Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development

Abstract

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Atherosclerosis evaluation and cardiovascular risk estimation using coronary computed tomography angiography

“…Numerous studies have evaluated the impact of statin therapy on plaque burden and plaque composition. 79 The PARADIGM registry involving 1255 patients who underwent serial CCTA, showed statin therapy to accelerate calcifications of non-calcified plaques, thus conferring plaque stabilization. 77 Progression of calcified plaque was not associated with MACE, while in contrast rapid progression of non-calcified lesions was reflective of unstable CAD and associated with future adverse outcomes.…”

“…Furthermore, the direct visualization of coronary atherosclerosis by CCTA allows for the evaluation CAD burden and morphology and, given its non-invasive nature, allows for serial assessment to identify temporal changes in an individual’s disease process. 79 Quantitative CCTA evaluation of atherosclerosis 135–141 —coupled with the near universal availability of CT scanners—may provide a useful tool to evaluate the effectiveness of medical therapy and lifestyle interventions over time integrating large-scale randomized controlled trial data with an ‘ n of 1’ approach that is dictated by actual CAD compared to optimization of imprecisely associated risk factors within a single individual ( Table 5 ). In the meantime, assessment of both stenosis and a visual assessment of plaque burden such as the segment involvement score, as advocated by CAD-RADS 2.0, 142 could significantly improve ASCVD risk stratification in current clinical practice.…”

Coronary Artery Calcification: Current Concepts and Clinical Implications

“…The promise of more advanced imaging techniques should enable following the progression of morphological characteristics of calcification to contribute to prognostic assessment of high-risk, vulnerable patients and may be helpful in the development of novel therapies. 108 For example, fragmented calcification on histology corresponds to spotty calcification on CCTA, which links to greater risk of rupture compared with sheet calcification on histology, which corresponds to diffuse/dense calcification on radiology. 109 Microcalcification, considered a high-risk plaque feature on histology, still presents a challenge for current noninvasive imaging techniques, but advanced imaging modalities such as PCCT and DECT offer promising results.…”

Computed tomographic angiography measures of coronary plaque in clinical trials: opportunities and considerations to accelerate drug translation

“…Several studies have shown that improvements in CAD plaque morphology appear to be associated with reductions of MACE risk, but at present, this evidence is insufficient for application in regulatory approval. For acceptance as a surrogate measure o drug development tool, it is essential that academic clinicians engage with both the pharmaceutical industry and regulatory authorities to develop an evidence base and consensus on specific CT-based measures that most closely predict the effect of intervention on MACE ( 10 ).…”