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OVERVIEW

Atherosclerosis, the primary cause of heart disease and stroke, is in greater abundance in high-risk individuals. An elevated level of low-density lipoprotein cholesterol (LDL-C) is a major modifiable contributor to the development of atherosclerosis, and statin drugs have surpassed all other classes of medicines in reducing the incidence of the major adverse outcomes of death, heart attack, and stroke. Statins have been shown to reduce the incidence of all-cause mortality, cardiovascular mortality, and nonfatal myocardial infarction (MI).^1,2,3,4

The National Cholesterol Education Program (NCEP) is responsible for evaluating new clinical data and making therapeutic recommendations for treatment targets for the medical community. Its most recent published guidelines recommend adjusting LDL-C target levels to less than 100 mg/dL in patients with known coronary artery disease (CAD) and include an option to lower LDL-C levels to an even lower level of 70 mg/dL in patients with CHD or CHD equivalent (those with a 10-y risk of CHD >20%).

Patients with diabetes mellitus, symptomatic carotid artery disease, peripheral artery disease, abdominal aortic aneurysm, or multiple risk factors that confer a 10-year risk of coronary heart disease (CHD) greater than 20% have been studied in major clinical trials that have addressed lowering LDL-C levels for secondary prevention of coronary events.

LDL REDUCTION WITH STATINS IN SECONDARY PREVENTION

Several recent trials showed that the reduction of LDL-C levels through use of statins in patients with established CAD is extremely beneficial.

4S

The Scandinavian Simvastatin Survival Study (4S)⁵ was a randomized double-blind study of 4,444 men and women aged 35-70 years with mean LDL-C levels of 188 mg/dL and a history of angina pectoris or MI. The patients were treated with simvastatin (20-40 mg/d) for an average of 5.4 years. The study reported that simvastatin lowered LDL-C levels by 35% (compared to a 1% increase in the randomized placebo group) and significantly decreased the primary end point of all-cause mortality by 30% (P = .0003). Coronary mortality decreased by 42% without an increase in the rates of death not caused by cardiovascular disease. In the simvastatin group, incidence of major coronary events (coronary death, non-fatal MI, and resuscitated cardiac arrest) was decreased by 34%. In short, 4S provided robust evidence that LDL-C level reduction with simvastatin safely reduced both CHD events and total mortality in men and women with known CHD.

CARE trial

The Cholesterol and Recurrent Events (CARE) trial² enrolled 4,200 post-MI men and postmenopausal women (aged 21-75 y) with average LDL levels (mean 139 mg/dL). LDL levels decreased by 28% with pravastatin (40 mg/d) relative to placebo. After 5 years, patients in the statin therapy group showed a 24% reduction in non-fatal MI or CHD death and demonstrated a 27% decreased need for coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA). Women demonstrated better outcomes than men, with a 46% versus 20% reduction in combined coronary events, including CHD death, nonfatal MI, PTCA, and CABG (both with P < .001). Cerebral vascular accidents (CVA) were reduced by 31% (P = .03). The oldest patients, aged 65-75, exhibited a decrease in combined coronary events of 32%; those who had undergone previous CABG, PTCA, or both, experienced a 36% reduction in nonfatal MI or CHD. Treatment benefit was similar regardless of the presence or absence of hypertension, diabetes, tobacco use, or left ventricular dysfunction. The CARE trial demonstrated that both men and women (including elderly patients) with a history of MI and only modest elevations in LDL-C levels experience fewer cardiovascular events when treated with pravastatin.

REVERSAL study

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study³ was a randomized double-blind trial that compared atorvastatin with pravastatin to determine whether the extent of progression of atherosclerotic coronary disease could be differentiated between the 2 drugs with the use of intravascular ultrasonography (IVUS). The study randomized 654 patients with a previous history of CAD into a group receiving pravastatin 40 mg/d (as moderate lipid-lowering therapy) or a group receiving atorvastatin 80 mg/d (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 C-reactive protein (CRP) levels, and changes in atheroma burden (as determined by IVUS). Serum LDL levels were reduced from 150.2 mg/dL to 110 mg/dL in the pravastatin group, and a level of 79 mg/dL was reached in the atorvastatin group. CRP levels decreased 5.2% with pravastatin and 36.4% with atorvastatin. Using all 3 prespecified efficacy measures, the study demonstrated a complete halting of coronary disease progression in the intensive arm compared to the moderate-treatment group. Plaque volume did not change from baseline in the intensive arm, indicating an absence of progression. The study concluded that, for patients with established CAD, intensive treatment with atorvastatin 80 mg/d better reduced progression of coronary atherosclerosis than did a more moderate regimen of pravastatin 40 mg/d.

