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 2006

Vancouver, British Columbia / October 21-25, 2006

The CALIPSO (Canadian Lipid Study-Observational) involved over 3000 high-statin prescribers whose patients were assessed for achievement of LDL-C targets while on statin therapy. The survey found that 68% of those receiving statin therapy were at high risk for cardiovascular disease (CVD) events, as defined by 2003 Canadian guidelines. After an average of 4.3 years of therapy, over 36% of those at the highest risk for CV events had not achieved LDL-C targets of £2.5 mmol/L.

Results would be even less optimal given the new thresholds in recent guidelines, which indicate LDL-C targets of <2 mmol/L for high-risk patients. As discussed by Dr. Jacques Genest, Jr., Director, Division of Cardiology, MUHC-Royal Victoria Hospital, Montreal, Quebec, new low targets for secondary prevention were based on findings from a number of studies indicating that the lower the LDL-C levels, the greater the reduction in clinical end points as well as atheroma burden compared with standard-dose statin therapy. The new targets for high-risk patients—those with established vascular disease in any arterial bed or diabetes—indicate that physicians also need to achieve a total cholesterol: HDL-C (TC:HDL-C) ratio of <4.

The new guidelines also advocate titrating patients up to the maximal dose of a chosen statin, but if patients fall short of the new targets, a second agent—such as ezetimibe—should be added to existing statin therapy.

Helping More Patients Reach Target

High-dose statin therapy may be the strategy of choice, but as pointed out by Dr. Alan S. Brown, Clinical Associate Professor of Medicine, Loyola Stritch School of Medicine, Chicago, Illinois, many physicians are reluctant to prescribe high-dose statin therapy because of a perceived or real increase in side effects. “The higher you go, the more you get muscle problems, and muscle problems are not just three times the upper limit of normal, a lot of these problems do not get picked up by clinical trials so we need to know more about the long-term safety of big doses of these statins,” cautioned Dr. Peter Sleight, John Radcliffe Hospital, Oxford, UK.

Thus, it is “exciting,” as Dr. Brown characterized, that the addition of ezetimibe 10 mg to any type of statin therapy has been shown to produce comparable if not greater reductions in LDL-C as high-dose statin therapy. Furthermore, the “maximum bang for your buck is with the starting dose of a statin,” as argued by Dr. Subodh Verma, Scientist and Assistant Professor, Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Ontario, with further lipid-lowering benefits being relatively modest as doses are increased.

Much has also been made of the pleiotropic effects of the statins and their contribution to lowering clinical risk but a recent meta-analysis confirmed that the majority of benefit from statin therapy comes from LDL-C reduction in and of itself, with every 1 mmol/L of LDL-C reduction translating into about a 20% relative risk reduction in CV mortality. According to Dr. Verma, the use of ezetimibe to inhibit cholesterol absorption plus a statin that inhibits cholesterol synthesis should help more patients get to target and get to target quicker.

In phase III trials, ezetimibe monotherapy produces about an 18% reduction in LDL-C but it is most effective when used with any statin at any dose. Combination with simvastatin 10 mg achieves the same degree of LDL-C reduction as maximal-dose simvastatin. “Likewise, 10 mg of ezetimibe plus 10 mg of atorvastatin is very similar to what you get with atorvastatin 80 mg,” Dr. Verma noted. He has also found that the combination of ezetimibe 10 mg plus rosuvastatin 10 mg brings most patients of South Asian origin to target, reducing LDL-C by approximately 60%, with this patient group being particularly responsive to rosuvastatin.

“Dual targeting” in the high-risk patient is an emerging concept. “Patients who achieve a LDL-C of <2 mmol/L and a C-reactive protein of <2 may derive greater [cardioprotective] benefit than those who achieve only one of the two outcomes,” Dr. Verma told delegates.

The addition of ezetimibe to ongoing statin therapy augments the effect that even a high-dose statin has on CRP. Similarly, when investigators looked at the effect that the combination of ezetimibe/rosuvastatin had on the apo B:apo A1 ratios—the strongest driver of myocardial infarction risk, according to the INTERHEART study—they found that almost 100% of high-risk patients treated with the combination as initial therapy were at target LDL-C goals by week 6. At the same time, there was a more pronounced reduction in the apo B:apo A1 ratio with the combination strategy vs. the statin alone.

“The combination of ezetimibe plus a statin allows many more patients to reach target and that by itself is one of the strongest determinants of outcomes,” Dr. Verma remarked, adding that it is a “unique and robust strategy that we can use to close the care gap.”

Results from EZE (STAT) 2

That ezetimibe added to any dose of any statin truly does allow more patients to achieve LDL-C targets than doubling the statin dose was demonstrated by a series of analyses of the EZE (STAT) 2 study presented by Dr. Shekhar Pandey, Cardiologist, Cardiac Care Centre, Cambridge Memorial Hospital, Ontario. The EZE (STAT) 2 was an open-label, randomized Canadian trial assessing the impact of adding ezetimibe to ongoing statin therapy vs. doubling the statin dose in high-risk patients not at 2003 LDL-C targets of £2.5 mmol/L on statin therapy alone.

The interim analysis included 353 patients in the ezetimibe arm and 176 patients in the double-dose arm. With identical LDL-C entry levels of 3.22 mmol/L, mean reduction in LDL-C at six weeks was over 30% in the combination arm compared to approximately 18% in the double-dose arm. The absolute change in LDL-C at six weeks was 1.0 mmol/L in the combination arm vs. 0.6 mmol/L in the double-dose arm, while over 73% of patients in the combination arm vs. approximately 48% of patients in the double-dose arm had achieved an LDL-C of <2.5 mmol/L at study end point. Over 87% of patients in the combination arm vs. approximately 70% of the double-dose arm achieved either LDL-C of <2.5 mmol/L or a TC:HDL-C of <4 at week 6.

Analyses of the diabetic subset in EZE (STAT) 2 also showed that they responded particularly well to the combination approach, the addition of ezetimibe to their usual statin again resulting in “very robust reductions” in LDL-C of over 30%, as Dr. Pandey noted. In the diabetic subgroup, “we were able to get the vast majority of patients to the current LDL-C target of 2.0 mmol/L. [Seeing] this type of robust response in patients that have always been among the most difficult to treat gives us a good opportunity to treat them in a different way,” Dr. Pandey concluded.