Why do anti-inflammatory therapies for coronary artery disease succeed—or fail?

Inflammation is now recognized as a major driver of coronary artery disease (CAD), contributing to atherosclerotic plaque formation, progression, destabilization and thrombosis. Yet translating this biological insight into effective treatment has proven far more difficult. Several anti-inflammatory strategies that appeared compelling on mechanistic grounds failed to consistently reduce cardiovascular events in clinical trials. This raises a fundamental question: why do some anti-inflammatory therapies succeed while others fail?

A new review in Science Bulletin, led by Prof. Xiang Cheng and colleagues from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, revisits the evolution of anti-inflammatory therapy in CAD and examines the factors that determine successful clinical translation. The authors synthesize evidence spanning inflammatory mechanisms, risk stratification and major cardiovascular trials, and propose a “4R framework” to guide the next phase of precision anti-inflammatory therapy.

The review first places CAD inflammation within a broader network linking systemic and local inflammatory processes. Bone marrow- and gut-derived signals can promote systemic inflammation, while the liver amplifies inflammatory signaling through the acute-phase response. Within the coronary artery, persistent inflammation contributes to plaque progression, instability and thrombotic complications. Because inflammatory burden varies substantially between patients, identifying residual inflammatory risk is an important prerequisite for targeted treatment.

High-sensitivity C-reactive protein (hsCRP) remains the most established clinical marker for this purpose. Importantly, the review highlights a population-specific issue: hsCRP levels are generally lower in East Asian populations than in Western populations. While an hsCRP level ≥2 mg/L is commonly used internationally to define residual inflammatory risk, current evidence suggests that hsCRP ≥1 mg/L may be a more appropriate threshold for risk stratification in East Asian patients with CAD.

The authors emphasize that biological involvement alone does not establish a pathway as a useful therapeutic target. In contrast to many earlier strategies, the NLRP3–IL-1β–IL-6 axis is supported by multiple layers of evidence, including mechanistic studies, human genetic data, inflammatory biomarkers and large randomized clinical trials. This broader evidence base has made the pathway the most mature translational example in cardiovascular inflammation to date.

The CANTOS trial provided a major proof of concept by showing that selective inhibition of IL-1β could reduce cardiovascular events without lowering lipid levels. Subsequent COLCOT and LoDoCo2 trials showed that low-dose colchicine could also reduce cardiovascular risk and helped move anti-inflammatory therapy toward clinical practice. However, the neutral result of the CLEAR-SYNERGY trial, in which colchicine was initiated early after percutaneous coronary intervention for acute myocardial infarction, suggests that therapeutic efficacy may depend not only on the drug or pathway being targeted, but also on the patient population and timing of treatment.

Drawing on these successes and failures, the authors propose a “4R framework” for clinical translation: the right target, the right patient, the right timing and the right benefit–risk balance.

The right target should have credible causal relevance to cardiovascular events, ideally supported by human genetic evidence, and its modulation should produce a meaningful and sustained reduction in inflammatory activity in humans. The right patient means identifying individuals with measurable residual inflammatory risk who are most likely to benefit from anti-inflammatory intervention. The right timing recognizes that inflammation may have different biological roles during chronic plaque inflammation and acute ischemic injury, making the disease stage an important determinant of treatment response. Finally, the right benefit–risk balance requires cardiovascular efficacy to be weighed against long-term safety and tolerability, including risks associated with sustained immune suppression.

Looking ahead, the review argues that anti-inflammatory therapy in CAD should move toward greater precision. Emerging pathways such as cGAS–STING, CCL2–CCR2 signaling, neutrophil extracellular traps and defective inflammation resolution may provide new therapeutic opportunities. At the same time, combining circulating inflammatory biomarkers with coronary imaging features and molecular phenotypes such as clonal hematopoiesis may help identify patients with persistent pathogenic inflammation more accurately. Future clinical trials will also need to define the optimal treatment window across different stages of CAD.

Rather than becoming a universal treatment for all patients with CAD, anti-inflammatory therapy may ultimately provide its greatest benefit when the target, patient, timing and safety profile are aligned. By organizing these determinants into the “4R framework”, the review provides a practical way to interpret past trial outcomes and to design more precise anti-inflammatory strategies for the future.