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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.

MEDICAL FRONTIERS - 31st Annual Congress of the European Society of Cardiology

Barcelona, Spain / August 29-September 2, 2009

According to investigators here this week, there were almost 350,000 fewer deaths due to coronary causes in the US in 2000 compared to 1980. One study concluded that 44% of this decrease could be explained by risk factor modification, with the most important components being reduction in both cholesterol and blood pressure (BP) (Ford et al. N Engl J Med 2007;356(23)2388-98) (Table 1). Another set of European studies, EUROASPIRE I, II and III, collected data on the prevalence of risk factors spanning a period from 1995 through 2006. “There is good and bad news: obesity and diabetes are increasing while the prevalence of dyslipidemia—a major concern—is decreasing, but we can still do better,” stated Dr. José Luis Zamorano, University Clinic San Carlos, Madrid, Spain.

Lipid-lowering Therapy

Statins are currently the cornerstone of dyslipidemia management and have allowed much more stringent targets to be reached. A range of secondary-prevention studies attested to the benefit of reducing cholesterol levels, LDL-C in particular. In the case of primary prevention, the authors of an important meta-analysis of 14 randomized trials with over 90,000 high-risk patients concluded that benefit was at least partly related to the absolute reduction in LDL-C (Baigent et al. Lancet 2005;366(9493):1267-78). Consequently, although statin therapy in itself may be beneficial, there appears to be clear benefit in lowering LDL as far as possible. “Lower is better,” Dr. Zamorano confirmed.

Added Dr. Anselm K. Gitt, Herzzentrum, Ludwigshafen, Germany, “As a result of these trials, action to lower LDL-C using statin-based therapy is now endorsed by leading groups as primary prevention and reflected in various guidelines.” In the case of the Canadian guidelines, in addition to attaining LDL-C <2.0 mmol/L, it is also recommended to decrease the total cholesterol: HDL-C ratio to <4.0 mmol/L.

Table 1.

Guidelines and Clinical Practice

Once evidence-based guidelines have been drawn up, a process of education and dissemination must take place in order to have a meaningful impact on clinical practice. It is also important to monitor how effective the recommendations are in a “real-life” situation. The selected clinical trial populations may not be representative of those patients attended to in everyday practice and adherence to guidelines and/or treatment is not always optimal.

“To collect data on everyday practice, registries are an extremely valuable tool,” explained Dr. Gitt. In one German study, the Lipid Lowering (2L) Registry investigated guideline adherence of patients with coronary artery disease or peripheral artery disease/diabetes who were receiving chronic statin therapy. Overall, only 27% of outpatients with peripheral artery disease/diabetes and 38% of those with coronary artery disease were able to reach the treatment goal. According to Dr. Gitt, these data highlighted the difficulties of achieving treatment goals in diabetic patients and those with peripheral artery disease. “Clearly we need to do more for these patients,” he concluded.

While it was encouraging how many of the treating physicians were aware of the treatment goals laid out in the guidelines, it was also somewhat disappointing that many physicians failed to recognize the need to adjust treatment in those who failed to achieve treatment goals.

GUIDE Study Findings

Here at the ESC, findings from the GUIDE (Guidelines Based on Undertaking for Improvement in Dyslipidemia Related Events) were discussed (Teoh et al. Am J Cardiol 2009;104(6):798-804). Results indicated there was over 90% adherence with guideline recommendations for statin therapy for lower LDL-C in a multicentre observational cohort of 2577 Canadian patients with persistent hypercholesterolemia. The authors characterized these findings as “outstanding” and “appreciably greater” than adherence levels to statin therapy noted in many other literature reports.

Yet only 41% of the cohort attained LDL-C levels of <2.0 mmol/L despite a comprehensive treatment regimen with statins and ezetimibe. GUIDE investigators suggested these results were “disconcerting” and which they felt might be indicative of less than optimal patient adherence; that some physicians might have been unaware of the latest guideline-recommended target lipid profile; that statin doses might have been insufficiently uptitrated; and/or that combination pharmacotherapies together with lifestyle changes might not have been adequately or aggressively enforced.

It is also interesting to speculate that some patients do not respond well to statin therapy, even at higher doses. This is important, as noted by Dr. Michel Farnier, Point Médical, Dijon, France, because many of the patients who do not reach their corresponding treatment goals are high-risk patients, such as those with diabetes. Dr. Farnier identified extrinsic factors such as poor therapeutic compliance and concomitant treatment.

