Influenza in the Elderly: Seeking More Effective Vaccine Strategies
University of Ottawa Heart Institute

Lower Is Better: New Data Confirm the LDL Hypothesis as New Options Are Identified for Improved Control

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 - American Heart Association (AHA) Scientific Sessions 2014

Chicago, Illinois / November 15-19, 2014

Chicago - New evidence of a cardiovascular (CV) benefit from lipid-lowering therapy with a non-statin has extended the lipid hypothesis, expanding opportunities for risk reduction. One of the trials presented at the 2014 Scientific Sessions of the AHA, called IMPROVE-IT, proved that the addition of a non-statin can further lower CV risk in high-risk patients despite treatment with high-intensity statins. This study provided evidence that the LDL-C level of minimal risk is lower than that defined in most current guidelines for those patients with established CV disease. In this context, new phase 3 trial data with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor capable of large LDL-C reductions, also presented at the AHA, appear likely to define the next major step forward in CV risk reduction.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Statins are the first-line lipid-lowering therapy for CV risk reduction in Canadian and U.S. guidelines, but a substantial proportion of patients cannot reach LDL-C goals on these agents due to inadequate lipid-lowering effect, intolerance, or both. A newly completed trial presented at the AHA, called IMPROVE-IT, showed that a LDL-C reduction with a non-statin provides further CV risk reduction to the use of a statin. It both confirms the lipid hypothesis and initiates a new era in CV risk management.

“These results are consistent with decades of research in high-risk patients, affirming the central role of aggressive LDL-C reduction,” reported Dr. Lori Mosca, Director of Preventive Cardiology, New York Presbyterian Hospital, New York City. In fact, the data “suggest that we should consider setting the LDL-C bar even lower in the high-risk population.”

IMPROVE-IT is a multinational trial that randomized 18,144 patients within 10 days of an acute coronary syndrome (ACS) to simvastatin alone or simvastatin plus ezetimibe, a non-statin that inhibits cholesterol absorption. In the arm randomized to receive both statin and ezetimibe, the reduction in the primary composite endpoint of CV events at 7 years relative to simvastatin alone was 6.4% (P=0.016), providing a correlation between LDL-C and CV risk reductions consistent with those observed previously with statins by the Cholesterol Treatment Trialists (CTT) (Lancet 2010;376:1670-81).

1 mmol/L of LDL-C lowering = 20% CV Risk Reduction

“What the CTT demonstrated was that for every 1 mmol/L of LDL-C lowering with a statin, you get about a 20% treatment benefit,” explained Dr. Michael Blazing, Director of Outpatient Services, Duke Heart Center, Duke University, Durham, North Carolina.

These data “reaffirm the lipid hypothesis,” according to the principal investigator of IMPROVE-IT, Dr. Christopher Cannon, Senior Physician, Brigham and Women’s Hospital, Harvard University, Boston. It may also redefine treatment goals. The greater risk reduction in the ezetimibe arm was achieved with a median time average LDL of 1.4 mmol/L, which is lower than the current goal defined in guidelines from the Canadian Cardiovascular Society (Anderson et al. Can J Cardiol 2013;29:151-67).

Greater LDL-C Lowering Predicts Greater Benefit

When added to statin therapy, ezetimibe can provide a LDL-C decrease of approximately 0.4 mmol/L, but phase 3 data presented at the AHA demonstrated much higher LDL-C reductions on the PCSK9 inhibitor alirocumab, suggesting that more high-risk patients can reach their LDL-C goal. This was demonstrated in the ODYSSEY ALTERNATIVE trial, which is part of the ODYSSEY phase 3 program.

In ODYSSEY ALTERNATIVE, 314 patients intolerant to statins were randomized after a placebo run-in. The primary comparison of the 24-week trial was between 75 mg of subcutaneous alirocumab administered every 2 weeks (increased to 150 mg if LDL-C goals were not achieved by week 8) and 10 mg of once-daily ezetimibe. There were 126 and 125 patients randomized, respectively, to these two arms. In a third arm included for safety analysis and not intended for a lipid-lowering efficacy comparison, 63 patients were treated with atorvastatin.

In the on-treatment analysis, LDL-C was reduced from baseline by 52.2% in the alirocumab arm and 17.1% in the ezetimibe arm, producing a 35.1% mean difference (P<0.0001) favoring alirocumab. In the moderate to high-risk patients, the LDL-C treatment goal was <2.5 mmol/L, which was reached by 61% of those in the alirocumab arm and 10% in the ezetimibe arm (P<0.0001). In the very high-risk patients, the treatment goal was <1.8 mmol/L. This was reached by 42% of those in the alirocumab arm versus 4% of those randomized to ezetimibe (P<0.0001). Only about 50% of those randomized to alirocumab required a dose increase at week 12 to reach their goal.

