Clinical and Pharmacological Implications of Time to Treatment with Interleukin-1 Blockade in ST-Segment Elevation Myocardial Infarction.

Interleukin-1 (IL-1) blockade with anakinra given within 12 hours from reperfusion has been shown to reduce the inflammatory response as well as prevent heart failure (HF) events in patients with STEMI. We sought to determine whether time-to-treatment influences the efficacy of anakinra on systemic inflammation and incidence of HF events in patients with STEMI. We divided the cohort in two groups base6d on the median time from percutaneous coronary intervention (PCI) to investigational drug, and analyzed the effects of anakinra on the area-under-the-curve for C reactive protein (AUC-CRP) and on incidence of the composite endpoint of death or new onset HF. We analyzed data from 139 patients: 84 (60%) treated with anakinra and 55 (40%) with placebo. The median time from PCI to investigational treatment was 271 (182-391) minutes. The AUC-CRP was significantly higher in patients receiving placebo versus anakinra both in those with time from PCI to treatment <271 minutes (222.6 [103.9-325.2] vs. 78.4 [44.3-131.2], P < 0.001) and those with time from PCI to treatment ≥271 minute (235.2 [131.4-603.4] vs. 75.5 [38.9-171.9], P < 0.001) (P > 0.05 for interaction). Anakinra significantly reduced the combined endpoint of death or new onset HF in patients with time from PCI to treatment <271 minutes (5 [11%] vs. 9n[36%], log-rank χ 2 5.985, P = 0.014) as well as in patients with time from PCI to drug ≥271 minutes (2n[5%] vs. 7 [23%], log-rank χ 2 3.995, P = 0.046) (P > 0.05 for interaction). IL-1 blockade with anakinra blunts the acute systemic inflammatory response and prevents HF events independent of time-to-treatment. SIGNIFICANCE STATEMENT: In patients with ST segment elevation presenting within 12 hours of pain onset and treated within 12 hours of reperfusion, interleukin-1 blockade with anakinra blunts the acute systemic inflammatory response, a surrogate of interleukin-1 activity, and prevents heart failure events independent of time-to-treatment.

Effect of IL-1 Blockade With Anakinra on Heart Failure Outcomes in Patients With Anterior Versus Nonanterior ST Elevation Myocardial Infarction.

ABSTRACT: Patients with ST elevation myocardial infarction (STEMI) are at risk of future heart failure (HF), particularly those with anterior STEMI. Interleukin-1 (IL-1) is a key mediator of the inflammatory response, and its blockade has emerged as a potential therapeutic strategy to prevent HF events. The aim of this analysis was to explore the effects of anakinra, an IL-1 receptor antagonist, on HF outcomes based on anterior versus nonanterior location STEMI and to explore whether this effect is mediated through the amelioration of left ventricular systolic function and cardiac remodeling. We pooled data from 3 early phase randomized clinical trials. The primary end point was a composite of all-cause death and new-onset HF at 1-year follow-up. The left anterior descending coronary artery as culprit vessel was used to identify anterior STEMI. We included 139 patients, 47 (34%) with anterior STEMI and 92 (66%) with nonanterior STEMI. Anakinra significantly reduced the combined end point of death or new-onset HF in patients with anterior STEMI [4 (13%) vs. 7 (42%), log-rank P value = 0.049] and in patients with nonanterior STEMI [3 (6%) vs. 9 (24%), log-rank P value = 0.014]. We found no significant differences comparing anakinra versus placebo in interval changes in left ventricular ejection fraction and volumes in anterior and nonanterior STEMI. In conclusion, anakinra is associated with a reduction of HF events in patients with STEMI, irrespective of anterior or nonanterior location, or of changes in left ventricular ejection fraction or cardiac remodeling.