PROVE IT-TIMI 22 trial

The Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial⁴ was a randomized double-blind clinical trial that included 4,162 patients who had been hospitalized for acute coronary syndrome (ACS). The patients were randomized to receive either pravastatin (40 mg/d) or atorvastatin (80 mg/d). The primary end point was a composite of all-cause mortality, MI, documented unstable angina requiring hospitalization (>30 d after revascularization), or stroke. After an average 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 through 2.5 years, confirming the benefits of high-dose statin therapy during the advanced phase of atherosclerosis. This trial demonstrates that greater cardioprotection is possible with intensive lipid-lowering therapy (P = .0004).

A to Z trial

The A to Z trial⁶ randomized 4,497 patients within 5 days of MI or ACS to 2 treatment regimens: an early intensive strategy of 40 mg of simvastatin daily for 30 days followed by 80 mg thereafter or placebo for 4 months followed by 20 mg of simvastatin daily. The early intensive group contained 2,265 patients and the less aggressive treatment group contained 2,232 patients. After 24 months, a nonsignificant 11% reduction was observed in cardiovascular events (P = 0.14), including death, nonfatal MI, readmission for ACS, or stroke. Surprisingly, although the difference in LDL-C level was 62 mg/dL after the first 4 months of treatment, no reduction was observed in adverse outcomes. Subsequently, the event curves showed gradual separation and a trend toward statistical significance by the end of the 24-month follow-up period. These results provide essentially useful insights into both the benefits and the risks of high-dose simvastatin therapy after ACS.

TNT trial

The Treating to New Targets (TNT) trial⁷ was a randomized double-blind trial that included 10,001 patients with stable CHD and LDL levels less than 130 mg/dL. These patients were randomized to receive either 10 mg or 80 mg of atorvastatin per day. Patients were monitored for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event (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/d of atorvastatin and to 101 mg/dL with 10 mg/d 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. These findings represented a 2.2% absolute reduction in the rate of major cardiovascular events and a 22% relative risk reduction (P < 0.001). The investigators concluded and the study provided evidence that intensive lipid-lowering therapy in patients with stable CHD provides additional clinical benefit, but this therapy was associated with a greater incidence of elevated liver enzyme levels.

MIRACL trial

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial⁸ was a randomized double-blind trial that studied 3,086 adults with unstable angina or non–Q-wave MI. The study reported benefits with early statin therapy (but not mortality benefits). Adults with unstable angina were randomly assigned to receive treatment with atorvastatin (80 mg/d) or placebo between 24 and 96 hours after hospital admission.

The primary end point (nonfatal infarction, cardiac arrest with resuscitation, or recurrent symptomatic ischemia requiring hospitalization) was less frequent in the patients receiving atorvastatin (14.8% vs 17.4% for placebo; relative risk reduction, 16%; 95% confidence interval [CI], 0.70-0.95); the benefit was primarily due to a 26% reduction in recurrent symptomatic ischemia that required emergency hospitalization. Treatment with atorvastatin did not prevent death, resuscitation cardiac arrest, or MI, and did not reduce the need for revascularization.

ASTEROID trial

A Study To Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) trial⁹ was an open-label uncontrolled study of intensive lipid-lowering therapy with rosuvastatin 40 mg/d in 507 patients. Patients were required to have undergone coronary angiography, have a greater than 20% narrowing of at least one vessel, and have a target vessel that would be evaluated by IVUS. This target vessel had to have a narrowing no more than 50% throughout a target segment and a minimum length of 4 cm.

IVUS was performed at baseline and at 24 months, and 349 patients had assessable IVUS examinations. A total of 158 patients were not included in the IVUS analysis, including 63 who were withdrawn after adverse events; an additional 3 patients were not included in the analysis of lipid levels. LDL-C levels decreased by 53%; HDL-C levels increased by 15%.

