Tribulations of Recent Cardiology Trials, the Audacity of Hope, and HOPE-3.

Canadian Journal of Cardiology (2015) 1e3 Editorial Tribulations of Recent Cardiology Trials, the Audacity of Hope, and HOPE-3 David D. Waters, MD, and Katherine Hsin-Yu Chau, MD Division of Cardiology, San Francisco General Hospital, and the Department of Medicine, University of California, San Francisco, San Francisco, California, USA See article by Lonn et al., pages xxx-xxx of this issue. Hope is an optimistic attitude of mind based on an expecta- tion of positive outcomes. For most recently completed large trials of drugs to reduce cardiovascular (CV) events, the hoped-for positive outcome did not materialize. Examining not just why these trials failed, but the basis for the hope that they would be successful, might lead to wiser decisions for future trials. Drugs That Increase High-Density Lipoprotein Cholesterol A low high-density lipoprotein cholesterol (HDL-C) level is such a strong, independent predictor of CV events that it seemed obvious that a drug that increased the level of HDL-C would reduce events. The calculation from epidemiologic data, that a 1 mg/dL increase in HDL-C is associated with a 2% decrease in coronary disease risk in men and a 3% decrease in women, 1 added precision to this relationship and made it seem more real. The failure of torcetrapib to reduce CV events in the ﬁrst large outcome trial of a cholesteryl ester transfer protein (CETP) inhibitor, despite a 72% increase in HDL-C, was rightly attributed to off-target toxicity. 2 The failure of the CETP inhibitor dalcetrapib to reduce CV events is more difﬁcult to explain. 3 Anacetrapib and evacetrapib, CETP in- hibitors that decrease low-density lipoprotein cholesterol (LDL-C) levels in addition to increasing levels of HDL-C, are currently being tested in large phase III clinical trials, and might well fulﬁl hopeful expectations. 4 An intracoronary ultrasound study of apolipoprotein A1 Milano infusions for 5 weeks in patients with acute coronary syndromes raised high hopes because the infusions were asso- ciated with a signiﬁcant improvement in the primary end point, a change in percentage of atheroma volume. 5 Although the trial was billed as “placebo-controlled,” changes in the placebo Received for publication August 19, 2015. Accepted August 19, 2015. Corresponding author: Dr David D. Waters, Division of Cardiology, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110, USA. Tel.: þ1-415-420-6646. E-mail: David.Waters@ucsf.edu See page 3 for disclosure information. group were not compared with changes in the active treatment groups. Two subsequent trials of HDL-C infusion therapies with intracoronary ultrasound end points did not show a beneﬁcial treatment effect. 6,7 A more recent, much larger intracoronary ultrasound trial of intravenous infusions of the HDL-C mimetic agent CER-001 also showed no beneﬁt. 8 Why have therapies to increase levels of HDL-C mainly failed, at least so far? Does not HDL-C promote cholesterol efﬂux from macrophages, and participate in a variety of other atheroprotective mechanisms? As recently summarized by Rader and Hovingh, 9 the genetic disorders associated with lifelong extremely low levels of HDL-C are not associated with premature coronary disease. HDL-C is still a useful marker of risk in populations, and is used in most CV risk calculators; however, how well HDL-C particles function and not their absolute number is more closely linked to athero- genesis. Treatments that increase HDL-C levels do not necessarily increase HDL-C function. Other Markers of CV Risk That Have Failed as Drug Targets Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a circulating enzyme secreted by inﬂammatory cells, bound mainly to apolipoprotein B-containing lipoproteins, and is expressed in the necrotic core of atherosclerotic lesions. 10 Lp- PLA 2 activity has been linked to increased coronary risk in several studies, but genetic variants with modest effects on Lp- PLA 2 activity were found not to be associated with increased coronary risk. 11 Darapladib, an Lp-PLA 2 inhibitor, prevented necrotic core expansion compared with placebo in an intracoronary ultra- sound study with virtual histology. 12 However, neither the primary end points of the trial, nor any of the other secondary end points, showed a positive effect of darapladib. On the basis of this evidence, 2 large clinical trials were performed, and in both of them darapladib did not reduce CV events. 13,14 Analogously, varespladib, an inhibitor of secretory phos- pholipase A 2 , a biomarker implicated in atherosclerosis, failed to reduce CV events in a clinical trial of patients who had an acute coronary syndrome; in fact, the drug was actually associated with an increase in myocardial infarction. 15 http://dx.doi.org/10.1016/j.cjca.2015.08.020 0828-282X/O 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.