Additive prognostic value of carbohydrate antigen-125 over frailty in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: To evaluate the additive prognostic value of myocardial, inflammatory, and renal biomarkers according to frailty status in patients undergoing transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS). METHODS: A total of 111 subjects who underwent TAVR at Hospital Italiano de Buenos Aires, Argentina between January 2016 and December 2018 were retrospectively reviewed. Plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high sensitivity troponin T (hs-cTnT), C-reactive protein (CRP), cystatin-c (Cys-C) and carbohydrate antigen-125 (CA-125) were assessed prior to TAVR. Frailty status was assessed according to the fried physical frailty phenotype (FPFP). The primary endpoint was defined as all-cause death and/or readmission for worsening congestive heart failure (CHF) within the first year after TAVR. RESULTS: Of the 111 patients included, 48/111 (43%) were considered to be "frail" according to the FPFP. Among biomarkers, we found CA-125 to be strongly associated with the primary endpoint (p = .006). CA-125 ≥ 18.2 U/ml was present in 41% and was associated with a higher rate of the primary endpoint (31% vs. 9%; p = .003). After multivariable adjustment, CA-125 ≥ 18.2 U/ml (hazard ratio [HR] 3.17; p = .024) was the only independent predictor of the primary endpoint. Finally, the inclusion of CA-125 to frailty significantly improved C-index (0.68-0.74; p < .05), and provided a Net Reclassification Improvement (NRI) of 0.34 (95% CI 0.19-0.49, p = .031), largely through reductions in risk estimates among pre-frail and frail patients. CONCLUSIONS: CA-125, a tumor biomarker, outperformed frailty for predicting the primary endpoint within the first year after TAVR.

Sarcopenia index as a predictor of clinical outcomes in older patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Sarcopenia is a prevalent condition in elderly patients and has been associated with adverse outcomes following transcatheter aortic valve replacement (TAVR). The present study aimed to determine the predictive value of serum creatinine-cystatin C ratio, that is, "Sarcopenia Index" (SI) as a surrogate marker of sarcopenia, and investigate its association with clinical outcomes after TAVR. METHODS: We conducted a retrospective observational study of patients undergoing TAVR between January, 2016 and December, 2018 at Hospital Italiano de Buenos Aires, Argentina. Patients were excluded if <65-years old, presented previous surgical aortic valve replacement, severe chronic kidney disease, or hemodialysis requirement. The SI was obtained at baseline before TAVR. All-cause mortality and/or readmissions for congestive heart failure (CHF) were defined as the primary endpoint. RESULTS: In total 100 patients met inclusion criteria for the purpose of the study. Sarcopenia Index was significantly correlated with Timed Up and Go (r = -0.272, p = .010) and Gait Speed (r = -0.278, p = .005). During follow-up, 5/100 patients died within 30 days and a total of 10/100 patients died at 1-year follow-up. Moreover, survival curves were significantly worse (Log-rank test = p = .02) and CHF readmissions were more prevalent in the lowest SI tertile (Log-rank test = p = .01). In multivariate Cox regression analysis, we identified low SI (cutoff ≤66) as an independent predictor of long-term adverse outcomes (HR = 4.01, 95% CI = 1.31-12.27, p = .015) at 1-year follow-up. CONCLUSION: Sarcopenia Index, surrogate for the degree of skeletal muscle mass (SMM), could be used as a predictor of adverse outcomes in patients undergoing TAVR.

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study.

BACKGROUND: Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. METHODS: We conducted a double-blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2 ) and minute ventilation/carbon dioxide production (VE/VCO2 ) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2 , ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12-week follow-up. RESULTS: The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM-1 min-1 , P = .036), VAT (+1.5 mL kg-1 min-1 , P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg-1 min-1 , P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (-12.1, P = .018). CONCLUSIONS: In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2 , VAT and quality of life.

Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.

