Stabilizing the plaque: does intensive medical treatment modify coronary atherosclerosis in women with INOCA?

This editorial refers to ‘Improved plaque composition from intensive medical treatment in women with angina and non-obstructive coronary disease’ by J. Lenell et al., https://doi.org/10.1093/cvr/cvag174. Ischaemia with non-obstructive coronary artery disease (INOCA) disproportionately affects women, carries a substantial burden of recurrent anginal symptoms, and confers an elevated risk of adverse cardiovascular events despite the absence of epicardial flow-limiting disease.1,2 The mechanistic heterogeneity underlying INOCA—encompassing microvascular dysfunction, coronary vasospasm, endothelial dysfunction, and diffuse atherosclerotic disease—has complicated systematic approaches to disease-modifying therapy, and the evidence supporting pharmacological intervention remains limited relative to the prevalence and clinical burden of the condition. Against this backdrop, Lenell et al.3 in the current issue use serial CT coronary angiography (CTCA) to examine the impact of combination intensive medical treatment (IMT) on coronary plaque composition in women with INOCA.3 This is a prospective imaging sub-study nested within the WARRIOR trial, with the IMT inclusive of high-intensity statin therapy, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), and low-dose aspirin.3 The biological rationale for this CTCA-based study is compelling. Non-calcified plaque (NCP), particularly its low-attenuation lipid-rich component, is independently associated with future myocardial infarction, whilst increasing plaque calcification, including that observed during statin therapy, is considered a marker of plaque stabilization.4,5 Amongst 186 women with baseline plaque who completed serial imaging at least 2 years after randomization, IMT was associated with a significantly greater reduction in NCP volumetric composition (−3.9% vs. −1.5%, P = 0.003) and a greater bi-annualized increase in calcified plaque (CP) volume (6.2 vs. 3.9 mm3, P = 0.013), without a between-arm difference in total plaque volume. In multivariable analysis, IMT assignment independently predicted NCP compositional change after adjustment for baseline plaque burden, peri-coronary adipose tissue attenuation, age, and hyperlipidaemia, and the finding remained robust in sensitivity analyses incorporating additional comorbidities. Whilst the study did not demonstrate a significant between-arm reduction in low-density non-calcified plaque volume (<30 Hounsfield Units, commonly known as low-attenuation non-calcified plaque volume), the use of this measure is commonly limited by study power secondary to lower numbers of individuals with this higher risk plaque phenotype. The observed significant increase in CP is consistent with a biological transition towards a denser and potentially less rupture-prone plaque phenotype. One of the main challenges of the parent WARRIOR trial was the substantial pharmacological overlap between treatment arms related to the real-world design, with usual care being left to physician discretion. At baseline, 59% of participants were already receiving statin therapy, 42% ACE inhibitor or ARB therapy, and 54% aspirin; 2 years after randomization, 89% in the IMT arm and 76% in the usual-care arm were taking any statin.6 This design, along with the impact of the COVID-19 pandemic on enrolment (only 55% of planned n = 4422), made it challenging for the primary endpoint to reach statistical significance.6 The imaging sub-study does provide supportive evidence that intensification of medical therapy can provide benefits on plaque biology. Amongst CTCA plaque metrics, NCP volume has emerged as the most promising surrogate biomarker for drug efficacy in coronary disease, demonstrating reproducible responsiveness to major adverse cardiovascular events (MACE)-reducing therapies whilst enabling a 92% reduction in required participant numbers and 60% shorter follow-up compared with conventional MACE-based trials.7 These attributes position CTCA-derived plaque endpoints as compelling tools to accelerate the evaluation of IMT and valid surrogates that could be adopted by regulatory bodies, such as the Food and Drug Administration, to facilitate broader clinical translation of novel therapeutic strategies in coronary disease. Interpretation of the results of the WARRIOR imaging sub-study needs to consider selection bias. Whilst the parent study suffered from declining adherence within the IMT arm (high-intensity statin use fell from 57% at 12 months to 39% at 36 months),6 the ancillary study eligibility required adherence to IMT and completion of follow-up visits. The ancillary cohort therefore represents a selectively adherent, imaging-enriched subgroup rather than the broader randomized WARRIOR population, potentially limiting external validity. The mechanistic implications of the WARRIOR CT sub-study remain uncertain. Exploratory mediation analysis demonstrated that neither changes in LDL cholesterol nor systolic blood pressure explained the observed effect on NCP composition. Whilst this finding is compatible with the recognized pleiotropic and anti-inflammatory effects of statins, as well as possible vascular effects of renin angiotensin aldosterone system (RAAS) inhibition,8 it does not isolate the contribution of any individual component of the combination regimen. Notably, the compositional plaque changes were not accompanied by differences in machine-learning ischaemia risk score or contrast-density difference, indicating that the observed biological signal did not translate into detectable differences in ischaemia burden or haemodynamic significance in this cohort. The findings of Lenell et al. nonetheless advance the field in two important respects. First, they provide prospective randomized trial evidence that guideline-directed medical therapy may favourably modify coronary plaque biology in women with suspected INOCA, a population for whom the rationale for intensive preventive therapy has largely been extrapolated from obstructive coronary disease cohorts. Second, the independent association between baseline peri-coronary adipose tissue attenuation and subsequent plaque compositional change identifies coronary inflammation as a potentially important upstream determinant of plaque vulnerability in this population.9 This raises the possibility that inflammatory imaging biomarkers could help identify individuals most likely to derive measurable biological benefit from intensified therapy. The logical next step is not simply larger replication studies, but more biologically enriched trials. Future studies should enroll women with confirmed ischaemia on functional testing and high plaque burden or adverse plaque phenotypes on CTCA, with clearer pharmacological separation between treatment arms and extended longitudinal follow-up. Factorial trial designs may help disentangle the relative contributions of statins, ACE inhibitor/ARB therapy, and aspirin to plaque remodelling. Serial quantitative CTCA using artificial intelligence-enabled plaque analysis,10 combined with inflammatory biomarker profiling and prospective cardiovascular outcome assessment, may ultimately determine whether modification of plaque composition translates into event reduction, as suggested by broader CTCA-guided prevention data.7 Until such data emerge, the findings of this ancillary study support the continued use of guideline-directed preventive therapy in women with INOCA. None.