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Background: Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure-related mortality.Methods: We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure-related mortality.Results: A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively; P<0.0001). The unadjusted hazard ratios for HHF with each dose of canakinumab compared with placebo were 1.04 (95% CI, 0.79-1.36) for 50 mg, 0.86 (95% CI, 0.65-1.13) for 150 mg, and 0.76 (95% CI, 0.57-1.01) for 300 mg ( P for trend=0.025). The composite of HHF or heart failure-related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78-1.29) for 50 mg, 0.88 (95% CI, 0.68-1.13) for 150 mg, and 0.78 (95% CI, 0.60-1.02) for 300 mg ( P for trend=0.042).Conclusions: These randomized double-blind placebo-controlled data suggest that therapy with canakinumab, an interleukin-1β inhibitor, is related to a dose-dependent reduction in HHF and the composite of HHF or heart failure-related mortality in a population of patients with prior myocardial infarction and elevations in high-sensitivity C-reactive protein.Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327846. [ABSTRACT FROM AUTHOR]

Introduction: Subclinical inflammation associates with an increased risk of heart failure, and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not succeeded in improving clinical outcomes. Hypothesis: We tested the pre-specified exploratory hypothesis that the IL-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF). Methods: We randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo, given subcutaneously once every three months. HHF events were reported by local physicians, and required a combination of symptoms, physical exam findings, laboratory and/or radiographic abnormalities, and alterations in therapy to meet the definition of HHF. Results: A total of 390 patients had a HHF event during a median follow up of 3.7 years. Patients who had HHF were older, had higher BMI, and were more likely to have diabetes, hypertension, and prior coronary bypass surgery. As anticipated, median (Q1, Q3) baseline concentrations of hsCRP were higher among those who had HHF during follow up than those who did not [5.6 mg/L (3.5, 9.9) vs. 4.2 mg/L (2.8, 6.9), respectively, P<0.0001] The unadjusted hazard ratios (95% CI) for HHF with each dose of canakinumab compared to placebo were 1.02 (0.78-1.33) for 50 mg, 0.87 (0.66-1.14) for 150 mg, and 0.76 (0.57-1.01) for 300 mg (P-trend = 0.028). After adjustment for a wide array of potential confounders, patients who achieved on-treatment hsCRP concentrations < 2 mg/L regardless of canakinumab dose had significant reductions in HHF rates compared to placebo (HR 0.80, 95% CI 0.70-0.91), while those with on-treatment hsCRP concentrations ≥ 2 mg/L did not (HR 0.98, 95% CI 0.79-1.23) (Table). These effects persisted when analyzed by alternative on-treatment hsCRP thresholds (Table). Conclusions: IL-1β inhibition with canakinumab led to statistically significant reductions in hospitalization for heart failure. Those reductions were particularly apparent amongst those who achieved low hsCRP on-treatment hsCRP concentrations, regardless of canakinumab dose. [ABSTRACT FROM AUTHOR]

Background: Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates., Methods and Results: Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n=3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n=11 965): 7.9% versus 8.9% (HR, 0.90; 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0%; HR, 0.72; 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3%; HR, 1.07; 95% CI, 0.88 to 1.30; 0.34% versus 0.77%; HR, 0.48; 95% CI, 0.15 to 1.54; and 8.5% versus 7.3%; HR, 1.28; 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant., Conclusions: In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non-procedure-related bleeding., Clinical Trial Registration: URL:http://www.clinicatrials.gov. Unique identifier: NCT00391872.