Interleukin-1 (IL-1) receptor antagonist (anakinra) has been shown to be effective in steroid-dependent recurrent pericarditis resistant to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. We sought to evaluate the acute efficacy of anakinra given early in patients with acute pericarditis. We enrolled patients within 24 hours of presentation of a first or recurrent episode of acute pericarditis who were experiencing severe pain (≥6 in 11-point Likert scale), despite treatment with at least one dose of NSAIDs and of colchicine. The primary outcome was pain relief at 24 hours. Subcutaneous anakinra 100 mg was administered in all patients, whereas NSAIDs and colchicine were suspended for 24 hours. Serum levels of interleukin-6 (IL-6) were measured at baseline and 24 hours. Data are reported as median (interquartile range). We treated 5 patients (4 male and 1 female; 38 [31-54] years old). Anakinra significantly reduced pain from 6.0 (6.0-7.5) to 4.0 (2.5-4.0) at 6 hours (P = 0.012 vs. baseline) and to 2.0 (1.5-2.5) at 24 hours (P = 0.0025 vs. baseline). No patients required rescue pain medication. IL-6 levels were also significantly reduced from 95.3 (24.2-155.1) to 23.9 (4.5-71.9) pg/mL at 24 hours (P = 0.037). The reduction in pain intensity paralleled the reduction in IL-6 serum levels (R = +0.966, P = 0.007). No adverse events related to treatment occurred. The administration of anakinra given early in acute pericarditis treatment course rapidly and significantly improved chest pain from acute pericarditis. The improvement is correlated with a reduction in IL-6 levels.

Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure.

ABSTRACT: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

Takotsubo syndrome: diagnostic work-up and clues into differential diagnosis.

PURPOSE OF REVIEW: Takotsubo syndrome represents an increasingly recognized clinical entity characterized by a reversible acute myocardial dysfunction, often triggered by an emotional or physical stress, and independent of an underlying epicardial coronary artery disease. The diagnosis is often challenging because of the nonspecific clinical presentation and the inconclusive noninvasive diagnostic imaging. RECENT FINDINGS: The present review provides a brief overview of Takotsubo syndrome clinical presentation and guides the clinician through the diagnostic work-up of Takotsubo syndrome, highlighting clues into differential diagnosis. A review of clinical management is also provided. SUMMARY: Despite increasing awareness and recognition, the diagnosis of Takotsubo syndrome remains challenging and Takotsubo syndrome is often underdiagnosed or misdiagnosed. The prompt recognition of Takotsubo syndrome portends relevant prognostic and therapeutic implications.

Stroke risk after transcatheter aortic valve replacement in patients with carotid stenosis: A systematic review and meta-analysis.

BACKGROUND: Stroke is a feared complication of transcatheter aortic valve replacement (TAVR). Patients undergoing TAVR typically have multiple comorbidities, such as carotid artery stenosis (CAS). We conducted the present meta-analysis to determine the risk of stroke and mortality following TAVR in patients with CAS. METHODS: We searched PubMed/Medline, Scopus, ScienceDirect, and Cochrane Clinical Trials databases for clinical studies that compared CAS ≥50% and CAS ≥70% versus non-CAS TAVR population. The endpoints included the 30-day incidence of stroke or transient ischemic attack (TIA) and 30-day all-cause of mortality. RESULTS: We identified seven studies that included 12,418 patients in the CAS group and 102,316 in the control group. CAS ≥50% was not associated with an increased risk of 30-day stroke or TIA after TAVR [risk ratio (RR): 1.38; 95% confidence interval (95% CI): 0.95-2.02; p = 0.09]. However, patients with CAS ≥70% had an increased risk of stroke or TIA (RR: 1.43; 95% CI: 1.02-2.01; p = 0.04). No difference in 30-day all-cause mortality was observed between CAS ≥50% or CAS ≥70% and control groups (RR: 1.09; 95% CI: 0.79-1.52; p = 0.59 and RR: 1.11; 95% CI: 0.85-1.45; p = 0.43, respectively). CONCLUSIONS: CAS ≥70% was associated with an increased risk of stroke or TIA following TAVR compared with patients without CAS.