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March 13, 2006

Antonio M. Gotto, MD, DPhil, Stephen and Suzanne Weiss Dean; Professor of Medicine, Cornell University Joan and Sanford I. Weill Medical College, New York, New York

The changing landscape of cardiovascular (CV) risk prevention suggests that a broader range of patients should be treated. In secondary prevention, the need for aggressive risk-factor management has long been accepted; now, its use in primary prevention is considered appropriate in high-risk patients.

The Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, discussed in more detail later in this report, shows that antihypertensive therapy is the most important step to lower risk of heart disease and stroke. Taking a combination of calcium-channel blockers (CCBs) and an angiotensin-converting enzyme (ACE) inhibitor together significantly reduces the risk of having a stroke or myocardial infarction (MI) and of developing diabetes compared with a beta blocker and a diuretic. By taking a combination of a CCB and an ACE inhibitor together with a statin, the risk of MI and stroke was decreased by more than half.

The Atherosclerosis Risk in Communities (ARIC) study, a prospective epidemiologic study conducted in four United States communities, investigated the causes and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in CV risk factors, medical care, and disease by race, gender, location, and date. It divided risk into quintiles. Low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein A were independent predictors of coronary heart disease (CHD). The lowest incidence of CHD events was in patients in the lowest LDL-cholesterol quintile (<100 mg/dL). LDL-cholesterol, triglycerides, apolipoprotein B, and lipoprotein A were higher, and HDL and apolipoprotein A-I were lower in subjects in whom CHD developed ( P<0.005).

Clinical Trials and CV Risk: Lipid Management

David D. Waters, MD, Maurice Eliaser Distinguished Professor of Medicine, University of California, San Francisco School of Medicine; Chief, Division of Cardiology, San Francisco General Hospital, San Francisco, California

Randomized clinical trials involving >100,000 patients confirm the efficacy of statins in reducing the risk of primary and secondary CHD. However, it was the Scandinavian Simvastatin Survival Study (4S) that started to change thinking about cholesterol lowering. It showed a reduction of about 30% in mortality overall and reduced CV events. Before then, a drug was not available that could reduce LDL-cholesterol over a long period.

Results of the first five landmark trials of statins showed that they reduce CV events in patients with and without CHD. They are safe and well tolerated and do not increase the risk of overall mortality. They also reduce the incidence of stroke. The more recent Heart Protection Study (HPS), which included about 6000 persons with diabetes—the largest number in any statin trial reported—revealed a cardiovascular disease (CVD) event rate for placebo-treated diabetics without CHD of 18.6%, compared with 22.5% for nondiabetics with CHD. Thus, the HPS confirms diabetes as a "coronary equivalent" risk disorder for CVD, as stated by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III. However, risk of CVD may vary from low to very high, depending on age and other risk factors, so the global risk of CVD must be determined for a patient with diabetes when assessing the need to treat with a statin. A key finding was that risk is reduced regardless of baseline LDL.

The Treating to New Targets (TNT) study, with a median follow-up of 4.9 median years, was the first randomized trial to demonstrate benefits of lowering LDL-cholesterol <100 mg/dL in patients with stable CHD. These benefits included a 22% reduced risk of CV events and a 25% reduction in the risk of stroke. Both of these reductions were achieved without significant additional safety risks in the high-dose group. No leveling of the effect of LDL lowering occurred; that is, the LDL-cholesterol level below which benefits on vascular events ceased was not reached.

The Collaborative Atorvastatin Diabetes Study (CARDS) trial was stopped early because of a beneficial effect of atorvastatin. Atorvastatin 10 mg/day reduced the risk of first CVD events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol levels. The authors suggested that there is no justification for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins.

The Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study included patients who were not taking a statin before randomization. With simvastatin treatment, LDL-cholesterol levels were reduced at 1 year by 33% in the simvastatin vs 47% in the atorvastatin group. More modest reductions of 5% and 27%, respectively, were seen in patients who had previously taken a statin. Mean LDL-cholesterol during the trial was 104 mg/dL in the simvastatin group and 81 mg/dL in the atorvastatin group. The effects of the two statins on HDL cholesterol were similar.