Both primary measures of efficacy exhibited improvement. The median atheroma volume decreased by 0.79% and the median atheroma volume in the most diseased 10 mm segment decreased by 9.1% (P < .001 vs baseline).

LIPID LOWERING VERSUS CORONARY INTERVENTION

AVERT trial

The Atorvastatin Versus Revascularization Treatment (AVERT) randomized trial¹⁰ compared the outcome of aggressive lipid lowering with atorvastatin (80 mg/d) with that of angioplasty in an attempt to delineate the importance of aggressive lipid lowering in all patients who were referred for coronary intervention. This study consisted of 341 patients with CAD in 1 or 2 vessels and LDL levels greater than 115 mg/dL.

After an 18-month follow-up, the reduction in mean LDL level was greater in the atorvastatin group (140mg/dL decreased to 77 mg/dL) than in the angioplasty group (140 mg/dL decreased to 119 mg/dL). An insignificant trend toward fewer composite end points (death, MI, stroke, resuscitated cardiac arrest, revascularization, and hospitalization for worsening angina) was observed in the atorvastatin group. Fourteen percent of patients in the atorvastatin group experienced ischemic events compared to 21% of the patients in the angioplasty group (relative risk, 1.5; 95% CI, 1.1-3.4). Patients in the atorvastatin group had a lower rate of bypass surgery than those in the angioplasty group (1.2% vs 5.1%) and lower rates of hospitalization for worsening angina (6.7% vs 14.1%). The time to the first ischemic event was significantly longer in the atorvastatin group than in the angioplasty group. Conclusions drawn from the study included that aggressive lipid lowering and percutaneous coronary intervention (PCI) should be used as complementary strategies for the treatment of CAD and that the selection of the patients who underwent the PCI contributed to their findings.

LDL REDUCTION WITH STATINS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

The cardiovascular risk reduction achieved by treatment with statins is greater in patients with diabetes than in those without diabetes. In the post-hoc analysis of the 4S trial,¹¹ simvastatin reduced total mortality by 43% (95% CI, 8-70%; P = .08) in patients with diabetes as compared to 29% in patients without diabetes, decreased major CHD by 55% (95% CI, 24-73%; P = .002), and decreased atherosclerotic events by 37% (95% CI, 8-57%; P = .018). In the CARE study, pravastatin reduced the absolute risk of coronary events for patients with diabetes by 8.1% and for patients without diabetes by 5.2%.¹² In the Heart Protection Study (HPS), treatment with simvastatin decreased the risk of coronary death, nonfatal MI, stroke, or revascularization by 25% in the subgroup of patients with diabetes.

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

ASCOT-LLA

The Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA) randomized study¹³ included 10,305 patients aged 40-79 years who had hypertension and no history of CHD but at least 3 other cardiovascular risk factors. Participants received either atorvastatin 10 mg/d or placebo. The trial was stopped prematurely after an average duration of 3.3 years because of the positive effect in favor of the atorvastatin arm. The study reported a 36% risk reduction in fatal CHD and nonfatal MI with atorvastatin compared to placebo (P < .0005).

LDL REDUCTION WITH STATINS IN THE ELDERLY POPULATION

Age is a risk factor for CVD. Issues of drug-to-drug interaction and potential adverse effects also play a greater role in elderly patients. In the double-blind Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial,¹⁴ which included 5,804 men and women aged 70-82 years with a history of or risk factors for vascular diseases, patients were randomized to receive either pravastatin 40 mg/d or placebo. Results revealed that LDL-C levels were reduced by 34% and that the incidence of coronary death and nonfatal MI risk were decreased 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%. The Heart Protection Study also reported significant risk reduction of first major vascular events in individuals aged 65 years or older.

CONCLUSION

Abundant clinical data indicate that virtually all patients with CAD should receive lipid-lowering drug therapy to reduce their risk of subsequent events. A high LDL level is the prominent risk factor for CHD, and intervention with diet and drugs to reduce cholesterol levels has been proven to decrease the risk of subsequent cardiovascular events, including total mortality.

REFERENCES

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