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

Toronto, Ontario / October 25-29, 2008

In a well-attended early-morning session chaired by Canadian lipid expert Dr. Jacques Genest Jr., Director, Division of Cardiology, MUHC-Royal Victoria Hospital, Montreal, Quebec, delegates had the opportunity to learn about what makes an atherosclerotic plaque vulnerable; whether those most at risk of plaque rupture and subsequent thrombosis can be better identified with risk stratification strategies other than the Framingham risk score; and the importance of high-sensitivity C-reactive protein (hsCRP) as a risk stratification strategy to predict outcomes.

As discussed by Dr. Subodh Verma, Associate Professor of Surgery, University of Toronto, Ontario, plaques prone to rupture have a large lipid core and undergo aberrant remodelling. Growing within the arterial wall (not the lumen), plaques also have a small fibrous cap containing smooth muscle cells and activated macrophages. Importantly from an imaging standpoint, the majority of these rupture-prone plaques occur in patients with less than 50% stenosis on coronary angiography. Thus most myocardial infarctions (MIs) occur in patients who do not have hemodynamically compromising stenosis, as Dr. Verma indicated—suggesting that the morphology, composition and degree of inflammation is likely much more important than absolute plaque burden in determining clinical outcomes.

The hsCRP Factor

As it turns out, hsCRP, a marker of inflammation, may be pro-atherothrombotic via diverse local effects on vascular repair and regeneration. hsCRP also appears to participate in lesion progression, again through a variety of mechanisms. “Thus, hsCRP blockade may offer unique benefits in terms of moving forward [towards cardiovascular disease (CVD) prevention],” Dr. Verma suggested. Certainly, there is ample evidence to support the relationship between elevated hsCRP levels and CV risk.

As discussed by Dr. Paul Ridker, Eugene Braunwald Professor of Medicine, Harvard Medical School, Boston, Massachusetts, guidelines have long advocated the use of statins to reduce MI and stroke risk in patients with established vascular disease, diabetes or those with overt hyperlipidemia. However, “half of all heart attacks and strokes occur among apparently healthy men and women with levels of LDL-C that are below currently recommended treatment guidelines,” as Dr. Ridker observed. Moreover, more than 70% of all vascular events occur among patients deemed to be at “intermediate” risk, for whom the guidelines again offer little guidance. Clearly, other factors contribute to the burden of CV morbidity and mortality, among them inflammation.

If, as Dr. Ridker argued, atherosclerosis is an inflammatory disease, “why only treat hyperlipidemia?” As one of the investigators responsible for much of the seminal findings on hsCRP, Dr. Ridker has repeatedly shown that hsCRP predicts CV risk. In one of many studies, for example, he showed that hsCRP was a better predictor than LDL-C levels for a woman’s first CV event in women with LDL-C levels below 3.36 mmol/L (130 mg/dL).

Moreover, LDL-C levels and hsCRP levels are unrelated, “so you cannot predict your patients’ hsCRP levels on the basis of their LDL-C level and you can’t predict their hsCRP response to a statin on the basis of their LDL-C response to a statin, either,” Dr. Ridker observed.

It is also important for physicians to recognize that getting patients to both LDL-C and hsCRP targets is crucial to optimizing outcomes, at least in high-risk patients, as Dr. Ridker noted. One example is the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) study conducted in patients with acute coronary syndrome. In this study, patients who had low hsCRP levels (<2 mg/L) after statin therapy had better clinical outcomes than those with higher hsCRP levels (>2 mg/L), regardless of the resultant level of LDL-C. Event rates were lowest among those whose LDL-C were under 1.81 mmol/L (70 mg/dL) and whose hsCRP were under 2 mg/L. “So if you got to both targets, you did very well,” Dr. Ridker observed. Strategies to lower CV risk with statins should include monitoring hsCRP as well as cholesterol. However, only 44% of patients in PROVE IT-TIMI 22 who received atorvastatin 80 mg achieved both target levels and fewer still on pravastatin 40 mg.

JUPITER Trial

This is why investigators chose rosuvastatin, a highly effective statin available for both LDL-C and hsCRP reduction, when they designed JUPITER (Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). It tested the novel hypothesis that treating apparently healthy men and women with LDL-C levels below current treatment thresholds of <3.36 mmol/L but who have high levels of hsCRP (>2 mg/L) would reduce their risk of hard clinical end points including first MI, stroke, CV death or hospitalization for revascularization procedures. Over 17,000 men and women—among whom a sizeable number of minority groups were also included—were randomized to rosuvastatin 20 mg/day or placebo for out to the year 2011.

However, at the end of March 2008, the Data Safety Monitoring Board stopped the trial due to a clear difference in treatment arms. “Thus, we already know rosuvastatin prevents first-ever CV events among those with an LDL-C of <3.36 mmol/L because that answer is in the public domain,” Dr. Ridker stated.

Several questions remain unanswered, at least until final results are revealed at the American Heart Association meeting in November. Among these is what the relative risk reduction in favour of rosuvastatin will be. “The trial is very large,” as Dr. Ridker remarked, “so we have to be cautious of the fact that the relative risk reduction could still be significant even if it is only modest.”

Nor can they yet determine if inhibiting inflammation is more important, equally important or less important than inhibition of LDL-C, or whether it is safe to reduce LDL-C to <1.30 mmol/L (50 mg/dL), as they expect approximately half of the cohort to achieve, given that rosuvastatin lowers LDL-C by about 50%.

“JUPITER is in no way challenging the LDL-C hypothesis,” Dr. Ridker stressed. “What JUPITER is saying is that we need to think about something in addition to LDL-C.” Dr. Ridker reported that he and others have previously shown that statin therapy reduces hsCRP levels. Among high-risk patients, the magnitude of benefit associated with statin therapy correlated in part with the achieved hsCRP levels. To date, however, no prospective outcome trial has directly addressed the question of whether apparently healthy individuals with levels of LDL-C below current treatment thresholds but with elevated levels of hsCRP might benefit from therapy.

Imaging Tools

A number of imaging tools have been used to better quantify atheroma burden and enhance CV risk assessment, among them, intravascular ultrasound (IVUS). As Dr. Eva Lonn, Professor of Medicine and Cardiology, McMaster University, Hamilton, Ontario, IVUS has “tremendous promise” by providing high-resolution cross-sectional images of the arterial wall. IVUS also depicts the extent of atheroma better than angiography and it does provide some data on plaque characterization and remodelling. Yet it remains an invasive technique and data correlating IVUS findings with clinical outcomes are still limited.

Carotid intima medial thickness (IMT) in turn has the advantage of being non-invasive and patients can be serially monitored for atherosclerosis progression over time. Epidemiological studies also suggest the higher the IMT measurements, the greater the risk of MI and stroke. On the other hand, in a well-treated patient population, changes in carotid IMT may be insignificant and may not contribute sufficiently to prognostic information.

Prevention: The Hardest Job in Medicine

As a world expert in preventive cardiology, Dr. Marc Pfeffer, Dzau Professor of Medicine, Brigham & Women’s Hospital, Boston, reminded delegates, it would be pointless to screen patients for the presence of abnormalities if no treatment exists to reverse them and, more importantly, prevent their consequences. Yet if a good treatment does emerge and is proven to save lives, then physicians need to at least consider using it.

“Prevention is the hardest thing we do but it’s the most important thing we do,” he stated. “You have to be convinced you are doing the right thing [when you introduce a new therapy] and you have to be a good enough physician to convince your patient to do the right thing for themselves.”