Certain genetically determined intrinsic factors also seem to play a role and one of the most important, according to Dr. Farnier, concerns cholesterol absorption in the intestine. Studies have shown that inhibition of cholesterol synthesis by statins can lead to compensatory increases in cholesterol absorption (van Himbergen et al. J Lipid Res 2009;50(4):730-9). “Such observations were behind the working hypothesis that poor responders to statin monotherapy would respond better to cholesterol absorption inhibitor/statin combination therapy,” he added.

Clinical Study Results

A number of studies have investigated the efficacy and safety of adding the cholesterol absorption inhibitor ezetimibe to statin therapy. For example, the VYMET study randomized 1128 patients with hypercholesterolemia and metabolic syndrome to ezetimibe 10 mg plus simvastatin 20 mg or ezetimibe 10 mg plus simvastatin 40 mg or to atorvastatin 10, 20 or 40 mg, and followed the percentage change from baseline in LDL-C. Patients were more likely to reach the LDL-C goal with both treatments combined. In addition, combining both treatments together was well tolerated. In a another study, the effectiveness of uptitration of atorvastatin from 40 mg to 80 mg was compared to the addition of ezetimibe 10 mg to atorvastatin 40 mg in achieving treatment goals in patients with a high risk of coronary heart disease (CHD). The primary analysis showed a significantly greater decrease in LDL from baseline for the combination treatment. A subanalysis presented here at the ESC meeting by Dr. Lawrence Leiter, University of Toronto, Ontario, also showed significant reductions in other risk markers such as apolipoprotein B and C-reactive protein.

The IN-PRACTICE trial randomized 786 patients with cardiovascular disease (CVD), patients at high risk of CVD and patients with diabetes to treatment with ezetimibe/simvastatin 10/40 mg, atorvastatin 40 mg or rosuvastatin 5/10 mg (according to labelling) for six weeks after a six-week run-in period of treatment with simvastatin. In the combination therapy group, 67.5% of the patients were able to meet the primary efficacy end point of LDL-C <2.0 mmol/L compared to 36.3% in the atorvastatin monotherapy group and 17.4% in the rosuvastatin group (P<0.001).

The IN-CROSS trial also had a six-week run-in period in which high-risk patients continued to receive the statin they were using before enrolment. Those who were not at goal after run-in were then randomized to either ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg for six weeks. In this case, the primary outcome measure was mean percentage change in LDL-C. In the overall population (n=618), the decrease in the combination therapy group was -27.7% compared to -16.9% in the rosuvastatin group (P<u><</u>0.001). In a subgroup analysis, patients were stratified by whether they had type 2 diabetes mellitus, as “It is generally hard to achieve treatment goals in such patients,” explained Dr. Farnier. Interestingly, the group differences were greater for patients with type 2 diabetes (-30.3% vs. -11.5%) than for those without (-26.5% vs. -18.0%) (P=0.015 for treatment-by-subgroup interaction). “Poor responders to statin monotherapy are the best candidates for combining ezetimibe with statin therapy and optimal LDL-C lowering can be achieved by inhibiting both cholesterol absorption and production,” concluded Dr. Farnier.

Aggressive Lipid Goals in Patients with Diabetes

Results from another relevant study were discussed at this year’s recent XV International Symposium on Atherosclerosis held this summer in Boston, Massachusetts. In the face of difficulties reaching treatment goals in patients with diabetes, the SANDS (Stop Atherosclerosis in Native Diabetics Study) compared aggressive vs. standard lipid- and BP-lowering therapy. It was initiated with the hypothesis that treating LDL-C and BP to lower targets further than currently recommended by US and other clinical guidelines could retard the progression of atherosclerosis. The study was conducted in 499 Native American men and women ³40 years of age with type 2 diabetes and no history of CVD events who were randomly assigned to either a standard treatment or an aggressive program. The goals of aggressive treatment were 1.8 mmol/L for LDL-C and 2.6 mmol/L for non-HDL-C, and 115/75 mmHg for BP. Lipid control was achieved either through lifestyle modification or, if that was unsuccessful, with a statin. If statin monotherapy was unsuccessful, ezetimibe was added. After getting to goal with statin monotherapy or with ezetimibe added, the authors then titrated to the non-HDL goal by adding fenofibrate, omega-3 fatty acids or niacin.

