Author + information
- Ahmed Tawakol, MD†∗ (, )
- Parmanand Singh, MD‡,
- James H.F. Rudd, PhD§,
- Joseph Soffer, MD‖,
- Gengqian Cai, PhD‖,
- Esad Vucic, MD‡,
- Sarah P. Brannan, DPhil‖,
- Elizabeth A. Tarka, MD‖,
- Bonnie C. Shaddinger, PharmD‖,
- Lea Sarov-Blat, PhD‖,
- Paul Matthews, MD‖,¶,
- Sharath Subramanian, MD‡,
- Michael Farkouh, MD#∗∗ and
- Zahi A. Fayad, PhD#,††
- †Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- ‡Cardiac MR-PET-CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- §Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom
- ‖Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
- ¶Division of Brain Sciences, Imperial College London, London, United Kingdom
- #Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- ∗∗Peter Munk Cardic Centre and the Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
- ††Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- ↵∗Cardiology Division, Massachusetts General Hospital and Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02114
To the Editor:
Previous reports have demonstrated that lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker, is associated with increased risk of cardiovascular events (1). Lp-PLA2 mediates formation of bioactive mediators (lysophosphatidyl choline and oxidized nonesterified fatty acids) known to elicit several deleterious inflammatory responses involved in the pathobiology of atherosclerosis. Lysophosphatidyl choline serves as a potent chemoattractant for monocytes, resulting in foam cell accumulation within the arterial wall. Additionally, Lp-PLA2 has been detected in rupture-prone and ruptured atherosclerotic plaques. Taken together, the data suggests that inhibition of Lp-PLA2 may attenuate intimal macrophage accumulation and consequently stabilize atherosclerotic plaque.
Positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) is a validated imaging technique widely used to quantify vascular inflammation within atheroma. In vivo measures of FDG-PET uptake are reproducible, positively correlate with metabolically active macrophages and macrophage infiltration into the vessel wall, and are modifiable by different pharmacological interventions targeted at reducing atherosclerotic inflammation (2). As such, this imaging approach has been increasingly utilized for noninvasive assessment of plaque inflammation with novel therapeutic agents.
In this multicenter, randomized placebo-controlled study, we tested the hypothesis that selective inhibition of Lp-PLA2 activity by rilapladib, an oral potent Lp-PLA2 inhibitor, reduces atherosclerotic inflammation (as assessed with FDG-PET imaging). The pre-specified coprimary endpoints were percentage of inhibition from baseline in Lp-PLA2 activity and change from baseline FDG uptake within the arterial wall after 84 days of treatment with rilapladib.
The study population consisted of 83 participants (78% male, mean age 63.9 ± 7.0) with stable atherosclerosis who were randomized to placebo once daily versus rilapladib 250 mg once daily, both in addition to chronic statin therapy (Online Fig. 1). At baseline, mean pre-dose values of Lp-PLA2 activity were similar between the treatment groups. Additional demographic and baseline characteristics of the study population are summarized in Online Table 1.
Seventy-one subjects were included in the primary FDG-PET imaging analyses. Target-to-background ratio (TBR) of the index vessel, defined as the artery (either right carotid artery, left carotid artery, or ascending aorta) with the highest average maximum TBR, was analyzed at baseline (pre-treatment) and day 84 (post-treatment). Three pre-specified approaches were used to quantify arterial inflammation within the index vessel: 1) the primary imaging endpoint of reduction in TBR of “all segments”; and 2) secondary imaging endpoints analyses of the “most diseased segment”; and 3) “active segments” (Fig. 1). A detailed explanation of the imaging and statistical methods can be found in the Online Appendix.
At follow-up, rilapladib inhibited Lp-PLA2 activity by approximately 82% (p < 0.0001) (Online Fig. 2). Rilapladib was tolerated well, with a safety profile similar to that of placebo (Online Table 2).
There was a significant reduction in the average maximum TBR of all segments within the index vessel from baseline to day 84 in patients randomized to rilapladib (2.21 ± 0.402 vs. 2.09 ± 0.279; p = 0.0072), as well as those randomized to placebo (2.11 ± 0.388 vs. 1.99 ± 0.320; p = 0.0012). However, the primary imaging endpoint of a difference between treatment groups was not statistically significant (ΔTBR = 0.05, 95% confidence interval [CI]: –0.06 to 0.16; p = 0.372) (Table 1). Similar results were observed in secondary imaging endpoints analyses of the most diseased segments and the active segments of the index vessel (Table 1).
