a. The West of Scotland Coronary Prevention Study (WOSCOPS) (1995) demonstrated that treatment of men at relatively high risk with profoundly ele vated cholesterol levels significantly reduced the risk of heart attack and death from heart disease. The double-blind study randomized 6,600 healthy men with a baseline mean LDL-C level of 193 mg/dL to pravastatin (40 mg/d) or to placebo, for an average of 5 years, and demonstrated a 31% relative reduction in the incidence of nonfatal MI or CAD death. Follow-up of this population published in 2007 showed that the statin group continued to experience lower rates of cardiovascular death after a further 10 years, even though only onethird continued to take statins during the additional follow-up period.

b. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (1998) demonstrated benefit among patients with more typical risk profiles, including lower cholesterol values, than among those in the WOSCOPS. AFCAPS/TexCAPS patients had a baseline mean TC level of 220 mg/dL. The study randomized 6,600 patients to lovastatin 20 to 40 mg daily or placebo and demonstrated a 36% relative risk reduction (RRR) for first acute major coronary events in the lovastatin group.

c. The Heart Protection Study (HPS) (2002) randomized 20,536 subjects in a 2 × 2 factorial design to daily simvastatin (40 mg) or placebo and to anti oxidants or placebo (the antioxidant arm did not show any benefit or harm).
The study focused on patients who were deemed high risk for CVD but not thought to merit treatment with statins based on the prevalent clinical practice at that time. Increased risk was defined as presence of or history of CAD, cerebrovascular disease, peripheral arterial disease, diabetes mellitus, or treated hypertension. Simvastatin therapy was associated with a 13% reduction in allcause mortality, including an 18% reduction in coronary death rate. The beneficial impact of statin therapy was seen with respect to all cardiovascular end points, with significant reductions in risk of nonfatal MI, incidence of first stroke, and coronary and noncoronary revascularization. Treating patients with LDL levels < 100 mg/dL was also associated with a beneficial reduction in vascular events. The benefit was maintained in patients receiving other cardioprotective medications, such as angiotensin-converting enzyme inhibitors, β-blockers, and aspirin. Although not strictly a primary prevention trial, the HPS provided evidence to support treatment of risk as endorsed by the National Cholesterol Education Program (NCEP) guidelines. However, the HPS results refuted the threshold LDL level (as proposed by NCEP III at that time) below which statins were not previously indicated.

d. Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) (2002) randomized 5,804 patients between the ages of 70 and 82 years to placebo or pravastatin. These patients had preexisting coronary, cerebral, or peripheral vascular disease or had a history of smoking, hypertension, or diabetes. The study demonstrated a 15% reduction in the composite of coronary death, nonfatal MI, and stroke over a period of 3 years. The study demonstrated efficacy of primary and secondary prevention in the elderly.

e. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) (2002) randomized 10,355 hypertensive patients with one other coronary risk factor and a baseline mean LDL-C level of 148 mg/dL to pravastatin 20 to 40 mg/d or usual care. The study did not demonstrate a mortality difference in the two arms after a follow-up period of 4.8 years. This lack of observable difference in outcome might have resulted from the relatively modest LDL reduction (17% with pravastatin vs. 8% in usual care) or the fact that 26% of the patients in the “usual care” group were taking a statin at the end of the trial.

f. The Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA) (2003) randomized 10,305 patients with hyperten sion and at least three other cardiovascular risk factors and a baseline mean LDL-C level of 133 mg/dL to atorvastatin 10 mg/d or placebo. The study was stopped prematurely after a median follow-up of 3.3 years by the safety monitoring committee because of a significantly higher incidence of the pri mary end point (nonfatal MI or fatal CHD) in the placebo group. The study demonstrated a 36% RRR for the primary end point in the atorvastatin group compared with the placebo group. Further analysis demonstrated that the benefit of statin therapy started after only 1 year of treatment. There was also a significant reduction (RRR of 27%) in the incidence of fatal and nonfatal stroke in the atorvastatin group. This study, like the HPS, provided further evidence of the benefit of statins in patients at high risk for CVD without regard for baseline TC or LDL levels.

g. The Collaborative Atorvastatin Diabetes Study (CARDS) (2004) ran domized 2,838 diabetic patients with one additional cardiovascular risk factor, no history of CVD, and an average baseline LDL-C of only 117 mg/dL to atorvastatin 10 mg/d or placebo. This study was also terminated prema turely owing to an excess incidence of the primary end point (a composite of acute coronary events, coronary revascularization, or stroke) in the placebo group after a median follow-up of 3.9 years. Overall, the atorvastatin group
had an RRR of 37% for the primary end point and 27% for all-cause mortality. The importance of this trial was its demonstration of the clinical benefit of statin use in diabetic patients regardless of baseline LDL-C level, making a compelling case for statin use in all diabetic patients with at least one additional cardiovascular risk factor. According to the NHANES III data, 82% of diabetic patients in the United States would meet the entry criteria for the CARDS trial.

h. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) (2005) trial focused on the prevention of CHD in patients with type 2 diabetes using fenofibrates. The study randomized patients with type 2 diabetes diagnosed after 35 years of age with no clear indication for cholesterol-lowering therapy at baseline to fenofibrate (200 mg/d) or placebo. The study failed to show a difference in the primary composite end point of CHD or nonfatal MI between the two groups at 5-year follow-up. However, several secondary end points were lower in the fenofibrate group including nonfatal MI and coronary revascularization.

i. Japan EPA Lipid Intervention Study (JELIS) (2007). The goal of this trial was to evaluate treatment with the fish oil supplement eicosapentaenoic acid (EPA) in addition to statin therapy compared with statin therapy alone among patients with hypercholesterolemia. The study randomized patients in an open-label manner to treatment with EPA (1,800 mg/d) in addition to statin therapy (pravastatin 10 mg/d) or simvastatin (5 mg/d) or to statin therapy alone. At a mean follow-up of 4.6 years, there was a significant reduction in the primary end point of major adverse cardiovascular events in the EPA plus statin group (2.8% vs. 3.5%). This was driven primarily by a significant reduction in rates of unstable angina and a trend toward lower rates of nonfatal MI and revascularization. No difference was seen in sudden cardiac death or fatal MI.

j. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) (2008) trial focused on patients with normal LDL-C levels but increased levels of high-sensitivity C-reactive protein (CRP). This was the first clinical trial to demonstrate that statin therapy may benefit patients with low-to-normal LDL levels and no known CVD. The study randomized 17,802 healthy subjects with an LDL-C < 130 mg/dL and a CRP > 2.0 mg/L to daily rosuvastatin of 20 mg or placebo. The trial was stopped early for a mortality benefit after a median follow-up of 1.9 years. The study demonstrated that after 1 year of therapy, there were lower levels of LDL-C (55 vs. 110 mg/dL) and lower levels of CRP (2.2 vs. 3.5 mg/L) in the rosuvastatin-treated group. There was also a lower incidence of the primary end point of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, arterial revascularization procedure, or confirmed death from cardiovascular cause (0.77 vs. 1.36 events per 100 person-life years) as well as the risk of all-cause mortality (1.00 vs. 1.25 deaths per 100 person-life years) in the rosuvastatin-treated group.

k. The Action to Control Cardiovascular Risk in Diabetes Lipid Trial (ACCORD Lipid) (2010) was designed to evaluate whether the addition of fenofibrate to statin therapy among patients with type 2 diabetes would be effective in preventing cardiovascular events. The study randomized half of the patients within the initial ACCORD trial with type 2 diabetes and treated with a statin medication to fenofibrate (160 mg daily) or placebo. Although a significant reduction in triglyceride level (186 to 170 mg/dL) was seen with the addition of fenofibrate to statin therapy, there was no reduction in the primary end point (first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke) when compared with statin therapy alone.