The primary end point was change over baseline in common carotid intima media thickness (CIMT) at 18 and 36 months’ follow-up. “Although carotid plaque is probably more predictive, you will not really see any changes with short-term intervention by external beam ultrasound, so we chose a change in CIMT as our primary end point,” explained Dr. William James Howard, Vice President, Academic Affairs, and Director, Lipid Clinic, Washington Hospital Center, Washington, DC.

For the primary end point, aggressive therapy was associated with a regression from baseline in CIMT, whereas standard therapy was associated with progression (-0.012 mm vs. 0.038 mm, respectively). According to a logistic regression model, change in both LDL-C and non-HDL-C predicted reduction in CIMT. The investigators also studied the influence of how patients achieved the ambitious LDL-C target—statin monotherapy or statin/ezetimibe. About one-third of patients in the aggressive treatment group required the addition of ezetimibe; however, it was the aggressive treating to target that accounted for the regression of CIMT compared with the progression seen among patients in the standard group.

“One of the strongest recommendations of SANDS is, let us at least treat to current standards, and we are not accomplishing that in the majority of our diabetics,” Dr. Howard remarked. He called for the initiation of more clinical trials focusing on treating to targets for lipids and BP rather than evaluating specific therapeutic regimens.

Trials with Hard Clinical End Points

Whether benefit in terms of CIMT or lower LDL-C levels in a high-risk group such as patients with diabetes will affect CV outcome is an important question that is currently being addressed by two large ongoing clinical trials.

IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is a randomized, active-control, double-blind study of patients with stabilized high-risk acute coronary syndrome. The primary objective is to evaluate the clinical benefit of a combination of ezetimibe 10 mg and simvastatin 40 mg compared with simvastatin 40 mg alone (the dose in this group can be increased to 80 mg if response is inadequate). The primary outcome is clinical benefit, defined as the reduction in the risk of the occurrence of the composite end point of CV death, major coronary events and stroke. Although the exact completion date depends on recruitment targets, projections suggest that results should be expected by 2012.

The phase III SHARP (Study of Heart and Renal Protection) is designed to determine whether reducing serum cholesterol with a combination of ezetimibe and simvastatin can prevent heart disease and stroke in patients with kidney disease. The question of whether lowering cholesterol can delay the need for renal dialysis will also be addressed. Results from SHARP are expected in July 2010.

Lipid Lowering in Patients with Aortic Stenosis

It has been established that reductions in LDL-C are associated with a reduction of coronary artery disease risk and major CV events. As discussed here during the scientific sessions, SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial investigators carried out a post-hoc analysis to examine the relationship between reductions in ischemic cardiac events (ICE) risk and changes in lipoprotein components among the tertile of patients with more severe aortic stenosis (AS).

Patients with AS were stratified by the degree of disease as assessed by jet velocity at baseline. In the overall cohort, treatment with simvastatin 40 mg combined with ezetimibe 10 mg reduced LDL-C by 50% and subsequent ICE risk by 22% compared with placebo. This reduction was less than expected for the degree of lipid-lowering achieved. However, in the two tertiles made up of patients with least severe stenosis, the post-hoc analysis revealed that the risk reductions were consistent with data from the Cholesterol Treatment Trialists’ meta-analysis of statin trials.

In contrast, for patients with the most severe AS, no treatment effect was observed compared to placebo. “This suggests that in the early stages of disease, cholesterol plays a role, but it is less relevant later,” noted Dr. Alberico L. Catapano, Department of Pharmacological Sciences, University of Milan, Italy.

Summary

Lipids researcher Dr. Ernest J. Schaefer, Professor of Medicine, Tufts University School of Medicine, Boston, noted that therapy combining statins and cholesterol absorption inhibitors may offer clinical benefit both to the majority of patients who respond to statins as well as to those who do not, either because of extrinsic factors such as poor compliance, diet, time of statin administration or concomitant drug therapy, or because of genetic factors. “A prediction: in my view, the addition of ezetimibe to statin therapy will favourably affect CHD risk in high-risk subjects as compared to statin therapy alone,” he suggested. “I do think that one needs to do a large enough trial to be able to answer this question. IMPROVE-IT, certainly, is powered to do that.”