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Management Evolution in Vulnerable Plaque

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

23rd Annual Cardiovascular Conference at Lake Louise

Lake Louise, Alberta / March 11-15, 2007

Longitudinal population-based studies such as the Framingham Heart Study have identified several “traditional risk factors” for the subsequent development of atherosclerotic vascular disease (ASVD). Progress has been made in the prevention of ASVD through modification of these risk factors, suggested Dr. Todd Anderson, Chief, Division of Cardiology, Libin Cardiovascular Institute, Foothills Medical Centre, and Professor of Medicine, University of Calgary, Alberta. However, the risk status of individuals without symptomatic coronary disease varies greatly and a more intensive level of intervention is required for some individuals, he noted. In addition, a substantial number of patients presenting with myocardial infarction have no identifiable risk factors. Yet effective primary prevention requires a detailed assessment of risk to select patients for appropriate investigation and treatment.

“Much research is underway to identify new predictive biomarkers of atherosclerotic risk,” Dr. Anderson told the audience. “Not only will these biomarkers be useful in identifying patients at increased risk who might benefit from more intense intervention, but they will also advance our understanding of the pathophysiology of atherosclerosis.”

New Imaging Modalities

A variety of imaging modalities are included in this list of potential surrogate outcome measures. The most studied is carotid ultrasound determination of plaque or intima-media thickness (IMT). Increased carotid IMT is associated with established coronary heart disease (CHD) and is a marker of atherosclerosis. Several longitudinal studies and a recent meta-analysis demonstrate a graded relationship with IMT and outcomes. Electron-beam computed tomography (CT) or multi-detector CT has been used to assess coronary calcium scores, whose prognostic utility has been demonstrated. In addition, negative scores have a very high negative predictive value, Dr. Anderson explained. Less studied but of potential use in the future includes 64-slice CT angiography for low-risk symptomatic patients. Its use in screening has not been established. Magnetic resonance imaging (MRI) of plaque vulnerability in the carotid system has been increasingly used for research end points.

Imaging can also be used to assess the physiological state of the endothelium, and recent studies suggest a prognostic importance of endothelial dysfunction, indicated Dr. Anderson.

Evolution of Statin Trials on Vulnerable Plaque

Atherosclerotic cardiovascular disease (CVD) results in more than 19 million deaths annually and CHD accounts for the majority of this toll, pointed out Dr. Christian Constance, Chief, Coronary Care Unit and Catheterization Laboratory, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, adding that recognition of the role of the “vulnerable plaque” has opened new avenues of opportunity in the field of CV medicine. A vulnerable plaque is an atheromatous plaque at high risk of disruption leading to thrombosis.

“It’s important to look for patients with the most vulnerable plaque,” advised Dr. Constance. “Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques.”

Recent clinical trials indicate that aggressive lipid-lowering therapy with statins decreases LDL-C to well below 2.0 mmol/L in high-risk patients and prevents CV events, confirmed Dr. Constance. According to lipid trial data analyzed by the Cholesterol Treatment Trialists Collaborators, each 1.0 mmol/L reduction in LDL-C produces a 21% reduction in vascular events (Baigent et al. Lancet 2005;366:1267-78). This translates into a “huge” reduction in CHD mortality, he stressed. “Statins do work, they do a great job.”

Aggressive lipid lowering is also being explored as a possible means of promoting regression of atherosclerosis and of affording greater protection from atherosclerotic events, he explained. A growing body of evidence indicates that intensive statin therapy, particularly in high-risk patients, slows the rate of progression of atherosclerosis compared with moderate therapy. Reductions of 40% in LDL-C are necessary to achieve atherosclerosis regression, noted Dr. Constance. However, some questions remain regarding the extent of regression achieved with statin therapy and the extent of the relevance of HDL increase.

“Recently developed assays (e.g. C-reactive protein), imaging techniques (e.g. CT and MRI), and emerging catheters (to localize and characterize vulnerable plaque in combination with future genomic and proteomic techniques) will guide us in the search for vulnerable patients,” he stated. “It will also lead us to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death.”

