Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients. A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053). Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.

Icosapent ethyl (IPE) significantly reduced ischaemic events in statin-treated patients with atherosclerosis or diabetes and elevated triglycerides in REDUCE-IT, including large reductions in myocardial infarction and elective, urgent, and emergent coronary revascularization. However, the mechanisms driving this clinical benefit are not fully known. The EVAPORATE trial demonstrated that IPE significantly reduced plaque burden. No study to date has assessed the impact of IPE on coronary physiology. Fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) data sets (FFR_CT) applies computational fluid dynamics to calculate FFR values in epicardial coronary arteries. Our objective was to assess the impact of IPE on coronary physiology assessed by FFR_CT using imaging data from EVAPORATE. A total of 47 patients and of 507 coronary lesions at baseline, 9 months, and 18 months with coronary CTA and FFR_CT were studied in a blinded core lab. The pre-specified primary endpoint was the FFR_CT value in the distal coronary segment from baseline to follow-up in the most diseased vessel per patient using IPE compared with placebo. The pre-specified secondary endpoint was the change in translesional FFR_CT (ΔFFR_CT) across the most severe (minimum 30% diameter stenosis) coronary lesion per vessel. Baseline FFR_CT was similar for IPE compared with placebo (0.83 ± 0.08 vs. 0.84 ± 0.08, P = 0.55). There was significant improvement in the primary endpoint, as IPE improved mean distal segment FFR_CT at 9- and 18-month follow-up compared with placebo (0.01 ± 0.05 vs. −0.05 ± 0.09, P = 0.02, and −0.01 ± 0.09 vs. −0.09 ± 0.12, P = 0.03, respectively). ΔFFR_CT in 140 coronary lesions was improved, although not statistically significant, with IPE compared with placebo (−0.06 ± 0.08 vs. −0.09 ± 0.1, P = 0.054). Icosapent ethyl demonstrated significant benefits in coronary physiology compared with placebo. This early and sustained improvement in FFR_CT at 9- and 18-month follow-up provides mechanistic insight into the clinical benefit observed in the REDUCE-IT trial. Furthermore, this is the first assessment of FFR_CT to determine drug effect.

Aims: Inflammation plays a crucial role in atherosclerosis and coronary artery disease progression. Colchicine, an inexpensive anti-inflammatory medication, has shown promising results in reducing cardiovascular events in patients with stable coronary artery disease (CAD). However, its effect on coronary plaque progression remains unclear. We investigated whether colchicine, as an adjunct to standard of care therapy, affects coronary plaque components in patients with stable CAD. Methods and results: We performed a prospective, randomized, double-blinded, placebo-controlled trial in 84 patients with stable CAD to receive either colchicine (0.5 mg/day) or placebo for 12 months. All enrolled patients had proven coronary artery disease as evidenced by coronary angiography, CT coronary angiography, or a Coronary Artery Calcium Score >400. The primary outcome was the rate of change in low attenuation plaque (LAP) volume, as measured by serial coronary computed tomography angiography (CCTA), utilizing volumetric plaque quantification software at 12 months between colchicine and placebo groups. The secondary endpoint was total plaque percent atheroma volume (PAV%). The sample size was set assuming a treatment difference of at least 8 mm³ change in LAP volume in favour of colchicine compared to placebo. The mean age of the 72 participants who completed the study was 64.6 ± 7.3 years, with 63 (88%) subjects being male. Baseline demographics, risk factors, medications, vitals, and inflammatory markers were not significantly different between the colchicine and placebo groups. One exception was that the colchicine group had significantly higher use of hypertension medications (75% vs. 44%) at the study start. There was no significant difference in the change in total LAP between the colchicine group with median (IQR) 0.1 (−02, 0.2) vs. 0.0 (−0.2, 0.3) in placebo, un-adjusted P = 0.342. Multivariable models, including known CV risk factors and baseline LAP, also showed no significant difference between the changes in LAP between treatment and placebo groups. A treatment effect was observed in the total PAV%. Follow-up total PAV at 12-month scan was significantly lower at median (IQR) 0.3 (−0.1, 1.3) in the colchicine group vs. 1.4 (0.4, 2.6) in placebo, P = 0.008 (unadjusted). In multivariate models, colchicine treatment was associated with lower PAV at 1 year, P = 0.015. Trends toward regression in non-calcified and fibro-fatty plaque were observed. Inflammatory markers were reduced with colchicine, but did not achieve statistical significance. Conclusion: In the EKSTROM trial, low-dose colchicine did not significantly reduce low attenuation plaque volume in patients with stable coronary artery disease over 12 months, but did achieve a significant reduction in total plaque burden (percent atheroma volume) and dense calcified plaque compared to placebo. Colchicine was well tolerated, with no major safety concerns. In this stable well-treated CAD population, LAP was rare and not significantly reduced; however, it slowed overall plaque progression, supporting further investigation of its role in secondary prevention of coronary artery disease. EKSTROM Trial: NCT06342609.

Blue zones are longevity hotspots around the world characterized by highest concentrations of healthy centenarians. Certified blue zone communities are designed by implementation of environmental and policy changes that promote healthy behaviors. To examine the trends of prevalence of zero CAC, a marker of ideal cardiovascular and overall health status and burden of cardiovascular risk factors in Beach Cities/certified blue zones of Southern California and rest of California. This is a population-based cohort study of persons aged 50 years or older in California, who underwent CAC screening between 2000 and 2019. A total of 3864 participants from Beach Cities of Southern California were identified by Zip Codes and compared with 35,537 participants from rest of California. We compared trends of prevalence of zero CAC and cardiovascular risk factors between the two groups, in 5-year intervals. Among 39,401 participants (mean age, 58.1 years; 36% women), 13,374 (34%) had zero CAC. The prevalence of CAC ​= ​0 was significantly higher in Beach Cities compared to the rest of California (p ​< ​0.001). Across the study period, the prevalence of cardiac risk factors including obesity, smoking, diabetes and hypertension remain significantly lower in Beach Cities. (p ​< ​0.001) This study, shows for the first time, that higher prevalence of zero CAC in Beach Cities of California, adds validity to excellent prognosis and longevity in these areas. The impact of policy implementation and environmental changes on lifestyle patterns, cardiovascular health and healthy ageing needs to be evaluated.