In the IBIS-II (Integrated Biomarker and Imaging Study) with darapladib, another selective Lp-PLA2 inhibitor, treatment effects were more evident when analyses were confined to lipid-rich atherosclerotic lesions (as assessed by virtual histology intravascular ultrasound). Furthermore, it is known that arterial locations with structural evidence of atherosclerosis, identified with magnetic resonance imaging (MRI) or computed tomography have greater macrophage infiltration and higher FDG-PET uptake than do arterial locations with lesser structural evidence of atherosclerosis (3). Accordingly, there are reasons to anticipate that a PET analysis that is limited to locations with evident structural atherosclerotic disease (i.e., a plaque-based analysis) might provide enhanced opportunities to evaluate a treatment effect.
For these reasons, we pursued an exploratory analysis, conceptually analogous to IBIS-II, whereby evaluation of treatment response was confined to arterial locations with morphological evidence of atherosclerosis on structural imaging. To accomplish this, MRI imaging was used to identify locations with visible atherosclerotic plaque in the subset of patients providing technically adequate carotid MRI data (n = 51; placebo = 25, rilapladib = 26) (Online Fig. 3, Online Table 3). We compared FDG uptake in locations with versus without evidence of plaque on MRI prior to randomization. Thereafter, we performed separate post-hoc plaque-based analyses to evaluate treatment effect confined within arterial locations with MRI evidence of plaque and both MRI evidence of plaque and PET evidence of increased inflammation (defined as TBR >1.6).
First, we observed that at baseline, the FDG signal (TBR) was higher in arterial locations with (vs. without) structural evidence of plaque on MRI (p < 0.001) (Online Fig. 4). In a plaque-based analysis of treatment effect limited to patients with MRI evidence of atherosclerotic plaque, rilapladib was associated with a significant reduction in absolute TBR (from baseline, Δ = –0.13; p = 0.01), whereas placebo was not (Δ = –0.07; p = 0.18). However, there was no significant difference between treatment groups (p = 0.39) (Table 2). Similar findings were observed in the post-hoc analysis that was limited to arterial sections with both MRI evidence of plaque and TBR >1.6 (Table 2).
Accordingly, neither the vessel-based nor plaque-based analyses demonstrated a significant effect of short-term rilapladib compared with that of placebo in individuals with stable atherosclerotic disease concurrently on statin therapy. It is notable that the study was powered to detect a 15% placebo-corrected reduction in activity; hence, it is underpowered to detect smaller yet potentially important changes in arterial FDG uptake (such as a ∼7% reduction that would be seen with low-dose statins) (4,5). It is further worth noting that in the plaque-based analysis, the nominal reduction from baseline seen in the rilapladib group (∼3% to 6%) begins to approach that typically observed with low-dose statins. Whether or not longer-term treatment with a Lp-PLA2 antagonism, using the related compound darapladib, translates to potential clinical benefit will be assessed by large clinical outcome trials currently being conducted in higher-risk populations.
The authors thank all of the Rilapladib investigators, their staff personnel, and patients that participated in this trial and Sue Casson of Fishawack Scientific Communications Ltd. for editorial assistance with the preparation of the manuscript.
Please note: Funding for this study and for editorial assistance with the preparation of the manuscript were provided by GlaxoSmithKline, PLC. Dr. Tawakol has reported that he has received grants from the National Institutes of Health, Genetech, and Bristol-Myers Squibb; and consulting fees from Genetech/Roche, Bristol-Myers Squibb, Novartis, Cerenis, and Siemens. Dr. Rudd has reported that his work has been supported by the National Institute for Health Research Cambridge Biomedical Research Centre, the British Heart Foundation, the Academy of Medical Sciences, and the Higher Education Funding Council for England; and he has received support from Roche and Genetech. Drs. Soffer, Cai, Brannan, Tarka, Shaddinger, Sarov-Blat, and Matthews are employees, with stock and stock options, of GlaxoSmithKline. Dr. Matthews has received honoraria from Novartis. Dr. Fayad has received research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb; and honoraria from Roche. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Tawakol and Singh contributed equally to this work. (The Stabilization of Plaques Using Darapladib Thrombolysis In Myocardial Infarction 52 Trial [SOLID-TIMI 52]; NCT01000727; The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903; An Imaging Study in Patients With Atherosclerosis Taking Rilapladib of Placebo for 12 Weeks; NCT00695305).
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