The primary composite endpoint of the trial (time to a major coronary event [coronary death, nonfatal MI, or cardiac arrest with resuscitation]) was reduced by 11% with atorvastatin compared with simvastatin. Although the reduction in the primary endpoint was not significant, a significant 17% reduction was seen in nonfatal MI, further supporting lowering LDL levels below currently recommended guidelines.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT-TIMI 22) trial differed from IDEAL and its "sister" clinical trial, Treating to New Targets (TNT), in that PROVE-IT was conducted in patients with acute coronary syndromes (ACS), whereas both IDEAL and TNT enrolled patients with stable CHD. PROVE-IT was a multicenter randomized study designed to compare reductions in CV event rates using "standard" statin therapy (pravastatin 40 mg/day) vs more-intensive therapy (atorvastatin 80 mg/day) to lower LDL-cholesterol to 70 mg/dL. Patients were followed for 2 years.

The overall results of the study found that ACS patients treated with the intensive regimen achieved an LDL-cholesterol level substantially below target levels (median 62 mg/dL) during follow-up and that these reductions translated into a clinically significant benefit. The primary composite endpoint of all-cause mortality, MI, unstable angina requiring hospitalization, or stroke at 2 years occurred in 26.3% of patients with standard therapy vs 22.4% in the intensive-therapy group, for an event risk reduction of 16% in favor of atorvastatin (P=0.005). This benefit was seen as early as 30 days and continued throughout follow-up.

Thus, statin primary- and secondary-prevention trials further support the concept that intensive therapy succeeds in achieving serum LDL-cholesterol levels. PROVE-IT showed that substantially lower levels than the currently recommended level of <100 mg/dL afford greater protection against future CV events.

Clinical Trials and CV Risk: BP Management

Peter S. Sever, MB, PhD, Professor of Clinical Pharmacology and Therapeutics; Director, International Centre for Circulatory Health, Imperial College London; Honorary Consultant Physician, St. Mary’s Hospital, London, UK

Two studies, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), included patients with a high global or calculated risk of CVD. In both of these studies, hypertension was one of the primary factors, but the patients didn't necessarily have hyperlipidemia. Is it beneficial to give a patient at high risk of CVD a statin regardless of what the LDL-cholesterol level is? This was the question that Dr. Sever posed.

The ALLHAT trial compared three antihypertensive regimens, one starting with a diuretic (chlorthalidone), another with an ACE inhibitor (lisinopril), and a third with a calcium channel blocker (CCB) (amlodipine). Drugs were added as needed to achieve target levels. However, The ALLHAT trial protocol called for suboptimal subsequent drug combinations to be used with the ACE inhibitor (lisinopril) and CCB (amlodipine) groups. This put the ACE inhibitor and CCB regimens at a disadvantage in a way that does not reflect routine clinical practice. Nevertheless, the study concluded that diuretics should be first-line antihypertensive therapy for most patients, although patients receiving diuretics had a 43% higher rate of new diabetes vs those receiving an ACE inhibitor and a 17% increase in incidence of diabetes.

In the lipid-lowering arm, ALLHAT patients had a baseline LDL-cholesterol level of 120-189 mg/dL or, if they had CHD, 100-129 mg/dL, and triglyceride levels of <350 mg/dL. The investigators planned for this study to have 20,000 patients in the lipid arm, but enrolled 10,000. They did not change their original event projection that had been based on the 20,000 subjects.

Patients were randomized to open-label pravastatin 20-40 mg/day. If needed, they could add a binding resin. The primary endpoint for the lipid arm of the trial was all-cause mortality.

At the end of follow-up, total cholesterol and LDL-cholesterol were reduced by 20% and 30%, respectively, in the pravastatin group, and by 11% and 16%, respectively, in the usual-care group. Total mortality was similar between the two groups and among all of the subgroups examined. Nonfatal MI and CHD deaths were 9% lower in the pravastatin group compared with usual care, but this difference was not statistically significant. Small, nonsignificant differences were noted in most subgroups except in blacks, in whom nonfatal MI/CHD deaths were 27% lower in the pravastatin group compared with usual care. Overall, the benefit from pravastatin was small due to the small reduction of LDL-cholesterol. The nonsignificant differences in events in ALLHAT, taking into account net cholesterol differences, were proportional to those shown for other major lipid-lowering trials.

The 5-year ASCOT Study was one of the largest hypertension trials ever conducted. It involved >19,000 patients in Europe with hypertension. The trial compared the CV effects of an amlodipine-based regimen vs an atenolol-based regimen in reducing cardiac events in patients with hypertension and multiple CV risk factors. In the amlodipine-based regimen, patients received perindopril and doxazosin as add-on therapy if additional blood pressure (BP) control was needed. Patients receiving atenolol received a diuretic (thiazide) and doxazosin if needed.

