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.

PRIORITY PRESS - Canadian Cardiovascular Congress 2009

Edmonton, Alberta / October 24-28, 2009

As presented by Dr. Ruth McPherson, Director, Lipid Clinic, University of Ottawa, Ontario, new LDL-C targets for high and moderate-risk patients is an LDL-C <2.0 mmol/L or at least a 50% reduction in LDL-C vs. baseline. As a primarily alternative target, physicians can reduce apolipoprotein B <0.80 g/L. For low-risk patients, the goal is to reduce LDL-C by at least 50% vs. baseline. Secondary targets include a TC:HDL-C ratio <4.0, triglycerides <1.7 mmol/L and a high-sensitivity C-reactive protein (hsCRP) <2 mg/L. These parameters are of interest primarily in high-risk patients and should be taken into account only when LDL-C is at goal. If patients fail to attain LDL-C targets, residual risk may be lowered with combinations of lipid-lowering agents, Dr. McPherson indicated. As argued in a scheduled debate by antagonist Dr. James Stone, Clinical Professor of Medicine, University of Calgary, Alberta, the new guidelines are LDL-C-“centric” because that is where the hard clinical evidence rests for cardioprotective benefit. Multiple studies and meta-analyses leave no doubt that a reduction in LDL-C with statin monotherapy significantly lowers major adverse cardiac event (MACE) risk—“and the lower you go, the better you do,” Dr. Stone confirmed. In contrast, trials evaluating combination strategies have no hard clinical end points upon which they can claim cardioprotective benefit, he indicated. Indeed, the new guidelines suggest the majority of patients can achieve target LDL-C on statin monotherapy. “If you cannot get to target, then you can use a combination approach,” Dr. Stone told delegates.

However, as Dr. Robert Hegele, Director, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, countered in the debate, there is considerable research showing a significant proportion of high-risk patients do not achieve LDL-C goals on statin monotherapy. Given that each 1.0 mmol/L reduction in LDL-C reduces cardiovascular disease (CVD) mortality and non-fatal myocardial infarction by between 20% and 25%, patients not at goal are prone to real residual risk. Moreover, even in well-conducted clinical trials where high-dose statin monotherapy reduces LDL-C to a mean of 2.0 mmol/L, “the standard deviation goes around the mean so in fact there are a lot of individuals within these excellent trials that do not reach this level,” Dr. Hegele noted. In a Canadian chart review cited by Dr. Hegele, for example, one-quarter of patients did not reach the LDL-C target of 2.0 mmol/L on the highest dose of atorvastatin.

The limitations of statin monotherapy were also demonstrated in CALIPSO (Canadian Lipid Study–Observational), where 38% of high-risk coronary artery disease patients did not achieve an LDL-C <2.0 mmol/L with optimal uptitration of statin monotherapy.“We have also established that physicians have to treat towards a 50% reduction in LDL-C but in fact, a high proportion of patients do not reach this goal either,” Dr. Hegele reported. Approximately one-third of a large cohort of high-risk patients did not achieve a 50% reduction LDL-C—“and this was with the highest dose of the most effective statin we have,” he added, “so if we take the guidelines at face value, a significant minority will need a statin in combination with another drug and we need to at least consider combination therapy.”

Dyslipidemia International Study

The DYSIS (Dyslipidemia International Study) has provided solid evidence that patients in Canada do not fare much better than those in international clinical trials. DYSIS assessed the prevalence of persistent lipid abnormalities according to different risk categories among patients already taking a statin. A total of 2436 patients were included in the analysis, some 80% of whom were high-risk according to Canadian guidelines.

Defining “not at goal” as an LDL-C <u>></u>2.0 mmol/L and a TC:HDL-C <u>></u>4.0, the study showed that 40% of patients with diabetes and 44.6% of patients with CVD were not at goal. Slightly over one-quarter of both groups also did not achieve an optimal TC:HDL ratio. “On top of that, another 40% had a low HDL-C while approximately 40% had high triglycerides,” noted Dr. Lawrence Leiter, Head, Endocrinology and Metabolism, St. Michael’s Hospital, Toronto, Ontario, “so there continues to be persistent lipid abnormalities, despite treatment.”

Dr. Leiter also noted that while the statin trials demonstrate that treatment reduces MACE from 35% to 40%, “this still means we are not preventing the other 60% to 70% of CV events, which raises the [possibility]: if we did a better job of optimizing LDL-C and taking care of other lipid abnormalities, perhaps there would be additional benefit.”

Get to Goal

A post-hoc analysis of two previously published studies presented here by Dr. Leiter suggests more patients get to goal when treated with additional ezetimibe rather than doubling or quadrupling the dose of the statin. The first study involved moderately high-risk patients who, already receiving atorvastatin 20 mg, were given either additional ezetimibe 10 mg or who were uptitrated to atorvastatin 40 mg. The second study involved high-risk patients already on atorvastatin 40 mg who also received additional ezetimibe 10 mg or who were again uptitrated to atorvastatin 80 mg. Mean baseline LDL-C values were 3.1 mmol/L in the moderately high-risk group and 2.3 mmol/L in the high-risk group.

Using the new 2009 cholesterol targets for their analysis (only one day after the guidelines were officially presented), Dr. Leiter and colleagues found that the proportion of patients who achieved lipid targets on the combination was consistently higher than doubling the dose of the statin, with the exception of triglycerides and hsCRP, where there was equal attainment of the target. Similarly, high-risk patients treated with the combination were more likely to achieve the new Canadian lipid targets than if they were on uptitrated statin monotherapy, again with the exception of triglycerides and hsCRP.

Baseline LDL-C levels were not known in either cohort so investigators were unable to calculate the proportion of patients who achieved a 50% reduction in LDL-C from baseline. However, there was an additional 31% reduction from treated baseline LDL-C values when ezetimibe was added to atorvastatin 20 mg in the moderately high-risk group vs. 11% for the uptitrated statin. In the high-risk group, there was an additional 27% greater reduction in LDL-C in the combination group vs. an additional 11% reduction with atorvastatin 80 mg. “Whichever one of the dual targets you want to look at, patients were more likely to achieve targets with the combination than with the uptitrated statin,” Dr. Leiter remarked, “and very few abnormalities were seen in either group.”

Elderly Patient Population

It is generally accepted that the elderly do not tolerate high-dose statin therapy well and that a combination strategy may be the preferred strategy in patients over the age of 65. In a separate study, patients not at LDL-C goal after six weeks of atorvastatin 10 mg received additional ezetimibe 10 mg or were uptitrated to atorvastatin 20 mg. After another six weeks, the dose of atorvastatin was doubled to 40 mg in patients still not yet at goal.

As presented by Dr. Christian Constance, Université de Montréal, Quebec, LDL-C was reduced by 26.7% in the combination arm by week 6 vs. a 12.8% reduction with double the dose of atorvastatin. At 12 weeks, the difference between the two arms was smaller (a 22.5% reduction in the combination group vs. a 17.9% reduction in the atorvastatin 40 mg arm). “The same trends were seen for TC:HDL ratio, triglycerides and HDL-C,” Dr. Constance reported. At six weeks, 62.3% of the combination vs. 31.1% of the statin monotherapy arm had achieved an LDL-C <2 mmol/L, with smaller differences between the two groups at 60.5% and 49.7%, respectively, at 12 weeks. “There were no meaningful differences between the two groups in discontinuation rates or serious adverse events,” Dr. Constance noted. “The combination increases our options in this patient population.”