NEJM original articles

Background. Percutaneous coronary intervention (PCI) is increasingly used for revascularization of unprotected left main coronary artery disease. Whether intravascular ultrasonographic (IVUS) guidance during PCI results in better clinical outcomes than conventional angiographic guidance alone is uncertain.

Methods. In an international, multicenter, open-label trial, we randomly assigned patients with unprotected left main coronary artery disease in a 1:1 ratio to undergo either IVUS-guided PCI or angiography-guided PCI. The primary end point was a patient-oriented composite of any stroke, any myocardial infarction, any revascularization, or death from any cause at the longest follow-up.

Results. A total of 806 patients underwent randomization; 401 were assigned to undergo IVUS-guided PCI and 405 to undergo angiography-guided PCI. The mean (±SD) age of the patients was 71.4±10.7 years, 78.4% of the patients were men, and 34.7% had diabetes. At a median follow-up of 2.9 years, a primary end-point event had occurred in 135 patients (33.7%) in the IVUS-guided PCI group and in 125 patients (30.9%) in the angiography-guided PCI group (hazard ratio, 1.11; 95% confidence interval, 0.87 to 1.42; P = 0.40). The incidence of death, myocardial infarction, or revascularization appeared to be similar in the two groups. The percentages of patients with procedure-related and overall safety events also appeared to be similar in the two groups.

Conclusions. Among patients with unprotected left main coronary artery disease, IVUS-guided PCI showed no additional benefit over angiography-guided PCI with respect to the incidence of stroke, myocardial infarction, any revascularization, or death from any cause at a median follow-up of 2.9 years. (Funded by Philips Image Guided Therapy Devices and Boston Scientific; OPTIMAL ClinicalTrials.gov number, NCT04111770.).

Background. Intravascular ultrasound (IVUS) guidance during percutaneous coronary intervention (PCI) has been associated with increased stent optimization and reduced adverse events among patients with complex coronary-artery lesions, but adoption of this strategy in Western countries remains low. Although practice guidelines recommend intracoronary imaging for anatomically complex lesions, evidence from current European practice is limited.

Methods. In this investigator-initiated, international, open-label, randomized, controlled trial, we assigned patients undergoing complex PCI to either IVUS-guided PCI, performed with the use of prespecified stent-optimization criteria, or angiography-guided PCI. The primary end point was target-vessel failure, defined as a composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-vessel revascularization.

Results. Of the 2020 patients who underwent randomization, 1010 in the IVUS-guided PCI group and 1009 in the angiography-guided PCI group were included in the primary analysis. The mean age of the patients was 69 years, 79.4% were men, and 27.4% presented with an acute coronary syndrome. The mean procedure duration was 88.8 minutes with IVUS-guided PCI and 66.2 minutes with angiography-guided PCI. Dilation with balloon angioplasty after stent implantation was performed in 91.3% of the IVUS-guided PCI procedures and in 84.5% of the angiography-guided PCI procedures. At a median follow-up of 19.0 months (interquartile range, 15.2 to 23.4), target-vessel failure had occurred in 140 patients (13.9%) in the IVUS-guided PCI group and in 112 patients (11.1%) in the angiography-guided PCI group (hazard ratio, 1.25; 95% confidence interval, 0.97 to 1.60; P = 0.08). Procedural complications occurred in 11.3% of the IVUS-guided PCI procedures and in 10.2% of the angiography-guided PCI procedures. The frequency of adverse events appeared to be similar in the two groups.

Conclusions. Among patients undergoing complex high-risk PCI, a strategy of routine IVUS-guided PCI performed with the use of prespecified stent-optimization criteria was not associated with a lower risk of target-vessel failure than angiography-guided PCI alone. (Funded by Boston Scientific; IVUS-CHIP ClinicalTrials.gov number, NCT04854070.).

Background. Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD). The allele HLA-DRB1*01:03 is the strongest genetic risk factor for ulcerative colitis.

Methods. We used a cellular interleukin-10 reporter assay and a confirmatory competitive enzyme-linked immunosorbent assay to assess neutralizing interleukin-10 autoantibodies in serum samples obtained from patients with IBD in the Oxford and U.K. IBD BioResource cohorts and from persons without IBD (controls). An in vitro cytokine-release bioassay was performed in a subgroup of patients to assess interleukin-10, interleukin-23, interleukin-1β, tumor necrosis factor, and interleukin-6. We performed HLA association analysis using imputation and high-resolution sequencing.

Results. Interleukin-10-neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%; 95% confidence interval [CI], 3.0 to 4.1) and in none of 1006 controls (P<0.001). High anti-interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response, consistent with functional neutralization of interleukin-10 signaling. Anti-interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0; 95% CI, 16.4 to 152.3; P = 6.14×10^-12) and the U.K. IBD BioResource cohort (odds ratio, 24.7; 95% CI, 14.5 to 42.1; P = 6.20×10^-32) and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5; 95% CI, 12.2 to 71.1; P = 4.85×10^-14).

Conclusions. Neutralizing interleukin-10 autoantibodies were present in a subgroup of patients with IBD and were strongly associated with HLA-DRB1*01:03. (Funded by the National Institute for Health and Care Research and others.).

Background. X-linked retinoschisis is a recessive disease characterized by progressive macular degeneration and vision loss due to pathogenic variation in RS1.

Methods. We administered a single subretinal injection of an AAV8 vector containing human RS1 complementary DNA (scAAV8-hRS1) into one eye of patients 5 to 18 years of age who had X-linked retinoschisis. The primary end point was safety during the 52-week period after injection. Secondary end points included the change from baseline to week 52 in the best corrected visual acuity (BCVA), retinal structure (assessed with swept-source optical coherence tomography; SS-OCT), the function of photoreceptor and bipolar cells (assessed with full-field electroretinography), and macular sensitivity to light (assessed with microperimetry).

Results. A total of 12 patients were enrolled. The dose-escalation phase included two cohorts of 3 patients each who received scAAV8-hRS1 at a dose of 7.5×10¹⁰ or 1×10¹¹ vector genomes. In the dose-expansion phase, 3 additional patients were enrolled in each cohort. Overall, 56 adverse events were reported during the 52 weeks after surgery. No patient was reported to have an adverse event of grade 3 or higher or ocular inflammation. A macular hole in the treated eye was observed at week 1 in 1 patient. The mean increase at week 52 in the BCVA was 10.8 letters among the treated eyes and 2.4 letters among the untreated eyes. SS-OCT imaging showed closure of the macular schisis cavity by week 13 in the treated eye in all 12 patients. The mean change at week 52 in central retinal thickness was -437.7 μm among the treated eyes and -17.2 μm among the untreated eyes; the outer retinal layers in the treated eyes of 9 patients were continuous at week 52. No clinically meaningful changes in the function of photoreceptor and bipolar cells or macular retinal sensitivity were observed in the treated eyes.

Conclusions. In this study of subretinal gene therapy with scAAV8-hRS1 in 12 patients with X-linked retinoschisis, there were no reports of adverse events of grade 3 or higher or ocular inflammation. Further clinical testing of scAAV8-hRS1 is warranted. (Funded by the National Natural Science Foundation of China and others; Chinese Clinical Trial Registry number, ChiCTR2300076682.).