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Controlling LDL and Atherosclerosis: Corroborative Evidence

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.

56th Annual Scientific Sessions of the American College of Cardiology

New Orleans, Louisiana / March 25-28, 2007

In patients with established coronary artery disease (CAD), many experts now believe that the LDL goal should be <1.8 mmol/L, based on evidence that this is associated with greater protection from events than <2.5 mmol/L, as currently recommended by the third Adult Treatment Panel (ATP III) guidelines (the goal of <1.8 mmol/L is characterized as optional). In asymptomatic patients with risk factors but no CAD, the current goal is <3.3 mmol/L, but atherosclerosis is progressive, starting years or even decades before symptoms. Intensive treatment relatively early in the process may offer the opportunity to prevent the disease from ever progressing to a degree at which plaque rupture precipitates thrombotic events, such as a myocardial infarction or a stroke. A new trial of very early use of a highly efficacious statin for lipid-lowering therapy supports that premise.

METEOR Findings

Lipid lowering with rosuvastatin in this multicentre, placebo-controlled study “basically halted the progression” that was observed in the placebo population over the two years of the study, reported Dr. John R. Crouse III, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Senior author of the trial called METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin), Dr. Crouse reported that the findings build on the previous evidence that LDL reductions protect against progression of atherosclerosis, but they extend this protection to patients “with low Framingham scores, evidence of subclinical carotid atherosclerosis, and only modestly elevated lipid concentrations.”

Although Dr. Crouse recommended a large trial that employs clinical end points to test the clinical implications of these findings, he reported that METEOR confirms that intensive LDL lowering alters the natural history of atherosclerosis even at early stages of disease. Specifically, these data suggest that the disease process can be controlled anywhere along the continuum that leads from a mild atherosclerotic burden to thrombotic events. While the dictum “lower is better” has been applied to LDL in patients at high risk, METEOR suggests that it may also pertain to patients with low to moderate risk. In the rosuvastatin group, the average LDL on treatment in the METEOR trial was 2.0 mmol/L. This is a 49% reduction from baseline and similar to that increasingly being recommended in high-risk patients.

Individuals were recruited from an asymptomatic population with no previously known evidence of atherosclerosis. For entry, men between the ages of 45 to 70 years and women between the ages of 55 and 70 years were required to have less than a 10% risk for a cardiovascular (CV) event on the basis of the Framingham risk score and to have a carotid intima medial thickness (CIMT) between 1.2 and 3.5 mm on B-mode ultrasound. Of the 5751 participants screened, 984 individuals with a mean age of 57 were entered. Many of those excluded exceeded the prespecified risk level of atherosclerotic burden.

The primary outcome was rate of change in maximum CIMT for 12 carotid sites as measured with B-mode ultrasound over two years (Figure 1). Changes in CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites as well as in mean CIMT of the common carotid artery sites were also monitored. At the end of the study, there was a 0.0014 mm/year regression in the maximum CIMT for the 12 carotid artery sites in the rosuvastatin group compared to a 0.0131 mm/year progression in the placebo group (P<0.001). The maximum change in the common carotid artery sites and the carotid bulb sites also demonstrated a reduction on rosuvastatin vs. progression on placebo (P<0.001). Although none of the regression on rosuvastatin was significant relative to baseline, the difference in all CIMT measurements significantly favoured active treatment over placebo.

“Results were robust for the rosuvastatin group, and differences between the two groups were consistent across all prespecified subgroups,” Dr. Crouse told listeneres, listing subgroup stratifications as those by age, gender, race, body mass index, and risk factors. Sensitivity analyses also were highly supportive of a significant advantage for active therapy.

