OVERVIEW

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. It accounts for almost 75% of the total mortality among the general population and for 80% of the total mortality among patients with diabetes^.1 Preventive efforts rely on identifying persons at high risk and starting intervention early enough in the course of atherosclerosis.

Elevated LDL levels are associated with increased risk of CVD^.2 Potent LDL-lowering medications called HMG CoA reductase inhibitors (statins) were found to reduce the incidence of all-cause mortality, cardiovascular mortality, and nonfatal myocardial infarction (MI) in several primary and secondary prevention trials.^3,4,5,6 However, major controversy still surrounds the decisions of when and how to treat dyslipidemia.

Recently, the updated recommendation of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP-III) of the National Cholesterol Education Program, supported by strong evidence, lowered the target LDL level for high-risk individuals from 100 mg/dL to 70 mg/dL. This goal is almost impossible to achieve without using higher doses of statins, adding other lipid-lowering medications, or both.

The American Heart Association has estimated that 38 million Americans would benefit from diet and drug therapy to lower LDL levels. However, fewer than half of them, including those in the highest-risk category, are currently treated. Only one third of persons receiving treatment achieve the updated ATP-III goal.

Developing methods to identify and assess high-risk individuals are the most challenging remaining tasks. The best use of new biomarkers, including inflammation markers such as serum C-reactive protein (CRP), is also debatable. Debate continues regarding the best way to achieve the new LDL target level in high-risk individuals. Individuals with the following factors are at high risk for CVD:

• Patients with established coronary heart disease (CHD)
• Patients with diabetes
• Individuals with multiple CHD risk factors and a 10-year CHD risk of greater than 20% (according to Framingham Risk Score)
• Patients with abdominal aortic aneurysms

LDL REDUCTION WITH STATINS IN PATIENTS WITH ESTABLISHED CHD

Several recent trials showed that the reduction of LDL cholesterol levels through use of statins in patients with established coronary artery disease (CAD) is extremely beneficial.

REVERSAL study

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study⁷ was a double-blind, randomized trial comparing the effects of 2 different statins, administered for 18 months, on atherosclerotic burden measured by intravascular ultrasound (IVUS). Six hundred fifty-four patients with a previous history of CAD were randomized into two groups: one group using pravastatin 40 mg as moderate lipid-lowering therapy and the other group using atorvastatin 80 mg as intensive lipid-lowering treatment. IVUS was performed during baseline catheterization and repeated after 18 months of treatment. Efficacy parameters included changes in LDL levels, changes in CRP levels, and changes in atheroma burden (determined by IVUS). Serum LDL levels were reduced from 150.2 mg/dL to 110 mg/dL in the pravastatin 40-mg group, and a level of 79 mg/dL was reached in the atorvastatin 80-mg arm. CRP levels decreased 5.2% with pravastatin and 36.4% with atorvastatin. The study demonstrated a complete halting of coronary disease progression in the intensive arm compared to the moderate-treatment cohort using all 3 prespecified efficacy measures. Plaque volume was unchanged from baseline in the intensive arm, indicating absence of progression. The study concluded that, for patients with established CAD, intensive treatment with atorvastatin 80 mg better reduced progression of coronary atherosclerosis compared to a more moderate regimen consisting of pravastatin 40 mg.

PROVE IT trial

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22)⁸ trial was a double-blind, randomized clinical trial that included 4162 patients who had been hospitalized for acute coronary syndrome (ACS). Patients were randomized to daily doses of either pravastatin 40 mg or atorvastatin 80 mg. The primary end point was a composite of all-cause mortality, MI, documented unstable angina requiring hospitalization (>30 d after revascularization), or stroke. After a mean of 24 months, pravastatin lowered LDL levels to 95 mg/dL and atorvastatin lowered LDL levels to 62 mg/dL, resulting in a 16% lower risk of the primary end point. The separation of the events curves was apparent within the first few months of study and continued throughout the duration of the study (2.5 y), confirming the benefits of high-dose statin therapy during the advanced phase of atherosclerosis. This trial demonstrates that greater cardioprotection is possible with an intensive lipid-lowering therapy.

