From Benchtop to Bedside: Lipid Lowering Therapy in the Management of Acute Coronary Syndromes

At a symposium held May 22, 2003, during the Annual Meeting of the American Academy of Physician Assistants, a panel of experts discussed the ongoing battle against cardiovascular disease, focusing on current treatment options as well as prevention measures.

This program was supported by an unrestricted educational grant from Bristol-Myers Squibb Company.

Heart Disease in America: The Ongoing Battle

John P. Raymond, PA-C, Northeast Cardiology Associates, Bangor, Maine, began with some statistics about the epidemiology of coronary heart disease, which is the leading cause of death in the United States, claiming over 515,000 lives in 2000.

“Coronary disease starts at a very young age and progresses over time,” said Mr. Raymond, noting that when it starts and how it progresses varies from person to person and that fatty streaks in arteries can show up as early as age 4. If plaque builds up to the point where it is unstable, it can rupture leading to an MI or stroke, depending on which artery is affected.

The well-known risk factors for coronary heart disease are listed in Table 1. Mr. Raymond also reviewed the National Cholesterol Education Program (NCEP) guidelines for cholesterol: total cholesterol should be less than 200 mg/dL; triglycerides less than 150 mg/dL; HDL-C higher than 40 mg/dL; and, most importantly, LDL-C less than 100 mg/dL.

“If you have a patient who’s had an acute MI who has an LDL-C level above 100 mg/dL, the best therapy is an HMG-CoA reductase inhibitor, a statin medication,” said Mr. Raymond. For patients with HDL-C less than 40 mg/dL or triglycerides over 400 mg/dL, the ACC/AHA Practice Guidelines recommend a fibrate medication, such as gemfibrozil or fenofibrate.

In conclusion, Mr. Raymond stated: “You need to identify patients at risk for CHD, address all risk factors, and aggressively treat them.” This will hopefully prevent a cardiac event. “But if they have an event, you have to be even more aggressive about getting them to the goals defined by the NCEP guidelines.”

“Medical advances in the past several decades have led many to believe that invasive therapy with angioplasty or stent is the most effective way to treat ischemic heart disease,” said Robert J. Chilton, DO, Associate Professor of Medicine, University of Texas Health Science Center, San Antonio, Texas.

“However, invasive procedures are extremely costly and it is currently unknown whether invasive treatment prevents coronary events to the same extent as use of more conservative approaches,” said Dr. Chilton. Conservative approaches include lifestyle changes and pharmacologic therapy with aspirin, beta-blockers, statins, and ACE inhibitors, all of which have demonstrated efficacy in reducing the risk of a future coronary event.

Dr. Chilton described one patient from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, which is examining the value of percutaneous coronary intervention in combination with aggressive medical therapy versus intensive medical therapy alone. The patient had a high grade blockage in the left anterior descending coronary artery, which was successfully treated with medical therapy alone.

Atherosclerosis alone doesn’t necessarily lead to strokes and myocardial infarctions, said Dr. Chilton. However if the plaque is unstable, even a partial blockage can rupture and cause an event.

Dr. Chilton explained that the presence of atherosclerosis can cause coronary and carotid artery walls to remodel and thicken, which can make plaque less stable. He also presented data from a study by Fuster in which patients with atherosclerosis and thickened carotid artery walls had their cholesterol lowered with statins. This resulted in regression of atherosclerosis and some shrinking of the thickened artery walls.

“These drugs have powerful endpoints,” said Dr. Chilton, “not just stabilization of plaques, but regression.”

He mentioned different guidelines which recommend cholesterol-lowering medication for prevention. The NCEP Guidelines advise giving statins to men over age 40 with a 20% risk of a cardiovascular event in 10 years and the European Guidelines suggest it for men with a 10% risk in the next 5 years.

Dr. Chilton emphasized the benefit of statins for prevention even in a low risk population. He cited several studies, which showed that “you only have to treat 45 people for roughly 5 years to prevent one cardiovascular event.”

Treatment with statins for secondary prevention produces even more impressive results, he continued. For example, according to the CARE trial, “you’d only have to treat 34 people for about 5 years to save one cardiovascular event.”

Statins can also improve endothelial function, noted Dr. Chilton. They also decrease C-reactive protein (CRP), an inflammatory marker that is a predictor of first heart attack in women.

Dr. Chilton next addressed blood pressure as a risk factor for cardiovascular disease. He referred to new guidelines released by the JNC VII, which now recommend keeping blood pressure below 120/80 mmHg because if pressure goes up to 135/85 mmHg risk for cardiovascular disease doubles and doubles again for every pressure increase of 20 mmHg.

“What is the real target for treating cardiovascular disease? Is it the LDL level, blood pressure, CRP, or something else?” queried Dr. Chilton. “I think they are all a problem,” he continued.