Figure 1. Change in Maximum CIMT (primary end point)


Asked to comment about these results, Dr. Robert Roberts, President and Chief Scientific Officer, University of Ottawa Heart Institute, Ontario, remarked that METEOR “really makes us think more actively about what we can do for prevention.” While cardiologists have typically concentrated on prolonging life in patients who have already had an event or are at very high risk of an event, “these data tell us that we can modify the disease process at an early stage.” A preventive approach is important because the first cardiovascular event may be terminal or produce sufficient damage to the heart or brain to prevent full recovery. “About half of men and more than half of women who die suddenly of coronary heart disease had no previous symptoms. Well over half of all CV events in men occur in those with one or fewer major modifiable risk factors,” Dr. Roberts observed. “We also know that the majority of individuals who live past 50 will develop coronary heart disease, so thinking about earlier control of the underlying disease process is something we need to be looking at.”

Atherosclerosis Inhibition

The METEOR study is the latest in a series of studies that have assessed intensive lipid lowering for control of atherosclerosis. Until recently, the majority of these trials, employing a variety of statins, have demonstrated slowing of atherosclerosis but have been unable to demonstrate a halt in progression or to achieve regression. Of the three studies that have successfully associated LDL reductions with prevention of further progression of atherosclerosis, allthree achieved LDL levels near or below 2.0 mmol/L. In addition to METEOR, these studies include REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering), which associated atorvastatin 80 mg with attenuation of progression over 18 months of treatment in high risk patients (Nissen et al. JAMA 2004;291:1071-80) and ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden), which associated rosuvastatin 40 mg with regression (Nissen et al. JAMA 2006;295:556-65). So far, ASTEROID has been unique in demonstrating actual regression of atherosclerosis. As in REVERSAL, in ASTEROID the atherosclerotic burden was measured at baseline and at study end with intravascular ultrasound (IVUS), a highly sensitive tool for measuring atheroma volume in the wall of the coronary arteries. After 24 months of treatment with rosuvastatin 40 mg in 349 patients, there was a 6.8% median reduction in total atheroma volume from baseline (P<0.001) with even greater reductions in the most diseased coronary artery segments. The mean levels of LDL were reduced from 3.3 mmol/L to 1.5 mmol/L, a 53.2% reduction. HDL was increased by 14.7%. “I think reductions in LDL are very important, but I also think that HDL is another factor, and that fairly nice rise in HDL in ASTEROID may have made a difference,” observed Dr. Steven Nissen, Outgoing President, American College of Cardiology, and Chairman, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Ohio. Although statistically significant regression was not observed over the 24 months of the METEOR study, the patient population did not have established coronary artery disease or advanced atherosclerosis at baseline, providing less opportunity to show a reduction. However, Dr. Crouse emphasized that the results of METEOR are consistent with ASTEROID in demonstrating that the process of atherosclerosis can be halted if sufficient reductions in LDL are achieved.

Identifying the Risks Before Symptom Onset

The evidence that progression can be halted even at relatively early stages of disease has major implications for managing risk in those patients at greatest likelihood of progressing to CAD, such as patients with a strong family history. Although Dr. Crouse cautioned that METEOR was not designed to provide guidance for routine therapy of asymptomatic patients, several commentators suggested that it reinforces a growing interest in being more aggressive in their management of patients at greatest risk. “Starting with the published guidelines makes a lot of sense, but you need to consider the whole patient and to interpret risk. Often the guidelines do not lead you to an accurate picture,” cautioned Dr. Christie M. Ballantyne, Center for Cardiovascular Disease Prevention, Baylor College of Medicine, Houston, Texas. He observed that he is often confronted with a middle-aged adult who scores relatively low on standard risk assessments even though he sees other risk characteristics that concern him. One example is a 50-year-old who does not smoke, has only mild hypertension and unremarkable blood lipid values. This patient may score low on standardized risk assessments but if he has an elevated body mass index and a strong family history of CV disease, Dr. Ballantyne sees reason for concern. “The Framingham risk score does not include family history, and this is an important predictor of risk. In a patient like this, I would be concerned. I would want to consider further diagnostic tests, and I would be inclined to initiate lipid-lowering therapy if I had any clue that something was going on,” stated Dr. Ballantyne, suggesting that such a patient might be a candidate for electron beam computed tomography or another tool to identify subclinical disease. He was not alone in this assessment. Reviewing a similar case, Dr. Nissen suggested that guidelines often miss patients who are clearly on a trajectory toward symptomatic CV disease. In an individual with several of the characteristics of an impending metabolic syndrome, such as an abnormal waist-to-hip ratio and impaired fasting glucose, he would also think of early intervention. While also emphasizing that family history is a strong impetus to consider a more aggressive approach in patients without sufficient risk factors to meet guidelines for treatment, he stated, “prevention is at the core of what we do. We have to be thinking about how we are going to prevent rather than treat CV disease.” Dr. Roberts, who has a major research interest in the genetics of CV disease, also considers family history a strong signal to think about intensive lipid lowering at an early stage. He indicated that such trials as METEOR have the potential to change thinking about when to intervene, suggesting that “lower is better” for LDL at any level of elevated CV risk. Strategies

