Reports

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.

Canadian Cardiovascular Congress 2007

Quebec City, Quebec / October 20-24, 2007

Cardiovascular disease (CVD) is largely silent prior to the first clinical event, many of which are fatal. One study found that 75% of those with a first myocardial infarction (MI) would not have qualified for lipid or blood pressure (BP)-lowering treatments prior to the event. This suggests that current risk stratifications are not sufficiently sensitive and that many patients are not receiving treatment that might be effective for preventing thrombotic events. New imaging strategies, such as intravascular ultrasound (IVUS), are proving effective for better identifying vulnerable patients while also demonstrating that aggressive lipid lowering, now reserved for the highest-risk patients, may reverse disease processes and may be appropriate at earlier stages. However, the first step is finding those patients who are at risk but are being missed by current methods of evaluation.

Revisiting Risk Scoring Systems

“Although the Framingham risk score remains a reasonable starting point for CV risk stratification, this strategy may underestimate risk in certain populations. The availability of new imaging techniques has created considerable excitement about how these might be employed as screening tools,” observed Dr. Milan Gupta, Division of Cardiovascular Surgery, St. Michael’s Hospital, Toronto, Ontario. He indicated that direct evidence of pathology, such as coronary plaque burden, intima media thickness (IMT) in the carotid artery and endothelial dysfunction, may all be useful to better stratify patients, particularly when other risk assessments are ambiguous.

A limitation with risk scoring systems is that they are very accurate for population screening but less accurate in the individual. Specific problems with the Framingham risk score include the fact that it was designed primarily to predict coronary events rather than all vascular complications, such as stroke, and that the data on which the scoring is based were primarily drawn from a Caucasian population. Data from Canadian populations suggest that Framingham is likely to underestimate risk in individuals with ethnic roots in Southeast Asia and overestimate risk in patients of Chinese heritage. However, all population-based methodology may be relatively insensitive to identifying vulnerable plaques in the individual. This has been the basis for interest in IVUS.

“More than 50% of all CV events occur in patients who would be characterized as having intermediate risk in most classification systems,” observed Dr. Khurram Nasir, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston. “What we are seeking now is better methods to identify the patient with plaques vulnerable to rupture.”

Mixed Patient Populations

The reason to focus on better risk stratification is that there are treatments with the potential to dramatically slow CVD progression or even reverse the process. The culmination of this evidence was the ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) study. While previous studies, such as REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering), were able to demonstrate that LDL levels of <2.0 mmol/L could halt growth of atherosclerosis, ASTEROID demonstrated that even lower lipid lowering with rosuvastatin, an effective LDL-lowering agent, produces regression. While this study was conducted in high-risk patients, a more recent trial called METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) showed similar results by measuring carotid artery IMT (CIMT) in intermediate-risk patients.

“The METEOR population was low-risk and asymptomatic with only early signs of atherosclerosis,” explained Dr. Jean-Claude Tardif, Director, Montreal Heart Institute Research Centre, Quebec. Specifically, patients had enrolled with a 10-year Framingham risk of <10% and only mildly increased CIMT (<3.5 mm). The 984 participants were randomized in a 5:2 ratio to 40 mg rosuvastatin or placebo and then followed with B-mode ultrasound. “At the end of two years, there was progression on placebo that was completely stopped with the lipid-lowering therapy,” he reported.

In the use of potent therapies for lipid lowering, there is increasing evidence that some of the benefit may be derived from anti-inflammatory effects. Although this mechanism may also be relevant in low-risk patients, the most important test of this potential effect is the soon-to-be-completed CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure). In this randomized, double-blind, placebo-controlled study, 5011 patients with chronic heart failure with an ischemic etiology have been randomized to 10 mg rosuvastatin or placebo. The primary outcome is a composite of CV morbidity and mortality outcomes. Results will be presented at the 2007 annual meeting of the American Heart Association.

“This is an important study addressing an unanswered question,” reported Dr. Christopher Granger, Director, Cardiac Care Unit, Duke University Medical Center, Durham, North Carolina. He indicated that this group might particularly benefit from the purported contribution of an anti-inflammatory effect to improvement in vascular function.

RAS Inhibition

An anti-inflammatory effect from aggressive lipid lowering, if confirmed, is an example of the effort to treat the underlying disease process rather than the risk factor alone. Another example has been the use of renin angiotensin system (RAS) inhibitors. As lead investigator of one of the landmark CHARM (Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity) trials (CHARM-Added), Dr. Granger noted that RAS inhibitors have multiple benefits independent of their effect on BP. In patients with heart failure, for example, they have been associated with protection from progressive remodelling, a benefit that has translated into major reductions in CV events in multiple trials, including CHARM. In CHARM-Added, which randomized patients already on an ACE inhibitor to candesartan, there was additional benefit for dual RAS blockade.

“The addition of candesartan decreased the primary outcome of CV death or hospitalization for heart failure by 15% (P=0.011) even on top of full-dose ACE inhibition,” Dr. Granger reported. Again, the added benefit was not attributed to additional antihypertensive effect. Rather, candesartan appeared to contribute to control of the disease process.

The same appears to be true even at the earliest stages of disease. In TROPHY (Trial of Preventing Hypertension), which randomized 809 participants with high normal BP (mean 134+/-4/85+/-4 mm Hg ) to candesartan or placebo, there was a 66.3% (P<0.001) reduction in the risk of hypertension (>140/90 mm Hg) at the end of four years.

Although treating pre-hypertension is not a standard of care due to concerns about healthcare costs, it underscores the potential for early identification of patients at risk to permit early initiation of treatment to halt disease processes. While RAS inhibitors are associated with BP-independent benefits after MI, in chronic kidney disease and in heart failure, use of these agents has also been associated with a reduction in new-onset diabetes. Although unproven, such associations suggest that angiotensin receptor blockers used for BP control in patients with essential hypertension may protect against end-organ processes, such as left ventricular hypertrophy and proteinuria, from developing. Better stratification of risk may help place vulnerable patients on lipid lowering and BP control.

Summary

The majority of CV events occur in patients at intermediate risk based on conventional risk scoring systems, such as the Framingham risk score. New approaches to identifying the vulnerable patient, including more sensitive stratification methodology and sophisticated imaging, have been proposed in order to initiate treatments early when disease can be halted or reversed. This includes initiation of lipid-lowering medications and antihypertensive drugs that appear to provide target-organ protection. Clinical studies suggest that it is now possible to treat beyond risk factors to control the underlying disease processes.

Based on the CCS/CCC-sanctioned sessions:

“The CV Show: Expert Insights into the Management of Cardiovascular Risk in the Vulnerable Patient,” Sunday, October 21, 7:00-10:00, Room 200B.

CCC #859. M Costa-Scharplatz, B Beamer, T Frial, SK Gandhi. Cost-effectiveness of commonly used statins in the management of dyslipidemia: A Canadian system perspective. Tuesday, October 23, 12:30-15:30, Community Forum.