He noted that there are data about statin drugs that show they are good for decreasing all-cause mortality as well as reducing cardiovascular events. In addition, data on ACE inhibitors show that even when the drugs are used in patients with relatively normal blood pressure, cardiovascular events are reduced. And aspirin has also been shown to decrease cardiovascular events for men over age 40.

Diet and exercise are also extremely important, partly because lipids are higher in overweight people and obesity is a major cause of diabetes, which raises risk for cardiovascular disease. According to Dr. Chilton, exercise “brings down blood pressure, decreases stress, decreases inflammation (which is related to CRP), reduces risk for diabetes, decreases lipids, and helps to lose weight.”

Certain foods have also been found to reduce risk for coronary heart disease, including phytochemicals in red wine, olive oil, and vegetables, and omega-3 fatty acids in fish.

Robert S. Rosenson, MD, Director, Associate Professor, Departments of Medicine and Preventive Medicine, Feinberg School of Medicine, North-western University, Chicago, discussed the potential mechanisms of cardioprotection with statin drugs and offered some practical recommendations for their use.

“Several studies of patients with established heart disease have shown consistent benefit of statin drugs,” he said. For example, three studies of patients with LDL-C levels ranging from 131 to 150 mg/dL found that only 28 to 33 patients needed to be treated for 5 years to prevent one cardiovascular event.

“The focus of my presentation is how to stabilize plaques in patients with coronary disease,” said Dr. Rosenson. Regarding atherosclerosis, he noted that “it’s the lesions that are very fatty and contain a lot of inflammatory cells that can lead to unstable plaques that may rupture and cause an acute coronary syndrome. Rupture of the plaque serves as a nidus for thrombus formation that can obstruct the lumen and lead to a heart attack or sudden death.”

The stability of the thrombus will influence whether an acute coronary syndrome will lead to a fatal or non-fatal event. An occlusive thrombus, which occurs when the rupture of the plaque is large and there’s low blood flow or high blood viscosity, can lead to MI or sudden death. A non-occlusive thrombus occurs when the plaque rupture is minimal, there’s high blood flow, and the thrombotic tendencies are low.

Dr. Rosenson continued with a discussion of the mechanisms of cardioprotection with statin drugs, which includes improved endothelial function, reduced inflammation, and decreased platelet-thrombus deposition. “Patients with coronary disease who have the most severe endothelial dysfunction have the worst outcomes over 10 years, and those with the least abnormal endothelial function do the best,” he said.

Statins improve endothelial function by changing coronary vasodilation and coronary blood flow, leading to an improvement in myocardial perfusion. Statins have also been shown to reduce angina and alleviate myocardial ischemia.

Dr. Rosenson presented results of a study by Dupuis of patients following an acute MI or unstable angina and who had LDL-C of 130 mg/dL or higher (Circulation.1999;99:3227-3233). They were randomized to pravastatin (40 mg) or placebo. After 6 weeks, flow-mediated dilation of the brachial artery was markedly improved.

Another study, this one in 768 male patients with stable coronary disease, found that the use of pravastatin reduced the duration of ST segment depression and reduced the number of ischemic episodes (Circulation. 1996;94:1503-1505).

But not all of the studies have shown benefit in endothelial function. In one study, fluvastatin did not significantly reduce ST segment depression, but it did reduce cardiovascular events (Eur Heart J. 2002;23:1931-1937).

He next discussed the effect of statins on inflammation. “Patients with acute MI or unstable angina have more oxidized LDL than patients with stable angina,” he said. In addition, levels of 8-isoprostane, an oxidized form of arachidonic acid, are elevated in patients with unstable angina compared to patients with stable angina.

High levels of oxidized LDL up-regulate chemokines, such as MCP1 and interleukin 8. These cytokines cause T-lymphocytes and mononuclear cells to get into the vessel wall. In addition, higher levels of inflammatory cytokines, such as interleukin-1 and interleukin-6, are found in patients with a complicated course following unstable angina compared to those with an uneventful course. “Interleukin-6 upregulates C-reactive protein, which is synthesized by the
liver,” said Dr. Rosenson.

Given these facts, it would be useful for statins to reduce LDL oxidation and inflammation, Dr. Rosenson remarked. He cited a study by Crisby (Circulation. 2001;103:926-933) in which patients in Sweden who were waiting 3 months to undergo carotid endarterectomy were randomized to pravastatin or usual care. Those taking pravastatin had a reduction in lipids and oxidized LDL, and there were fewer macrophages and T-lymphocytes in their atheroma.

“So, the plaques became more stable, with less inflammation,” said Dr. Rosenson. He noted that this was related to a reduction in metalloproteinases, which are proteolytic enzymes that break down the protective fibrous cap.

