimen, produced only a modest reduction in cholesterol levels compared with usual care in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)20. Pravastatin also produced a small; but not statistically significant reduction in all-cause mortality and CHD deaths20. The small difference in cholesterol lowering between the pravastatin-treated and usual-treatment groups resulted in the study lacking the power to distinguish between the clinical outcomes in the two groups. Furthermore, the non-blinded nature of the trial and a population that included larger proportions of older participants, women, blacks, and Hispanics than other trials to date, may have contributed to the study lacking sufficient power20. Interestingly, although all-cause mortality did not differ significantly in the overall population, there was a significant reduction in the rate of CHD deaths plus nonfatal MI in blacks compared with non-blacks (p = 0.03). While there is no way of determining whether patients with documented CHD were predominantly black, thereby complicating this subgroup analysis, these data serve to suggest that statins may be beneficial in all ethnic groups.

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), atorvastatin 10mg/day reduced the risk for nonfatal MI and fatal CHD 36% compared with placebo (p = 0.0005) in patients with hypertension with at least three additional CVD risk factors but no history of CHD with average or mildly elevated TC levels (≤ 250mg/dL)21. Risk reductions with atorvastatin were independent of baseline cholesterol levels. The risk reduction in patients with diabetes was comparable to the overall population but did not achieve statistical significance, probably due to the relatively small cohort of patients with diabetes and the lack of power to reliably determine the efficacy of lipid-lowering therapy in this group. The early termination of the trial shortened the follow-up period and may have led to an underestimation of the benefits of statin therapy21.

Two other studies in which aggressive lipid-lowering therapy was used as a part of a multifaceted approach to treating several risk factors simultaneously demonstrate the benefits of such a treatment modality in practice. In one study, patients with CHD given maximal treatment (lipid-lowering therapy to goals, comprehensive diet, monthly follow-up, extensive CV medication) showed a 78% risk reduction for CV events versus those provided usual care (often with no lipid-lowering therapy, continued smoking, no dietary interventions), demonstrating the benefit of treating the sum of the patient's risk factors rather than just one (Figure 2)24. In the other study, patients with diabetes and microalbuminuria were given either conventional treatment in accordance with guidelines or multifactorial intensive therapy targeting multiple CHD risk factors25. Predictably, the intensive treatment group experienced approximately 50% fewer CV events than the conventional treatment group (p = 0.008). While neither study was designed to specifically target the patient's global risk, the results from these studies provide direct data supporting the importance of intensive treatment based on global CHD risk.

Table 2. Comparison fo major statin trials

Statin therapy reduced risk across a wide baseline cholesterol range in several primary prevention trials (Figure 3), casting doubt whether a lower limit for LDL-C levels should be set26. Cholesterol levels below which lipid-lowering therapy no longer provides risk reduction for CHD have yet to be found, and clinical trials demonstrate that primary prevention of CHD is effective, even in patients with average or only moderately elevated TC levels. Strict adherence to existing LDL-C guidelines, which focus on patients diagnosed with CVD or who may have other conditions (e.g., diabetes) that identify them as being at high risk for CVD, may mean that at- risk patients with average to mildly elevated cholesterol levels are less likely to receive the benefits of lipid-lowering therapy such as statins.

Impact on future dyslipidemia management of global risk in high- risk patients without known CVD

Clinical trials of statins in patients with hypertension demonstrated benefits over and beyond those derived from the antihypertensive medications patients received during the trials. The Anglo-Scandinavian Cardiac Outcomes Trial demonstrated the impact of atorvastatin on CV outcomes in patients with multiple risk factors21. Subgroup analysis from ALLHAT demonstrated a significant reduction of CHD events in the black population, indicating that the benefits of statin therapy may extend to other ethnic groups20. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, ASCOT, and HPS each analyzed data from patients with different clusters of CHD risk factors, but with no history of the disease, and observed a CHD risk reduction with statin therapy. The results from these trials suggest that patients' global risk, rather than solely cholesterol levels, may be a more appropriate treatment guide.

Conclusions

Many serious CV events occur in individuals without clinically evident disease. Many of these potentially identifiable individuals possess multiple risk factors and are at significant risk for CHD. Although an isolated risk factor, such as dyslipidemia, may not be sufficiently severe to merit intervention, treatment may be required if the patient has additional risk factors because of their cumulative impact on CHD risk.

Figure 2, Kaplan-Meier estimates of the rate of cardiovascular events in the conventional therapy group and the intensive therapy group (Gaede et al.25)

Figure 3. CHD risk reduction rates relative to LDL-C levels in landmark primary prevention statin trials. Adapted from Shepherd et al.'7, Downs et al.'8, Heart Protection Study Collaborative Group19, ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group20, Sever et al.2', and Colhoun et al.23. S = statin- treated; P = placebo-treated; U = usual treatment

Statins can reduce the number of coronary events in a wide range of high-risk individuals without CVD, including those who would not conventionally be deemed dyslipidemic. Risk reduction with statin therapy is similar in patients with and without dyslipidemia. These results indicate that lipid-lowering therapy can benefit a diverse range of patients at risk for CVD.

Treatment strategies for CVD should be based on an assessment of global risk and should appropriately target multiple risk factors. Primordial prevention along with intensive care and early treatment of asymptomatic, at-risk patients, whatever their age, race, or gender, could significantly reduce the burden of heart disease worldwide.

Acknowledgment

Declaration of interest: I have in the past received research grants from AstraZeneca, Merck & Co., Pfizer, Novartis and Bristol Myers Squibb, but received no financial assistance with this manuscript. I also received editorial assistance from Dr Mukund Nori.

References

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15. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid- Lowcring Treatment to Prevent Heart Attack Trial (ALLHAT). J Am Med Assoc 2002;288:2981-97

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21. 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

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24. Sdringola S, Nakagawa K, Nakagawa Y, et al. Combined intense lifestyle and pharmacologie lipid treatment further reduce coronary events and myocardial perfusion abnormalities compared with usual- care cholesterol-lowering drugs in coronary artery disease. J Am Coll Cardiol 2003;41:263-72

25. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. New Engl J Med 2003;348:383-93

26. Nadar S, Lim HS, Beevers DG, et al. Lipid lowering in hypertension and heart protection: observations from the AngloScandinavian Cardiac Outcomes Trial (ASCOT) and the Heart Protection Study. J Hum Hypertens 2002;16:815-7

CrossRef links are available in the online published version of this paper:

http://www.cmrojournal.com

Paper CMRO-2966_3, Accepted for publication: 22 April 2005

Published Online: 14 June 2005

doi:10.1185/030079905X50552

Keith C. Ferdinand

Heartbeats Life Center, New Orleans, LA, USA

Address for correspondence: Keith C. Ferdinand, MD, FACC, Heartbeats Life Center, 1201 Poland Avenue, New Orleans, LA 70117, USA. Tel.: +1 504 943 1177; Fax: +1 504 943 1298; email: kcferdmd@aol.com

Copyright Librapharm Jul 2005

Source: Current Medical Research and Opinion

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