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

As discussed by Dr. Jacques Genest, Jr., Director of Cardiology, MUHC-Royal Victoria Hospital, Montreal, Canadian Lipid Guidelines now indicate high-risk patients, including most patients with diabetes, need to achieve an LDL-C target of <2.0 mmol/L. This new target was chosen as the primary lipid-lowering goal as it has been consistently shown that intensive lipid-lowering provides additional cardiovascular (CV) risk reduction in high-risk patients. Once this new, low LDL-C target is met, attempts should be made to reduce the total cholesterol: HDL-C ratio to <4.0, again in high-risk patients, Dr. Genest stated.

As many studies have shown, the greater the reduction in LDL-C, the greater the coronary artery disease (CAD) risk reduction. Indeed, for every 1-mmol/L reduction in LDL-C, there is a 23% reduction in major coronary events and a 21% reduction in major vascular events, according to a meta-analysis of 14 statin trials involving over 90,000 patients. “We do not know what the lower limit yet is, but we can say quite clearly now that the more you lower the LDL, the greater will be the risk reduction,” reaffirmed NCEP guidelines chair Dr. Scott Grundy, Director, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas.

Dr. Grundy also observed that epidemiological studies show that people with very low LDL levels have very little CAD. Based on these observations, “the earlier you can start with LDL reduction, the greater will be the risk benefit,” Dr. Grundy suggested. For example, if LDL-C is lowered by at least 25% starting at the age of 40, “you can get a 70% to 75% reduction in risk,” Dr. Grundy observed, with lesser degrees of risk reduction accruing with later initiations of LDL-C lowering interventions.

“I truly believe the focus should be on LDL-C and not on HDL-C,” Dr. Grundy stressed, “and I also believe the future of this field lies in primary prevention because the real problem is the development of CAD in the first place.”

GUIDE and CALIPSO

If the lower the LDL-C, the better, then high-risk Canadian patients are not faring as well as they could be, at least according to results from recent studies. The GUIDE (Guidelines Based Undertaking for Improvement in Dyslipidemia) experience involved 224 Canadian primary care physicians and specialists who were asked to enrol 2567 high-risk patients with an LDL-C above the recommended target despite being on statin therapy. Physicians then followed an algorithm of increasing tolerated statin therapy or adding the cholesterol absorption inhibitor ezetimibe to achieve an LDL-C target of <2.5 mmol/L in those enrolled prior to September 2006, or <2.0 mmol/L in patients enrolled thereafter. Patients were then evaluated three times over a period of 26 weeks.

At baseline, no patients with or without diabetes were at LDL target. By the fourth visit at 26 weeks, 66% of patients with diabetes were at target (median LDL-C 2.1 mmol/L) but for those without diabetes, only 62.5% were at target (median LDL-C 2.3 mmol/L) at the same assessment point. From these findings, GUIDE investigators concluded that treatment of hypercholesterolemia in high-risk patients, including those with diabetes, needs to be “more intensive” and in accordance with 2006 CCS guidelines.

Data from Ontario and Quebec from CALIPSO (Canadian Lipid Study-Observational) also confirmed that between one-quarter and one-third of high-risk patients were not achieving the LDL-C target of 2.5 mmol/L (Bourgault et al. Can J Cardiol 2005;21(13):1187-93). In CALIPSO, a number of Canadian physicians enrolled 15 patients who had been diagnosed with hypercholesterolemia and who had been taking a statin for at least eight weeks. Out of the 3721 patients involved in the study, 46.4% had established CV disease, 33.9% had diabetes and 59.5% had hypertension. Patients had also been treated with statin therapy for an average of 4.3 years and 24.2% were on high-dose statin therapy. Despite this, 27.2% of patients overall, and 36.4% of those judged to be high-risk patients, were not at the then-LDL-C target of <2.5 mmol/L. Had that LDL-C target been at the currently recommended goal of <2.0 mmol/L, then approximately 70% of patients would not be at target.

In another recent Canada-wide survey of general practitioners, on average, only about half of all high-risk patients were reaching a target of <2.6 mmol/L and barely 20% were reaching a stricter target of <1.8 mmol/L.

Overcoming Barriers

As observed by Dr. Milan Gupta, Assistant Clinical Professor of Medicine, McMaster University, Hamilton, there are a number of reasons why patients fail to achieve LDL-C targets, not the least of which are concerns about safety. Even though data from clinical trials and meta-analyses have consistently affirmed the safety of currently available statins, “some physicians are reluctant to go to higher doses,” Dr. Gupta noted, largely out of concern that patients will not tolerate them well (it is known, for example, that muscle symptoms are more likely to occur at higher doses of statin therapy).

Another reason patients fail to achieve LDL-C targets concerns a lack of enthusiasm for uptitration of the statin dose because the incremental increase in LDL-C lowering achieved with uptitration is small, about 6% for each doubling of the dose. In one example cited by Dr. Gupta, 52% of some 2800 high-risk patients started on a statin did not get to target, and over half of those not at target were not titrated.

Of the other half who were titrated up, only one-third achieved LDL-C goals, “so two-thirds of patients did not get to target despite uptitration and at the end of the day, even with the best of intentions, only 55% of all patients got to target,” Dr. Gupta reported. In contrast, other evidence shows that patients who receive the combination of ezetimibe plus simvastatin are more likely to achieve LDL-C targets of both <2.5 mmol/L and <1.8 mmol/L than atorvastatin alone (Ballantyne et al. Am Heart J 2005;149(3):464-73).

Findings that the combination approach can be very effective even when LDL-C targets are quite low were corroborated by a recent analysis of COURAGE trial data. At 60 months, approximately 30% of COURAGE patients were receiving ezetimibe, almost always with a statin. The proportion of patients who achieved the LDL-C target of <2.2 mmol/L at study end point was very high (approximately 60%). Some 40% of the same cohort were also able to achieve an LDL-C of <1.81 mmol/L at 60 months. As Dr. Gupta reminded delegates, in TNT, atorvastatin 80 mg reduced median LDL-C to 2.0 mmol/L—“but that was the median,” he stressed, “and that means that half of patients who got atorvastatin 80 mg did not get to 2.0 mmol/L—and this is in the best-case scenario of a randomized clinical trial.” Thus, as he concluded, “more patients are likely to get to target on combination therapy than on monotherapy and combination therapy is safe and well tolerated. So for physicians who are uncomfortable with high doses of statins, I would propose that combination therapy is the right approach.”

Based on the CCS/CCC-sanctioned sessions:

“The 3rd Annual Medical Debate in Lipid Management: Meeting the Challenge of Evolving Evidence.” Monday, October 22, 7:00-9:00, Room 200A, Level 2.

“Pharmacological Approaches to Reaching LDL Targets – Statin Monotherapy Achieves Canadian Lipid Targets in Most Patients, Combination Therapy Achieves Lipid Targets with Greater Ease.” Wednesday, October 24, 7:20, during the symposium “Expert Opinions: Current Issues in Cardiology,” 7:00-9:00, Room 200B, Level 2. Presenter: Dr. Milan Gupta

CCC #641. Langer A, Bissonnette S, Goodman SG, Tan M, Casanova A, Leiter L. Dyslipidemia management in patients with diabetes: the guidelines-based undertaking for improvement in dyslipidemia-related events (GUIDE) experience. Tuesday, October 23, 10:00-12:30, Community Forum.

These symposia are accredited and co-developed as an Accredited Group Learning Activity under Section 1 of the framework of Continuing Professional Development options as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC).