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PRIORITY PRESS - Canadian Cardiovascular Congress 2009

Edmonton, Alberta / October 24-28, 2009

The newly issued 2009 Canadian Cardiovascular Society guidelines for the treatment of dyslipidemia (Genest et al. Can J Cardiol 2009;25:567-79) are both simpler and more rigorous than the previous recommendations. Intermediate-risk patients have been folded into the high-risk category because of compelling evidence of clinical benefit from achieving the same treatment goals. The guidelines identify high-sensitivity C-reactive protein (hsCRP) as a useful risk marker in intermediat-risk patients, suggesting inflammation is part of the pathophysiological process.

Vulnerable Plaque

One issue raised by inflammatory markers such as hsCRP is whether these will identify patients with atherosclerotic plaques vulnerable to rupture.

“Finding biological markers for plaque vulnerability has become a huge industry with a number of novel markers being evaluated,” stated Dr. G.B. John Mancini, Division of Cardiology, University of British Columbia, Vancouver. He noted that angiography is not effective for identifying the presence of these lesions. Although there are a variety of innovative imaging techniques that do show promise, the expense and the difficulty of scanning the vascular tree makes biological markers far more attractive.

The vulnerable plaque is characterized by a large lipid core and a thin fibrous cap that makes it susceptible to destabilizing factors, including inflammatory cytokines. When the plaque ruptures, it exposes the contents to the bloodstream to induce a cascade of events that leads rapidly to thrombus formation. This is now thought to be a major source of vascular events. In the past, the main benefit of lipid lowering was attributed to halting the growth of atherosclerosis, but the ability of lipid lowering to stabilize the plaque and reduce circulation of pro-inflammatory factors may also be important for immediate reductions in vascular risk.

JUPITER Findings

The best evidence of the potential importance of an anti-inflammatory effect from lipid lowering was generated by the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), which was cited in the new Canadian guidelines. In this multinational study, otherwise healthy adults (men over age 50, women over age 60) with LDL levels <3.4 mmol/L but hsCRP levels >2.0 mg/L were randomized to rosuvastatin 20 mg q.d. or placebo. At the end of a median of 1.9 years when the study was stopped early because of overwhelming benefit in the active treatment arm, those on rosuvastatin had a 44% reduction (HR 0.56; 95% CI, 0.46-0.69; P<0.00001) in the primary composite end point of myocardial infarction (MI), stroke, arterial revascularization, hospitalization for unstable angina or death from cardiovascular (CV) causes.

On the basis of this study, hsCRP elevation was identified as a useful risk marker for intermediate-risk patients, defined by either the Framingham (FRS) or the Reynolds Risk Score (RRS), as a 10-year 10% to 19% probability of a CV event. In those with a higher risk, hsCRP is not a useful discriminator because the current LDL goal of <2.0 mmol/L or a 50% reduction from baseline should be pursued regardless of hsCRP. In low-risk patients, the value of hsCRP as a risk discriminator has not been established. According to Dr. Jacques Genest, Director, Division of Cardiology, MUHC-Royal Victoria Hospital, Montreal, Quebec, hsCRP should be measured only if it is likely to influence risk management. Although he called hsCRP a “robust risk marker,” he specified that “most of us accept hsCRP as a biomarker and not as a modifiable risk factor.”

Risk Marker Debate

There is very little evidence that hsCRP is a causal risk factor, but there is dissension about its potential to serve as a marker of treatment efficacy. In a debate about whether inflammation is targetable, Dr. Mancini pointed to a variety of sources, including JUPITER, that suggests patients who achieve a low LDL and a low hsCRP have better outcomes than those who achieve reductions in either alone. In addition to clinical trials, he cited atherosclerosis regression studies that have demonstrated the same principle. While these results are likely to be generated by the advantage of controlling the inflammatory response, they still indicate that lowering hsCRP may be a valuable treatment goal.

“Is it just lucky that we consistently see lower event rates when we lower hsCRP as well as LDL? I don’t think so,” remarked Dr. Mancini, advocating hsCRP as a tool to confirm efficacy from current strategies. Although his opponent, Dr. David C.W. Lau, Chair, Diabetes and Endocrine Research Group, University of Calgary, Alberta, acknowledged that hsCRP is a useful tool for identifying individuals who will benefit from LDL lowering, he cautioned that hsCRP has never been studied as an end point, so that basing treatment decisions on change in hsCRP with therapy is “not yet ready for prime time.” He is waiting for trials now underway that will evaluate benefit from hsCRP as the target of treatment.

Whether or not hsCRP is a targetable risk factor, the addition of a 50% reduction in LDL to the previous goal of a <2.0 mmol/L level is a substantial modification in the new Canadian guidelines. According to the guidelines, the modification was “based in large part on the JUPITER trial” and suggests that treating LDL below 2.0 mmol/L does provide additional benefit. In JUPITER, the 50% reduction in LDL among those randomized to rosuvastatin 20 mg brought the median LDL at 12 months to 1.4 mmol/L. Other studies have also demonstrated even greater risk reductions for incremental LDL reductions below 2.0 mmol/L.

“We recommend that these goals be achieved with a monotherapy using a robust statin,” Dr. Genest told delegates. Although he acknowledged that not all patients could get to the new goals on a single treatment, Dr. Genest estimated that the majority could do so, and the advantage of a single drug is that it facilitates compliance. He noted that all of the major statins are safe and effective at approved doses.

Other Guideline Modifications

One of the changes in the new guidelines is the decision to accept apolipoprotein B (apoB) as an alternative target for LDL. Although the guidelines acknowledge that many clinical laboratories are not currently equipped to measure apoB, the authors suggested that it correlates well with LDL, there may be less laboratory error with apoB, and that it may be a better marker of the efficacy of LDL-lowering therapy. The apoB target is <0.8 g/L. Additionally, the new guidelines include a TC:HDL-C ratio <4.0, a non-HDL-C level < 3.5 mmol/L, an apoB:apoA1 ratio <0.80, a triglyceride level <1.7 mmol/L and an hsCRP level of <2.0 mg/L, having been identified in previous clinical trials, as secondary targets. Adjusting lipid-lowering therapy to optimize one or more of these secondary targets may be considered in the high-risk patient after achieving target LDL-C or apoB levels, but the clinical advantages of this approach with respect to patient outcomes remain to be proven.    These targets are based on evidence that they will reduce CV events over the long term, but the promise of effective LDL is also for short-term reduction. Major clinical studies, including JUPITER, have typically demonstrated a separation of event curves within several months. This period would suggest that lipid lowering, whether achieved directly through reductions in serum cholesterol or indirectly through reductions in inflammation, stabilizes vulnerable plaques to reduce the ruptures which produce thrombotic events.

Summary

The new Canadian guidelines for LDL, which are now appropriate for intermediate-risk as well as high-risk patients, have added a 50% reduction in LDL from baseline to the previous target of <2.0 mmol/L. These more rigorous goals will require more aggressive therapy but the authors of the guidelines suggest that most patients should be able to reach targets on monotherapy with a potent statin. The guidelines also acknowledge inflammation as a participant in CV risk. Although hsCRP has not yet been shown to be a treatable risk factor for thrombotic events, it has been shown to be effective for identifying patients who will benefit from aggressive LDL lowering.