Clinical bottom line
Novel anti-inflammatory therapies represent a promising adjunctive approach to reduce cardiovascular events in patients with established atherosclerotic disease. Targeting inflammation beyond standard lipid-lowering and antithrombotic treatments has shown modest but statistically significant reductions in major adverse cardiovascular events (MACE). However, benefits vary by agent, patient population, and inflammatory biomarker status, and risks such as infection must be carefully weighed. Current evidence supports selective use of these agents in high-risk patients with residual inflammatory risk despite optimal guideline-directed therapy, pending further validation and cost-effectiveness analyses.
What the evidence shows
Atherosclerosis is increasingly recognized as a chronic inflammatory condition, with inflammation playing a key role in plaque progression and destabilization. Landmark trials over the past decade have evaluated anti-inflammatory agents targeting this pathway:
- The CANTOS trial (2017) demonstrated that canakinumab, a monoclonal antibody targeting interleukin-1β, reduced recurrent cardiovascular events by 15% in patients with prior myocardial infarction and elevated high-sensitivity C-reactive protein (hsCRP) despite statin therapy (Ridker PM, et al. NEJM 2017;377:1119-31. PMID: 28845751). This established proof-of-concept that selective inflammation inhibition can improve outcomes independent of lipid lowering.
- The COLCOT trial (2019) showed that low-dose colchicine (0.5 mg daily), an anti-inflammatory agent with broad effects on neutrophil function and inflammasome activity, reduced the composite endpoint of cardiovascular death, myocardial infarction, stroke, and urgent coronary revascularization by 23% in patients shortly after myocardial infarction (Tardif JC, et al. NEJM 2019;381:2497-505. PMID: 31792526). Colchicine’s oral administration and lower cost enhance its clinical appeal.
- The LoDoCo2 trial (2020) extended these findings to patients with stable coronary artery disease, where low-dose colchicine reduced MACE by 31% over a median 29 months (Nidorf SM, et al. NEJM 2020;383:1838-47. PMID: 33009593).
Meta-analyses incorporating these and smaller studies suggest a consistent relative risk reduction of approximately 20% for MACE with anti-inflammatory therapy in secondary prevention populations (Ridker PM, et al. Circulation 2021;143:1179-91. PMID: 33546469). Importantly, these benefits appear most pronounced in patients with elevated inflammatory biomarkers such as hsCRP, supporting a precision medicine approach.
Caveats and uncertainty
Despite encouraging results, several caveats remain:
- Canakinumab’s high cost and increased risk of serious infections limit its widespread use. The CANTOS trial reported a higher incidence of fatal infections, underscoring the need for careful patient selection.
- Colchicine, while generally well tolerated, can cause gastrointestinal side effects and rare myotoxicity, especially when combined with certain drugs. Long-term safety data beyond 3 years are limited.
- The magnitude of absolute risk reduction is modest, and the number needed to treat (NNT) to prevent one event is relatively high, particularly in lower-risk populations.
- Most trials enrolled patients with prior myocardial infarction or stable coronary disease; data in primary prevention or other atherosclerotic manifestations (e.g., peripheral artery disease, cerebrovascular disease) are sparse.
- The optimal inflammatory biomarker threshold for initiating therapy and the role of serial biomarker monitoring remain undefined.
- Other anti-inflammatory agents targeting different pathways (e.g., methotrexate, TNF inhibitors) have not demonstrated cardiovascular benefit in randomized trials, highlighting the complexity of inflammation in atherosclerosis.
How this may change practice
Clinicians should recognize residual inflammatory risk as a modifiable contributor to recurrent cardiovascular events in patients with atherosclerotic disease despite optimal lipid lowering and antithrombotic therapy. Measurement of hsCRP can help identify candidates who may derive incremental benefit from anti-inflammatory therapy.
Low-dose colchicine is emerging as a practical option for secondary prevention in selected patients, particularly those with recent myocardial infarction or stable coronary disease and elevated inflammatory markers, after careful assessment of contraindications and drug interactions.
Use of canakinumab remains largely investigational due to cost and safety concerns but may be considered in highly selected patients within specialized centers or clinical trials.
Further research is needed to refine patient selection, optimize dosing, evaluate long-term safety, and assess cost-effectiveness before routine adoption of anti-inflammatory therapies in broader populations.