Dr. Constance compared the results of ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) with those from several other intravascular trials (REVERSAL, CAMELOT). ASTEROID was a 24-month study using intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA) to evaluate the effect of rosuvastatin 40 mg q.d. on the regression of coronary artery atheroma in 507 patients with coronary artery disease requiring coronary angiography (Nissen et al. JAMA 2006;295(13):1556-65). Findings revealed significant regression of atherosclerosis as measured by IVUS, a technique in which a tiny ultrasound probe is inserted into the coronary arteries to measure plaque. ASTEROID demonstrated that there exists no apparent threshold LDL-C level beyond which the benefits of statin therapy are no longer evident. If regression of disease is the desired outcome, then lower LDL-C is better.

ASTEROID achieved larger reductions in LDL-C than were seen in the REVERSAL study and HDL levels increased by 14.7%, Dr Constance indicated.

He also referred to a recent trial led by Nicholls et al. (JAMA 2007;297(5):499-508) which found that statin therapy is associated with regression of coronary atherosclerosis when LDL-C is substantially reduced and HDL-C is increased by more than 7.5%. Results indicated that the increase in HDL-C that occurs during statin therapy is clinically relevant when combined with intensive lowering of LDL-C and should also be considered in the selection of therapy and subsequent management of patients with CAD.

Statins are an effective treatment for dyslipidemia, and have been shown to retard progression or promote carotid IMT regression in patients at high risk of CHD. A new large, two-year, primary prevention study, commenced in August 2002, is now evaluating the impact of long-term 40-mg rosuvastatin treatment on carotid IMT progression in 984 low-risk, asymptomatic, hypercholesterolemic individuals with signs of subclinical atherosclerosis.

The results of METEOR (Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin in Subclinical Atherosclerosis) will be presented at the upcoming ACC meeting, Dr. Welsh informed listeners. This randomized, parallel-group study is using B-mode ultrasound to compare the effects of rosuvastatin or placebo for 104 weeks, as determined by thickened carotid artery walls. The primary end point will be the change in carotid IMT in patients receiving rosuvastatin vs. placebo from baseline to study end. Other efficacy end points include changes in the serum lipid profile and C-reactive protein. Safety parameters are also being assessed.

The SHAPE Task Force

As stated by Dr. Robert Welsh, Associate Professor of Medicine, University of Alberta, Edmonton, “There are numerous risk factors for coronary artery disease and numerous means of testing for risk to predict events. We have clinical practice guidelines for screening tests for body mass index, blood pressure [BP], lipid profile, glucose testing, breast examination, Pap smear, colorectal and prostate-specific antigen/digital rectal examination tests. However, in contrast, we have no screening test to try to prevent coronary artery disease, the highest cause of death.”

The Screening for Heart Attack Prevention and Education (SHAPE) task force has issued controversial “guidelines” recommending blanket screening for subclinical atherosclerosis, Dr. Welsh told the audience. SHAPE has brought attention to the fact that although CVD accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic atherosclerosis.

The move is to address individual as well as population health risk and to identify both low-risk and high-risk individuals, he explained, adding that you can predict risk in the majority of adults. Only 5 to 10% of the population is deemed very low-risk, everyone else is considered to have atherosclerosis. “Atherosclerosis is a disease we all have,” he remarked. “The question is, what do you do about it?”

Current CV guidelines in primary prevention recommend initial assessment and risk stratification based on traditional risk factors followed by goal-directed therapy. This approach identifies persons at very low or very high risk of a CV event within the next 10 years. However, the majority of the population belongs to an intermediate risk group in which the predictive power of risk factors is low, suggested SHAPE task force members. “The time has come to replace traditional risk assessment in primary prevention with an approach largely based on non-invasive screening for the disease itself (subclinical atherosclerosis).”

The task force proposed that all apparently healthy men 45 to 75 years of age with no history of CHD and considered not to be at very low risk undergo screening for atherosclerosis. Following non-invasive screening with CT-based coronary artery calcium score and ultrasound-based carotid IMT, the patient’s risk is reclassified and appropriate advice for lifestyle modification and medical treatment delivered.