A to Z trial

This randomized, double-blind trial compared patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) to patients with ACS receiving placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232).⁹ The primary end point was a composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke. After a follow-up period of 6-24 months, 16.7% of patients in the placebo plus simvastatin group experienced the primary end point compared with 14.4% in the simvastatin only group (hazard ratio 0.89). The study concluded that, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

Treating to New Targets (TNT) trial

This randomized, double-blind trial included 10,001 patients with stable CHD and LDL levels of <130 mg/dL randomized to receive either 10 mg or 80 mg of atorvastatin per day^.10 Patients were monitored for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal MI not related to a procedure, resuscitation after cardiac arrest, or fatal or nonfatal stroke. LDL levels were reduced to 77 mg/dL with 80 mg of atorvastatin and to 101 mg/dL with 10 mg of atorvastatin. A primary event occurred in 8.7% of patients receiving the 80-mg dose compared with 10.9% of those receiving the 10-mg dose of atorvastatin. These results represent a 2.2% absolute reduction in the rate of major cardiovascular events and a 22% relative risk reduction (hazard ratio 0.78). The study concluded that intensive lipid-lowering therapy in patients with stable CHD provides additional clinical benefit but was associated with a greater incidence of elevated liver enzymes.

LDL REDUCTION WITH STATINS IN PATIENTS WITH TYPE 2 DIABETES

Earlier data from large intervention studies such as the Scandinavian Simvastatin Survival Study (4S)¹¹ and Cholesterol And Recurrent Events (CARE) study¹² showed that the absolute risk reduction in coronary events resulting from lipid lowering with statins was larger in patients with diabetes than in individuals without diabetes. More recent studies have also confirmed the potential benefit of aggressive lowering of LDL levels in patients with diabetes.

Collaborative Atorvastatin Diabetes Study (CARDS)

This randomized, double-blind trial included 2838 patients with type 2 diabetes, no previous CHD, and mean LDL levels of less than or equal to 159.5 mg/dL randomized to receive either atorvastatin 10 mg/d or placebo^.13 Patients were monitored for a median duration of 3.9 years. Assessed separately, acute CHD events were reduced by 36%, coronary revascularizations by 31%, rate of stroke by 48%, and death rate by 27% in the atorvastatin group in comparison to placebo. The study suggested that treatment would be expected to prevent at least 37 major vascular events per 1000 patients with diabetes treated with atorvastatin 10 mg/d for 4 years.

Heart Protection Study (HPS)

This randomized, double-blind trial included 5,963 adults in the United Kingdom who have diabetes and 14,573 patients without diabetes but with occlusive arterial disease randomized to receive 40 mg/d of simvastatin or placebo^.3 The primary end point included first major coronary event (ie, nonfatal MI or coronary death) and first major vascular event (ie, major coronary event, stroke, or revascularization). For the first occurrence of any of these major vascular events among participants with diabetes, the event rate in the simvastatin group was reduced by 22%. Among the participants with diabetes who did not have any diagnosed occlusive arterial disease, a highly significant reduction of 33% occurred. The study suggested that, in patients with diabetes but without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1,000 from having at least 1 major vascular event.

LDL REDUCTION WITH STATINS IN PATIENTS WITH HYPERTENSION OR MULTIPLE RISK FACTORS

The Anglo Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)¹⁴ included 10,305 patients aged 40-79 years with hypertension and no history of CHD but with at least 3 other cardiovascular factors. Participants were randomized to receive either atorvastatin 10 mg/d or placebo. The trial was stopped prematurely after an average duration of 3.3 years because of the strong predictor positive effect in favor of the atorvastatin arm. The study showed a 36% risk reduction in fatal CHD and nonfatal MI compared to placebo.

LDL REDUCTION WITH STATINS IN THE ELDERLY POPULATION

Elderly individuals have the highest incidence of CVD. Safety concerns have resulted in a paucity of clinical trials conducted in this age group. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial¹⁵ has provided recent data on the efficacy of statins in the elderly population. This randomized, double-blind trial included 5804 men and women aged 70-82 years with a history of, or risk factors for, vascular diseases randomized to receive either pravastatin 40 mg/d or placebo.

After 3 years of intervention, pravastatin lowered LDL cholesterol levels by 34% and reduced the incidence of coronary death and nonfatal MI risk by 19%. The mortality rate from coronary disease was reduced by 24%, but the risk for stroke was unaffected; the incidence of transient ischemic attacks was reduced by 25%. New cancers were more frequent among pravastatin-treated individuals (+25%), but incorporation of these data in a meta-analysis of all pravastatin trials and all statin trials revealed no overall increase of cancer risk. The Heart Protection Study (HPS) also reported significant reduction in the risk of first major vascular events in individuals aged 65 years or older.

CONCLUSION

References

1. American Heart Association: Heart disease and stroke statistics—2005 update. 2005. Available at: http://www.americanheart.org/downloadable/heart/1105390918119HDSStats2005Update.pdf

2. Kannel WB, Castelli WP, Gordon T: Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med 1979; 90(1): 85-91.

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4. The Scandinavian Simvastatin Survival Study Group (4S): Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet 1994; 344(8934): 1383-9.

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12. 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(14): 1001-9.

13. 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(9435): 685-96.

14. 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 concentration, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361(9364): 1149-58.