It is not yet established that preventing progression of atherosclerosis is the goal in lipid management, particularly in primary prevention, but such a goal will require intensive therapy. To reach LDL levels near 2.0 mmol/L, many patients will require a reduction of 50% or more from their pretreatment level. According to Dr. Ballantyne, the only choices for achieving a LDL reduction of 50% or greater with a single statin are atorvastatin 80 mg or rosuvastatin 20 mg, although some of the more moderate statins may achieve this degree of LDL lowering at their highest doses if combined with ezetimibe 10 mg (Ballantyne et al. Am J Cardiol 2007; in press). In patients who require even greater LDL reductions, Dr. Ballantyne reported that rosuvastatin plus ezetimibe has provided LDL reductions exceeding 70%, which is the greatest he has yet observed with pharmacologic therapy. Although one concern with high-dose statins has been myalgias, this risk does not appear to be related to LDL lowering. In METEOR, the incidence of myalgias was 12.7% on rosuvastatin and 12.1% on placebo, a non-significant difference despite an on-treatment LDL level that was approximately half as great as the one in the active treatment group. Arthralgias were reported in 10.1% of rosuvastatin patients vs. 7.1% of those on placebo. Musculoskeletal stiffness and muscular weakness occurred infrequently in either arm with a numerical but non-significant advantage for rosuvastatin. According to Dr. Michael H. Davidson, Director, Preventive Cardiology Center, Rush University Medical Center, Chicago, Illinois, these findings are consistent with a trial that evaluated myalgia on rosuvastatin in patients who had discontinued another therapy due to this or another side effect. After a median treatment duration of 44 weeks, only one of 61 patients switched to rosuvastatin 10 mg developed muscle pain (Glueck et al. Clin Ther 2006; 28:933-42). “Statins are as safe as [ASA] and at least as beneficial, if not more so, in reducing CV risk,” in the opinion of Dr. Davidson. Expressing concern that physicians are not using these agents intensively enough and that patients have not been sufficiently reassured of their safety, he emphasized that more has to be done to encourage adequate therapy and improve compliance. He estimated that failure to prescribe and maintain patients on optimal levels of statin therapy is a substantial source of avoidable morbidity and mortality. “For one million people with elevated cholesterol, statins will reduce 10,000 CV events but only one or two patients will develop serious life-threatening side effects,” Dr. Davidson told listeners. He indicated that the new trial data, while reinforcing the safety of these agents, is increasing the proportion of patients who should be considered for treatment.

Summary

The placebo-controlled METEOR trial, which demonstrated that the progression of atherosclerosis can be halted even in asymptomatic patients with a relatively low 10-year risk of CV events, has confirmed the critical role played by LDL lowering in altering the natural history of this disease. The study reinforces similar protection against atherosclerosis in patients with established coronary artery disease and confirms that LDL levels of near 2.0 mmol/L are needed to prevent progression. Although an events trial is needed to confirm that this halt in progression reduces risk of CV events in an asymptomatic population, it reinforces a role of providing intensive LDL lowering in those individuals who are candidates for this form of risk reduction.

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