He cited the CARE (Circulation. 1998;98:839-844) trial, which showed that patients with inflammation, as measured by CRP and serum amyloid A protein (SAA), have the greatest benefit from statin therapy (pravastatin, 40 mg).

Dr. Rosenson continued with a discussion of the effect of statins on the thrombus. He explained that tissue factor expression by the macrophage is reduced by statin therapy. Statins also affect platelet thrombus formation and reduce levels of plasminogen activator inhibitor. “Unstable plaque has macrophages and T-lymphocytes and oxidized lipids that start the process going,” he said. “The oxidized lipids lead to endothelial dysfunction and inflammation, and can also initiate thrombus formation.”

He next presented data from clinical trials of patients with acute coronary syndromes treated with statins. The Lipid-Coronary Artery Disease (L-CAD) study was an open label trial of patients following acute MI or angioplasty for unstable angina who had LDL-C higher than 130 mg/dL (Am J Cardiol. 2000; 86:1293-1298). They were randomized to pravastatin or conventional care for 2 years. In the lipid-lowering group, there was evidence of regression of stenosis and patients had fewer coronary events. (Figure 1) “You only had to treat about three people to prevent a single event,” said Dr. Rosenson.

The Myocardial Infarction Reduc-tion with Aggressive Cholesterol Lowering (MIRACL) study looked at patients with non-Q-wave infarction or unstable angina who were given atorvastatin (80 mg) or placebo. The average LDL-C was 124 mg/dL, which was reduced 40% in the treatment arm. “After 4 months, there was a 2.6% absolute benefit with atorvastatin, meaning you had to treat only about 37 people to prevent one event,” said Dr. Rosenson.

The benefit was mainly related to a reduction in ischemia, which Dr. Rosenson attributed to the effect of statins on endothelial function, which occurs before some of the other benefits.

In conclusion, Dr. Rosenson stated: “Treatment with a statin immediately after an acute event is feasible, it’s very effective, and it’s safe.”

Evidence-Based Approach to Cardiovascular Disease Prevention: A Case-Based Approach

Dr. Rosenson continued his presentation with a discussion of the following case:

A 46-year- old Caucasian female had an inferior wall myocardial infarction in September 1999. She had a coronary artery stent. She is 5’8” and weighs 228 pounds. Vital signs: blood pressure 146/94 mm Hg; heart rate 86 beats per minute. On admission for her MI, the lipids were: total cholesterol 148 mg/dL, triglycerides 60 mg/dL, LDL-C 91 mg/dL, HDL-C 39 mg/dL.

“Should this patient be placed on a statin?” Even though her LDL-C was below 100 mg/dL, Dr. Rosenson focused on her HDL-C level. “For a woman, every 5 mg/dL decrement below the median value of 55 mg/dL HDL-C increases risk of heart attack by about 25%,” he said, adding that low HDL indicates the possibility of metabolic syndrome.

This patient had three of the five criteria necessary for a diagnosis of metabolic syndrome: central obesity, high blood pressure, and low HDL. “People with metabolic syndrome have insulin resistance, which makes plaque more likely to ulcerate or rupture and makes the thrombus more likely to remain stable,” said Dr. Rosenson.

The patient was put on aspirin, clopidogrel, a beta-blocker, and atorvastatin. In justifying the statin, Dr. Rosenson noted that LDL measured during an MI may be falsely low because inflammation acutely lowers the LDL, known as the acute phase response. He added that studies suggest that all coronary artery disease patients should be placed on a statin.

Despite this treatment, in February 2001, the patient developed unstable angina. The coronary arteriography revealed a left circumflex stenosis of 95%, and it was necessary to place two stents in the left circumflex coronary artery.

While it’s not clear what went wrong in this case, Dr. Rosenson reviewed some of the controversies surrounding the treatment; for example, a possible drug interaction between clopidogrel and atorvastatin. Clopidogrel, which has highly effective antiplatelet activity, is activated by the cytochrome P450 3A4 system. Atorvastatin is an inhibitor of the cytochrome P450 3A4 activation system.

“A small study showed that atorvastatin took away the antiplatelet activity of clopidogrel, whereas pravastatin did not,” said Dr. Rosenson. Further studies have shown that this was caused by changes in cytochrome P450 activation.

“An area that requires further study is whether there is a difference between statins with regard to plaque stability,” said Dr. Rosenson. The more lipophilic the statin the greater the likelihood there will be toxicity to both smooth and skeletal muscle cells, causing them to die through programmed cell death or apoptosis. “This is where hydrophilic agents have a better effect because they don’t enter the smooth or skeletal muscle cell,” he said.

Dr. Rosenson noted that a study called PROVE IT, which is comparing pravastatin to atorvastatin, will address some of these controversies. Results are expected in March 2004.