Progression of Gastrointestinal Injury During Antiplatelet Therapy After Percutaneous Coronary Intervention: A Secondary Analysis of the OPT-PEACE Randomized Clinical Trial.

Importance: Gastrointestinal injury progression induced by antiplatelet therapy in patients after percutaneous coronary intervention (PCI) has not been well studied. Objective: To assess the association of aspirin, clopidogrel, and their combination with gastrointestinal injury progression among patients without high bleeding risk after PCI. Design, Setting, and Participants: This secondary analysis assessed data from the Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by ANKON Magnetically Controlled Capsule Endoscopy (OPT-PEACE) double-masked, placebo-controlled, multicenter randomized clinical trial. The OPT-PEACE trial was conducted at 28 centers in China, and recruitment took place from July 13, 2017, to July 13, 2019. The trial included patients with stable coronary artery disease or acute coronary syndromes without ST-segment elevation after PCI. Statistical analysis was conducted from September 13, 2022, to January 23, 2023. Interventions: Patients underwent magnetically controlled capsule endoscopy (MCE) at baseline and after 6 months of dual antiplatelet therapy (DAPT) with aspirin (100 mg/d) plus clopidogrel (75 mg/d). Those with no evidence of gastrointestinal ulcers or bleeding (ie, the intention-to-treat [ITT] cohort) were randomized (1:1:1) to aspirin (100 mg/d) plus matching placebo (aspirin alone), clopidogrel (75 mg/d) plus matching placebo (clopidogrel alone), or DAPT for an additional 6 months. A third MCE was performed 12 months after PCI. Main Outcomes and Measures: The primary outcome was the rate of gastric injury progression as assessed with the results of the 3 MCEs (at baseline, 6 months, and 12 months) in the modified intention-to-treat (mITT) population. The key secondary outcome was the rate of small-intestinal injury progression. Gastric or small-intestinal injury progression was defined as a quantitative increase in erosions or ulcers between the second and third MCEs (at 6 and 12 months, respectively). Results: This study included the 394 patients in the mITT cohort. Their mean (SD) age was 56.9 (8.7) years, and most were men (296 [75.1%]). A total of 132 patients were randomized to aspirin alone, 132 to clopidogrel alone, and 130 to DAPT. Gastric injury progression occurred in 49 aspirin users (37.1%), 64 clopidogrel users (48.5%), and 69 DAPT users (53.1%) (P = .02), reflecting a lower rate of gastric injury progression among aspirin users vs DAPT users (risk ratio [RR], 0.70 [95% CI, 0.49-0.99]; P = .009). No significant difference was observed between clopidogrel alone and DAPT (48.5% vs 53.1%; P = .46) or between aspirin alone and clopidogrel alone (37.1% vs 48.5%; P = .06). A total of 51 aspirin users (38.6%), 65 clopidogrel users (49.2%), and 71 DAPT users (54.6%) (P = .03) developed progressive small-intestinal injury, reflecting a lower rate of small-intestinal injury among aspirin users vs DAPT users (RR, 0.71 [95% CI, 0.50-0.99]; P = .01). No difference was observed between patients treated with clopidogrel vs DAPT (49.2% vs 54.6%; P = .38) or with aspirin vs clopidogrel (38.6% vs 49.2%; P = .08). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ongoing use of aspirin, clopidogrel, or their combination between 6 and 12 months after PCI was associated with progressive gastric and small-intestinal injury in a substantial proportion of patients, more so with DAPT than with monotherapy. Clopidogrel was at least as likely as aspirin to induce gastrointestinal injury progression. Future research is warranted to determine what impact the findings from MCEs would have on decision-making of antiplatelet therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03198741.

Reduced endoplasmic reticulum stress might alter the course of heart failure via caspase-12 and JNK pathways.