Complexity of Statin-Intolerant Population

In the atorvastatin arm, only 25.4% discontinued therapy due to treatment-emergent adverse events, indicating that nearly 75% of a patient population identified as intolerant was able to remain on statin therapy over the course of the 24-week trial. These data underscore the “complexity of the statin-intolerant population,” according to principal investigator, Dr. Patrick M. Moriarty, Director, Lipid Apheresis Center, University of Kansas Medical Center, Kansas City. He also reported that any skeletal-muscle events were significantly more common on atorvastatin than alirocumab (P=0.042).

Although a high proportion of statin-intolerant patients were able to complete this 24-week trial, this does not diminish the need for alternatives to statins, according to the AHA-invited discussant of ODYSSEY ALTERNATIVE, Dr. Karol E. Watson, Co-Director, Center for Cholesterol and Lipid Management, University of California, Los Angeles. She noted, “Whether intolerance is defined subjectively or objectively, these are patients who are not going to adhere to their therapy.”

In addition to ODYSSEY ALTERNATIVE, which demonstrated the efficacy of alirocumab as a more effective lipid-lowering therapy than ezetimibe in statin-intolerant patients, several new phase 3 trials also presented at the 2014 AHA Scientific Sessions evaluated the role of alirocumab as an addition to statins to bring patients to treatment goals.

PCSK9 Inhibition Brings Patients to Goal

In the 24-week ODYSSEY OPTIONS I and II trials, presented by Dr. Harold Bays, Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky, alirocumab demonstrated an advantage for LDL-C reductions relative to any of the most common clinical options or strategies currently used when patients do not achieve LDL-C goals. In both trials, patients with a history of CV disease or multiple CV risk factors not at treatment goals on standard doses of atorvastatin (OPTIONS I) or rosuvastatin (OPTIONS II) were randomized to one of three arms: alirocumab in addition to the statin; ezetimibe in addition to the statin; or intensification of the statin, including switching from atorvastatin to rosuvastatin. In both studies, the average LDL-C reductions in the alirocumab arms, ranging from 36.3% to 54% relative to baseline, were more than double that of any other strategy at 24 weeks.

In the placebo-controlled ODYSSEY COMBO I study, presented by Dr. Dean J. Kereiakes, Lindner Research Center, Cincinnati, Ohio, patients at high CV risk who were not at goal on a maximally tolerated statin with or without another lipid-lowering therapy were randomized to receive alirocumab or placebo in addition to their statin or other lipid-lowering therapy. Relative to placebo, the reduction in LDL-C was 46% on an intention-to-treat (ITT) analysis and 50% on the on-treatment analysis (both P<0.0001) at week 24. On the ITT analysis at 24 weeks, LDL-C <1.8 mmol/L was achieved by 75% of those in the alirocumab arm versus 9% of those on placebo (P<0.0001). As is typical in the phase 3 ODYSSEY program, treatment-emergent adverse events “were generally comparable between the alirocumab and placebo arms” in ODYSSEY COMBO I, Dr. Kereiakes reported.

The ODYSSEY OUTCOMES trial now underway will specifically evaluate the impact of alirocumab on reducing CV events. Encouraging data were presented from a post-hoc analysis of adjudicated CV events from 3549 patients enrolled in 5 ODYSSEY phase 3 placebo-controlled trials. In this analysis, the 35% reduction in major CV events in patients with at least 52 weeks of follow-up produced an encouraging trend (P=0.0985), said Dr. Janet G. Robinson, Director, Prevention Intervention Center, University of Iowa, Iowa City. She noted that the composite endpoint (coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal stroke, and unstable angina requiring hospitalization) is the same as that being used in the ODYSSEY OUTCOMES trial.


The IMPROVE-IT trial has reaffirmed the lipid hypothesis by demonstrating that a non-statin therapy can achieve an LDL-C decrease that translates into a similar CV risk reduction as that previously observed with statins. LDL-C reductions with ezetimibe are relatively modest, but PCSK9 inhibitors, which are in late stages of clinical testing, have proven to offer significantly larger reductions in LDL-C and an opportunity to bring most moderate to very high-risk patients to treatment goals. Large on-going outcomes trials are testing whether these LDL-C reductions will also translate into commensurate CV risk reductions. The encouraging preliminary data suggest the potential for a new era in CV risk management.   


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