A chart review presented by GOALL (Guidelines Oriented Approach in Lipid Lowering) Registry investigators confirms that while the majority of high-risk patients with either diabetes or known cardiovascular disease (CVD) across Canada receive statin therapy, fewer than half achieve LDL-C targets of <2.5 mmol/lL. This finding prompted investigators to suggest that “more intensive therapy appears warranted to improve the outcome of these high-risk patients.” Part of the reason why achieving LDL-C targets—and subsequent reductions in CV events—is not as successful as the guidelines would dictate may have to do with the relative efficacy of the statins themselves.
  According to Dr. Bruce Gregory Brown, Professor of Medicine, Cardiology Division, University of Washington Medical Center, Seattle, Canadian lipid guidelines are more suitable in helping physicians decide when to initiate lipidlowering therapy in patients who have unremarkable total cholesterol (TC) and LDL-C levels, but who have low HDL-C levels, high triglycerides and a relatively high TC:HDL-C ratio. Indeed, this type of dyslipidemia actually describes over half of patients in the catheterization laboratory who have coronary artery disease (CAD) and who need treatment in his practice, he noted. Although the statins have been shown to reduce cardiovascular (CV) events by up to 35%, Dr. Brown reminded delegates that it remains to be seen how physicians can improve outcomes in these very high-risk patients.
  Framingham data indicate that for every 1% of LDL-C lowering, there is a 1% decrease in the CV events, and that for every 1% increase in HDL-C, there is a similar 1% decrease in

In the early FATS (Familial Atherosclerosis Treatment Study) (N Engl J Med 1990;323:1289-98), the combination of immediaterelease niacin plus colestipol led to a 0.9% regression in average proximal stenosis compared with a 2.5% increase in placebo controls. In the 10-year follow-up study of FATS, aggressive lipid-lowering with the combination of niacin, lovastatin and colestipol also reduced the combined end point of CV death and MI by 68%. In HATS (HDL-Atherosclerosis Treatment Study) (N Engl J Med 2001;345:1583-92), the combination of simvastatin plus niacin led to a 0.4% regression in angiographic disease compared with an increase of 3.9% for placebo controls.

Furthermore, C-reactive protein levels were halved in the combination arm of HATS; over two-thirds of patients with small dense LDL-C at baseline had significant increases in large buoyant LDL particles at the end of treatment. Most importantly, 91% of patients receiving the active treatment combination were event-free at three years compared to 78% of placebo controls, for a 60% reduction in the combined end point in favour of the combination strategy.
“In the future, we will be treating both LDL-C and HDLC rather than just LDL-C and when we do, we should get twice the benefit for patients, and if we do get twice the benefit, this will represent a sea change in how we practice cardiology,” Dr. Brown concluded.

An immediate-release formulation of niacin is associated with approximately eight episodes of flushing per month, a common side effect that often led to treatment discontinuation. However, studies evaluating a new, extended-release formulation indicated that there are 78% fewer flushing episodes with the extended-release agent than with the immediate-release formulation. Although most patients will experience at least one flushing episode with the extendedrelease formulation, Dr. Brown recommended that physicians simply tell patients that when treatment is first initiated, flushing is likely to occur, a sign that the agent is working and if taken at night with a low-fat snack, “it helps people to stay with it.” Taking ASA 30 minutes prior to taking niacin also reduces risk of flushing, Dr. Brown told delegates.
  For patients with significant disease or who are at high risk for CVD, a target dose of 2 g/day is ideal, “as patients benefit a lot more with 2 g as opposed to 1 g/day,” Dr. Brown observed. He explained that in support of the cardioprotective benefits of raising HDL-C, a number of quantitative angiographic studies indicated that the combination of niacin plus other lipid-lowering agents can have profound effects on atherosclerotic disease progression.

Dr. Koon Kang Teo, Professor of Medicine, McMaster University, Hamilton, Ontario, concurs with Dr. Brown, indicating that raising HDL-C while lowering LDL-C simultaneously may well represent a major step forward in achieving cardioprotection in high-risk patients. To test this hypothesis, the new AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High

Triglyceride and Impact on Global Health Outcomes) study will seek to determine whether extended-release niacin plus simvastatin will provide greater benefit to simvastatin alone for the same levels of LDL-C in reducing CV events in patients with vascular disease, low HDL-C and normal LDL-C. Exclusion criteria from the study are: patients who have been hospitalized for acute coronary syndromes and discharged within four to eight weeks of planned enrolment; CABG within five years unless there has been an intercurrent acute vascular event more than four to eight weeks prior to planned enrolment; planned PCI within four weeks; stroke within eight weeks of planned enrolment; patients with fasting plasma levels in excess of 10 mmol/L, and those who cannot use a glucometer at home; individual with CAD associated with unstable angina and symptoms refractory to maximal medical therapy; those whose post-MI course is complicated by persistent angina at rest, shock or heart failure; patients for whom the need for urgent revascularization is likely; those with a ≥50% left main coronary artery stenosis (unprotected left main disease); an ejection fraction of <30%; cardiogenic shock; pulmonary edema; or heart failure unresponsive to standard medical therapy.
As Dr. Teo reported, AIM-HIGH will enrol 3300 individuals with vascular disease and an HDL-C of 40 mg/dL in men (1.0 mmol/L) and 50 mg/dL in women (1.3 mmol/L). Triglycerides will be between 150 and 400 mg/dL (1.7 to 4.5 mmol/L) and LDL-C will be 160 mg/dL (4.1 mmol/L) (all values are off therapy). Target LDL-C levels will be <80 mg/dL (approximately 2.0 mmol/L). Some 60 centres in all will participate in AIM-HIGH, 20% of which will be Canadian.
“The primary end point is a composite of CAD death, non-fatal MI, non-hemorrhagic stroke and hospitalization for NSTEMI ACS,” Dr. Teo noted, “and the follow-up will be for three to five years.” Patients will be randomized to the combination of simvastatin 10 to 80 mg and extended-release niacin 500 mg and 1000 mg; niacin will be increased to 2 g and simvastatin will be titrated to reduce mean LDL-C levels to <2.1 mmol/L in both treatment arms. To ensure target LDL-C levels are achieved, ezetimibe 10 mg may be added to simvastatin.
Dr. Teo concluded, “If the AIM-HIGH trial can prove the hypothesis that combination therapy directed towards multiple lipid targets improves CV disease and CAD events compared with statin monotherapy, it will provide a clinically meaningful approach to optimizing event-free survival rates in a large and growing population of high-risk patients for whom present treatment is less than adequate.”