BACKGROUND: Endoplasmic reticulum (ER) stress plays an important role in mediating ischemic heart cell death. The aim of this study was to investigate whether manipulation of a key factor of the ER stress pathway, eukaryotic translation initiation factor 2 subunit α (eIF2α), can change the natural history of heart failure (HF). METHODS: HF was induced using coronary artery ligation in adult rats and a selective eIF2α dephosphorylation inhibitor, salubrinal (Sal), was used. Thirty minutes after ligation, rats were randomly assigned to 3 groups: myocardial infarction (MI) plus placebo injections (dimethyl sulfoxide; n = 12), MI plus Sal injection (Sal; n = 12), and MI (HF; n = 12). Hemodynamic parameters were examined. Hearts were harvested for apoptosis assessment after 8 weeks of Sal treatment by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labelling and flow cytometric analysis. Hearts were harvested to determine ER chaperones by Western analysis, real-time polymerase chain reaction and immunohistochemical analysis. RESULTS: Cardiac function was significantly improved in Sal-treated rats. Apoptosis was reduced by Sal treatment. Glucose-regulated protein-78 and -94 were increased in HF but normalized by Sal treatment. HF caused a significant increase in eIF2α phosphorylation, which was further increased by Sal treatment, and caspase-12 and phospho-c-JUN NH2-terminal kinase were markedly increased in rats with HF alone but significantly reduced by Sal treatment. CONCLUSIONS: Our results suggest that reduction of ER stress and myocardial apoptosis through inhibition of eIF2α dephosphorylation might alter the natural history of HF, which might provide a new approach for its treatment.

[Analyses of super-response to cardiac resynchronization therapy in patients with congestive heart failure: a multiple center trial].

OBJECTIVE: To evaluate the incidence of super-response and the potential predictors related to super-response after cardiac resynchronization therapy (CRT) in patients with congestive heart failure. METHODS: 190 patients [145 men and 45 women;age: (60.48 ± 11.91) years] underwent CRT between March 2001 and March 2012 were enrolled in this multi-center trial, of which, 54 patients with ischemic cardiomyopathy and 136 patients with non-ischemic cardiomyopathy. These patients were followed up from 6 months to 11 years (mean 58 months) post CRT. RESULTS: Ten patients died within 6 months post CRT, the others were followed up for more than 6 months. At 6-month follow-up, 51 patients were identified as CRT super-responders (28.33%), 75 patients were CRT responders (41.67%) and 29 patients were CRT non-responders (16.11%), and 25 patients were CRT negative responders (13.89%). Super-response occurred more frequently in non-ischemic cardiomyopathy patients, while non-response most commonly occurred in ischemic cardiomyopathy patients (P < 0.05); patients in the negative response group had higher serum creatinine level than other groups (P < 0.05) , and patients in the non-response group and negative response group had higher pulmonary artery pressure than patients in the super-response group (P < 0.05); the average QRS duration was ≥ 160 ms before CRT, and the mean decrease was around 30 ms after CRT in the super-response group while the average QRS duration was 139 ms before CRT, and the mean reduction was around 8 ms after CRT in the negative response group (P < 0.05). LV lead position in the super-response group was usually in the middle and base of the heart, while in the negative response group it was more commonly located in the apex of the heart (P < 0.01) . CONCLUSIONS: LV lead located at the middle and pre-CRT ORS duration ≥ 160 ms are associated with super-response post CRT procedure in this patient cohort.

[Causes of non-response to cardiac resynchronization therapy in heart failure patients with permanent atrial fibrillation].

OBJECTIVE: To evaluate the long-term effects and analyze causes of non-response to cardiac resynchronization therapy (CRT) in heart failure (HF) patients with permanent atrial fibrillation (AF). METHODS: Thirty-three patients with HF and AF [29 men, mean age (61 ± 10) years, NYHA class III or IV, left ventricular ejection fraction (LVEF) ≤ 35%, QRS ≥ 120 ms in 31 cases] underwent bi-ventricular pacing (n = 26) or bi-ventricular pacing and atrioventricular node ablation (AVN-ablation, n = 7) were included in this study. Non-response was defined: the increase of left ventricular ejection fraction (LVEF) was less than 15%. Patients were followed-up for 4 years. RESULTS: Six patients died during follow up. Non-responder to CRT was observed in 6 out of 27 survived patients (22.22%). Six out of 7 patients underwent AVN-ablation were in responder group and 1 in non-responder group. Comparing with responder group, the baseline LVEF was significantly higher (37% vs. 32%, P = 0.003), and the history of HF was significantly longer (6.3 years vs. 4.1 years, P = 0.039), pulmonary artery pressure was significantly higher (53 vs. 32 mm Hg, P = 0.027), bi-ventricular pacing percentage (BIVP%) was significantly lower (75.86% vs. 91.73%, P = 0.007) in non-responder group. CONCLUSIONS: Higher LVEF, longer HF history, higher pulmonary artery pressure and lower BIVP% are factors linked with non-responses to CRT in this patient cohort. CRT plus AVN-ablation is associated with high response rate to CRT in this patient cohort.