Dr. Welsh commented, “Although the SHAPE task force guidelines provide a novel approach to reducing the burden of CVD and potentially reducing the current epidemic, they have been developed by an interest group without a standard ‘guideline’ process and have no randomized evidence that they will modulate physician or patient behaviour.”

Risk Stratification and Medical Therapy

According to Dr. James Stone, Clinical Associate Professor of Medicine, University of Calgary, the drivers of atherosclerosis are still the “gang of four: diabetes, dyslipidemia, hypertension and smoking. The fewer the atherosclerotic drivers, the better the outcomes,” he confirmed. Physicians should still recommend lifestyle changes (including smoking cessation, weight loss and its management, and exercise) and behavioural modification, as these are extremely important to reduce risk factors, he stressed.

“You can see that we have a huge challenge ahead of us as LDL target levels get lower and lower,” he noted. “In Canada, we’re agreed upon the importance [for patients] to know their vascular risk and that comes down to risk stratification goals. All individuals should know their vascular risk. It’s important to know your vascular treatment targets in terms of BP, cholesterol, physical activity and smoking cessation and to know how to actually get to those treatment targets.”

Adherence to medical therapy is vital, pointed out Dr. Stone, citing evidence that patient adherence is linked to lower mortality.

“Medication adherence works and medication adherence matters,” he confirmed. Quality of care is also critical. Cardiac rehabilitation research has shown a “huge” difference in outcomes between maximal care and poor care over five years, he reported.

Aggressive Medical Therapy vs. Interventional Therapy

Dr. Robert Roberts, President and CEO, University of Ottawa Heart Institute, Ontario, and Dr. Vladimir Dzavik, Associate Professor of Medicine, University of Toronto, Ontario, debated the value of aggressive medical therapy vs. interventional therapy.

Atherosclerosis is pandemic, stated Dr. Roberts, adding that the time has come to use the medical therapies available to prevent heart disease and to treat aggressively because “with medical therapies, the earlier you get there, the better it will be.” Statin therapies have outstanding benefits and are very safe, he suggested, pointing out that very few therapies, other than vaccines, have offered such high benefits with a low adverse-event profile. “If you want to treat this disease and prevent coronary events… you now have a drug that’s been proven, that’s been given to millions of people with very few side effects.”

Numerous trials indicate that percutaneous coronary intervention (PCI) is more effective than medical therapy for high-risk unstable patients to improve physical functioning and quality of life, stated Dr. Dzavik.

Dr. Roberts and Dr. Dzavik concluded that PCI and medical therapies are complementary, not competing therapies.

Summary

Atherosclerosis, the main cause of coronary artery disease, has become a global epidemic. In determining the risk of a given patient, it is important to remember that, whether a patient has obvious atherosclerosis or not, in our society today, the development of atherosclerosis accompanies aging in all people. Lifestyle modification is extremely important in high-risk individuals to lower CHD risk. ASA and statins remain the cornerstone of medical therapies to modulate CV risk. The benefits of lowering LDL-C with statins are well proven. New clinical trials assessing their impact on vulnerable plaque have shown that statins are an effective treatment for dyslipidemia and retard progression or promote carotid IMT regression in patients at high risk of CHD. The ASTEROID study, for instance, found that there is a strong correlation between LDL-C reduction and reduction in atheroma volume. Cardiology experts stressed here that it is always critical to choose the right tool for the task. Today there are many tools, including novel imaging technologies, for cardiologists to choose from when attempting to measure vulnerable plaque more precisely.

They also acknowledged that while the evidence for lowering LDL-C is extremely robust, more research is needed to determine the importance of raising HDL-C.

As suggested by Dr. Jacques Genest Jr., Professor of Medicine, McGill University, Montreal, increasing HDL is more widely recognized as important but is less well studied than lowering LDL-C.

“There’s more research these days on HDL,” revealed Dr. Anderson. “Now that we’ve lowered LDL about as much as we can, we’d like to see if we add HDL-raising medications on top on that whether that will make a difference or not. We’re just exploring that realm. We’ll proceed with further research.”

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