ASCOT showed an 11% reduction in total mortality in patients taking the amlodipine-based regimen compared with patients taking the atenolol. Amlodipine also yielded a 23% reduction in fatal and nonfatal strokes and a 24% reduction in CV death compared to patients taking the atenolol. In addition, patients taking the amlodipine-based regimen showed a 10% reduction in the primary endpoint of fatal CHD and nonfatal MI (nonsignificant).

In addition to antihypertensive treatment, 10,000 patients in ASCOT with normal to mildly elevated cholesterol levels—not typical candidates for lipid-lowering treatment—received 10 mg of atorvastatin or placebo to evaluate the CV benefits of lipid-lowering therapy in hypertensive patients. In October 2002, the lipid-lowering arm of ASCOT was stopped early due to a significant benefit in the reduction of MI with atorvastatin.

The key message from ASCOT, Dr. Sever concluded, is that rapid BP reduction is a good strategy for CV risk reduction. The addition of statins in hypertensive patients with only moderately high lipid levels contributed a substantial additional benefit. With the addition of CCBs and ACE inhibitors, CVD risk can be reduced by more than 50%. Contrary to a common perception, the CCB did not increase the risk of heart failure.

Systemic Markers and Clinical Implications of CV Risk Reduction

Christopher P. Cannon, MD, Associate Professor of Medicine, Harvard Medical School, Senior Investigator, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts

The benefits of reducing CVD risk, including stroke, with statin therapy are well documented. However, Dr. Cannon discussed what part of the benefit is related to LDL reduction and what might be explained by pleiotropic effects of statins, in particular the reduction in inflammation in the vasculature.

The A to Z trial enrolled 4497 patients in 41 countries. The patients were randomly assigned to an early intensive statin-treatment strategy (40 mg/day of simvastatin for 30 days and then 80 mg/d of simvastatin thereafter) (n=2265) or to a less-aggressive strategy (placebo for 4 months and then 20 mg/day of simvastatin thereafter) (n=2232). In the placebo + simvastatin group, median LDL-cholesterol levels increased by 11% during the 4-month placebo period, from 111 to 124 mg/dL, and then decreased to 77 mg/dL at month 8 after the initiation of 20 mg of simvastatin (31% change from baseline). In the simvastatin-only group, the median LDL-cholesterol level decreased by 39%, to 68 mg/dL, over the first month of treatment with 40 mg simvastatin and then decreased an additional 6%, to 62 mg/dL, 4 months later. The primary endpoint of CV death, MI, readmission for ACS, and stroke occurred in 343 patients (16.7%) in the placebo + simvastatin group vs 309 (14.4%) in the simvastatin-only group. The findings from the A to Z trial support the strategy of aggressive LDL-cholesterol lowering after ACS to prevent death and major CV events. The investigators stated that statins should be initiated early after ACS.

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study enrolled 3086 patients hospitalized with ACS and cholesterol levels <270 mg/dL (no lower limit for cholesterol was used). They were randomly assigned to placebo or atorvastatin 80 mg/day. A primary endpoint event occurred in 17.4% of patients in the placebo group and 14.8% of patients in the atorvastatin group, for an absolute risk reduction of 2.6% and a relative risk reduction of 16%. The time to first occurrence of a primary event differed between the groups (P=0.048), favoring the treatment arm. After 16 weeks, patients receiving atorvastatin had 34% lower levels of C-reactive protein (CRP). CRP levels fell by 74%, from 11 to 2.9 mg/L, in the placebo group, and 83% from 11.6 to 1.9 mg/L in the atorvastatin group (P<0.0001).

In the PROVE IT study of aggressive vs standard statin therapy, the curves started to separate even earlier, at 3 weeks. With regard to CRP, there was a 1 mg/dL difference at 30 days with intensive therapy. In both MIRACL and PROVE IT, in which CRP was reduced, there was an early clinical benefit with more intensive therapy. In contrast, the A to Z trial did not show an early difference in CRP level and did not show an early clinical benefit.

Researchers have concluded that the reduction of LDL-cholesterol may have influenced chronic processes in the arterial wall and may promote prompt improvement in vascular endothelial function, platelet blood vessel interactions, and vascular inflammation. This suggests that there could be clinical benefits to starting statin therapy early after ACS. He suggests a “dual role” for statins: lowering LDL-cholesterol and lowering CRP. Dr. Cannon further proposes that lower CRP levels may be a “global barometer” of CV risk.