In a subgroup analysis, a trend toward benefit of fenofibrate was shown in the group of patients with diabetes that had a significant dyslipidemia (low HDL and high triglycerides). Additional subgroup analysis showed a trend toward harm in women (but not men) in the fenofibrate group that warrants further investigation in future studies.

a. The Scandinavian Simvastatin Survival Study (4S) (1994) was the first secondary prevention trial to demonstrate a clear reduction in total mortal ity. Simvastatin reduced total mortality among patients with CAD by 30%, largely because of a 42% reduction in deaths from CAD. The 4S treated 4,444 men and women with CAD and mean baseline LDL of 188 mg/dL, with a range of 130 to 266 mg/dL.

b. The randomized, controlled Cholesterol and Recurrent Events Trial (CARE) (1996) was designed to evaluate the effects of treatment with pravastatin on 4,159 persons who had experienced acute MI 3 to 20 months before randomization and had moderately elevated TC levels (mean 209 mg/dL). The benefits of pravastatin therapy in preventing recurrent coronary events were similar in the subset analysis of age, sex, ejection fraction, hyper tension, diabetes mellitus, and smoking.

c. The Long-Term Intervention with Pravastatin in Ischemic Disease Study (LIPID) (1998) was the first to examine the use of a statin for patients with a history of unstable angina. The LIPID study provided new data on non coronary mortality (i.e., stroke) and on other groups, such as women and patients with diabetes, who previously had been underrepresented in clinical trials. LIPID demonstrated improved CAD outcomes among all patients, including those with unstable angina.

d. The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) (1999) was a multicenter study that randomized patients with known CHD and low high-density lipoprotein cholesterol (HDL-C) (≤ 40 mg/dL) and LDL-C (<140 mg/dL) levels to gemfibrozil (1,200 mg/d) or placebo with a mean follow-up of 5.1 years. The study showed that gemfibrozil therapy was associated with a significant 22% reduction in the combined incidence of nonfatal MI and CHD death. This was the first lipid intervention trial to show that raising HDL-C concentrations in patients with CHD and low HDL-C and LDL-C levels will reduce the incidence of major coronary events.

e. Myocardial Ischemia Reduction with Acute Cholesterol Lowering Trial (MIRACL) (2001). This trial demonstrated cardiovascular benefits with ini tiation of early statin therapy following acute coronary syndrome (ACS). The trial randomized 3,086 adults with unstable angina or non—Q-wave MI to high-dose atorvastatin (80 mg/d) or placebo between 24 and 96 hours after hospital admission. There was a reduction in the primary end point of nonfatal infarction, cardiac arrest with resuscitation, or recurrent symptom atic ischemia requiring hospitalization in the atorvastatin group (14.8% vs. 17.4%, RRR of 16%). The benefit was driven primarily by a 26% reduction in recurrent symptomatic ischemia. The trial did not show a mortality ben efit (death, MI, or need for revascularization).

f. Pravastatin or Atorvastatin Evaluation and Infection Therapy—TIMI 22 (PROVE-IT-TIMI-22) (2004). This trial was designed to determine whether intensive lipid-lowering therapy in patients with ACS reduced major coronary events and mortality more than “standard” lipid lowering. A total of 4,162 patients who had been hospitalized for ACS within the preceding 10 days were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d. After 2 years of follow-up, the composite end point (all-cause mortality, MI,
unstable angina, coronary revascularization, and stroke) was significantly reduced by 16% with atorvastatin compared with pravastatin. High-dose atorvastatin was well tolerated, with no cases of rhabdomyolysis. Of note, the LDL-C level attained on atorvastatin 80 mg/d was 33 mg/dL lower than on pravastatin with a mean of 62 mg/dL. These results suggested that the use of intensive lipid-lowering therapy to achieve very low LDL-C levels was of benefit in a group of patients at high risk for recurrent coronary events.

g. A to Z Trial: Phase Z (2004)—Early Intensive vs. a Delayed Conservative Simvastatin Strategy in Patients with Acute Coronary Syndromes (2004). This trial studied whether early initiation of high-dose statin therapy would lead to a reduction in long-term cardiac events compared with a more conservative, delayed low-dose statin strategy in high-risk patients with ACS. The trial enrolled a total of 4,497 patients with a recent ACS, TC level ≤250 mg/dL, and at least one additional risk factor who were randomized to either intensive statin therapy strategy (simvastatin 40 mg for 1 month, followed by 80 mg through 2 years) or a conservative strategy (placebo for 4 months followed by simvastatin 20 mg through 2 years). Although the study showed an early and sustained reduction in LDL in the aggressive strategy arm, it did not show a significant reduction in the primary composite end point of cardiovascular events (cardiovascular death, MI, readmission for ACS, and CVA) or death from any cause compared with a more conservative strategy. There were also more patients who developed creatine kinase (CK) concentrations more than 10 times the upper limit of normal in the aggressive strategy arm (9 vs. 1) and 3 patients who developed rhabdomyolysis while on simvastatin 80 mg.

h. The Treating to New Targets (TNT) (2005) trial sought to demonstrate the benefit of intensive lipid-lowering therapy in patients with stable coronary disease. The trial randomized 10,001 patients with clinically evident CHD and baseline LDL-C levels < 130 mg/dL to atorvastatin 80 mg/d or atorvastatin 10 mg/d. After 4.9 years of follow-up, the group receiving atorvastatin 80 mg/d had a 22% RRR in the primary composite end point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke compared with the group receiving atorvastatin 10 mg/d. High-dose atorvastatin was remarkably safe, with a 1.2% incidence in elevation of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) more than three times the upper limit of normal, compared with a 0.2% incidence in the atorvastatin 10 mg group. Rates of myalgias and rhabdomyolysis were similar between the two groups. This study provided compelling evidence that the use of intensive statin therapy to reduce LDL-C to levels below 100 mg/dL had marked clinical benefit in patients with stable CHD.

i. The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) (2005) trial randomized 8,888 patients with a prior history of acute MI to atorvastatin 80 mg/d or simvastatin 20 mg/d. After 4.8 years of follow-up, there was a nonsignificant difference in the risk of the composite end point of coronary death, acute MI, or cardiac arrest. However, if either stroke or revascularization was added to the primary end point, the results favored the atorvastatin group, and the associated hazard ratios were similar to the results of PROVE-IT and TNT. Despite the published negative result of this trial, it provided complementary evidence for the benefit of intensive LDL lowering in patients at high risk for coronary events.

j. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH) (2011) was a study that compared treatment of extendedrelease niacin versus placebo among statin-treated patients with established heart and vascular disease. The study randomized 3,414 patients with
optimally treated LDL-C and low HDL-C with established vascular disease (documented by coronary angiography or by prior MI, or carotid angiography or prior ischemic stroke, or peripheral arterial disease) to extendedrelease niacin (1,500 to 2,000 mg/d) or placebo. There was no significant difference in the primary composite outcome of CHD death, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary/cerebral revascularization (16.4% in the extended-release niacin group vs. 16.2% in the placebo group). The study was terminated 18 months early after it was evident that the addition of extended-release niacin would not be beneficial. Furthermore, there was a small (numerical) excess in ischemic strokes and hospitalizations for ACS.

a. CTT Collaborators (Lancet, 2005). A large meta-analysis of 90,056 indi viduals from 14 randomized trials of statin drugs, this analysis demonstrated an impressive 12% reduction in all-cause mortality for each 1 mmol/L (39 mg/dL) reduction in LDL. There was a 19% reduction in coronary mortality and 21% reduction in MI, coronary revascularization, and stroke. Statin use showed benefit within the first year of use, but was greater in sub sequent years. Statins were also remarkably safe, with no increase in cancer seen and a 5-year excess risk of rhabdomyolysis of 0.1%.

b. Cannon—Intensive Statin Therapy (J Am Coll Cardiol, 2006). A meta analysis of 27,548 patients from four trials that investigated intensive versus standard lipid-lowering therapy found a significant 16% odds ratio reduc tion in coronary death or MI in the group that received intensive therapy. There was a nonsignificant trend toward decreased cardiovascular mortality.