Abciximab reduces mortality in diabetics following percutaneous coronary intervention

AbstractOBJECTIVESWe sought to determine whether abciximab therapy at the time of percutaneous coronary intervention (PCI) would favorably affect one-year mortality in patients with diabetes.BACKGROUNDDiabetics are known to have increased late mortality following PCI.METHODSData from three placebo-controlled trials of PCI, EPIC, EPILOG, and EPISTENT, were pooled. The one-year mortality rate for patients with a clinical diagnosis of diabetes mellitus was compared with the rate for nondiabetic patients treated with either abciximab or placebo.RESULTSIn the 1,462 diabetic patients, abciximab decreased the mortality from 4.5% to 2.5%, p = 0.031, and in the 5,072 nondiabetic patients, from 2.6% to 1.9%, p = 0.099. In patients with the clinical syndrome of insulin resistance—defined as diabetes, hypertension, and obesity—mortality was reduced by abciximab treatment from 5.1% to 2.3%, p = 0.044. The beneficial reduction in mortality with abciximab use in diabetics classified as insulin-requiring was from 8.1% to 4.2%, p = 0.073. Mortality in diabetics who underwent multivessel intervention was reduced from 7.7% to 0.9% with use of abciximab, p = 0.018. In a Cox proportional hazards survival model, the risk ratio for mortality with abciximab use compared with placebo was 0.642 (95% confidence interval 0.458–0.900, p = 0.010).CONCLUSIONSAbciximab decreases the mortality of diabetic patients to the level of placebo-treated nondiabetic patients. This beneficial effect is noteworthy in those diabetic patients who are also hypertensive and obese and in diabetics undergoing multivessel intervention. Besides its potential role in reducing repeat intervention for stented diabetic patients, abciximab therapy should be strongly considered in diabetic patients undergoing PCI to improve their survival

Double-blind randomized proof-of-concept trial of canakinumab in patients with COVID-19 associated cardiac injury and heightened inflammation

AIMS: In coronavirus disease 2019 (COVID-19), myocardial injury is associated with systemic inflammation and higher mortality. Our aim was to perform a proof of concept trial with canakinumab, a monoclonal antibody to interleukin-1β, in patients with COVID-19, myocardial injury, and heightened inflammation. METHODS AND RESULTS: This trial required hospitalization due to COVID-19, elevated troponin, and a C-reactive protein concentration more than 50 mg/L. The primary endpoint was time to clinical improvement at Day 14, defined as either an improvement of two points on a seven-category ordinal scale or discharge from the hospital. The secondary endpoint was mortality at Day 28. Forty-five patients were randomly assigned to canakinumab 600 mg ( CONCLUSION: There was no difference in time to clinical improvement at Day 14 in patients treated with canakinumab, and no safety concerns were identified. Future studies could focus on high dose canakinumab in the treatment arm and assess efficacy outcomes at Day 28

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis

Background The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. Methods Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. Results A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). Conclusions At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .)

Cardiorenal risk of celecoxib compared with naproxen or ibuprofen in arthritis patients: insights from the PRECISION trial

AIMS Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, both prescribed and over the counter. The long-term cardiovascular safety of NSAIDs in patients with arthritis has engendered controversy. Concerns remain regarding the relative incidence and severity of adverse cardiorenal effects, particularly in arthritis patients with established cardiovascular (CV) disease or risk factors for disease as illustrated by the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen) trial participants (NCT00346216).We further investigated whether the selective COX-2 Inhibitor celecoxib has a superior cardiorenal safety profile compared with ibuprofen or naproxen in the PRECISION population. METHODS AND RESULTS Twenty-four thousand eighty-one patients who required NSAIDs for osteoarthritis or rheumatoid arthritis (RA) and had increased CV risk randomly received celecoxib, ibuprofen, or naproxen. The current pre-specified secondary analysis assessed the incidence, severity, and NSAID-related risk of the pre-specified composite cardiorenal outcome (adjudicated renal event, hospitalization for congestive heart failure, or hospitalization for hypertension) in the intention-to-treat (ITT) population. An on-treatment analysis assessed safety in those taking the study medication. Following a mean treatment duration of 20.3 ± 16.0 months and a mean follow-up of 34.1 ± 13.4 months, the primary cardiorenal composite outcome occurred in 423 patients (1.76%) in the ITT population. Of these 423 patients, 118 (28%) were in the celecoxib, 166 (39%) in the ibuprofen, and 139 (33%) in the naproxen group. In a multivariable Cox regression model adjusted for independent clinical variables, celecoxib showed a significantly lower risk compared with ibuprofen [hazard ratio (HR) 0.67, confidence interval (CI) 0.53-0.85, P = 0.001) and a trend to lower risk compared with naproxen (HR 0.79, CI 0.61-1.00, P = 0.058). In the ITT analysis, clinically significant renal events occurred in 220 patients with events rates of 0.71%, 1.14%, and 0.89% for celecoxib, ibuprofen, and naproxen, respectively (P = 0.052), while in the on-treatment analysis the rates were 0.52%, 0.91%, and 0.78% (P &amp;lt; 0.001). CONCLUSION In the current era, long-term NSAID use was associated with few cardiorenal events in arthritis patients. At the doses studied, celecoxib displayed fewer renal events and hence more favourable cardiovascular safety compared with ibuprofen or naproxen. These results have considerable clinical implications for practitioners managing individuals with chronic arthritis pain and high risk of impaired renal function and/or heart failure.Clinical Trial Registration: NCT00346216

Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthritis and Patients With Rheumatoid Arthritis: A Randomized Clinical Trial

OBJECTIVE To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long-term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA). METHODS A total of 24,081 patients with OA or RA who had a moderate or high risk for CV disease were enrolled internationally into a double-blind randomized controlled trial. Interventions included celecoxib at a dosage of 100-200 mg twice daily, ibuprofen at a dosage of 600-800 mg 3 times daily, or naproxen at a dosage of 375-500 mg twice daily. The main outcomes were the first occurrence of a major adverse CV event, GI event, or renal event, and mortality. RESULTS In the subgroup of patients with OA, the risk of a major adverse CV event was significantly reduced when celecoxib was compared with ibuprofen (hazard ratio [HR] 0.84, 95% confidence interval [95% CI] 0.72-0.99), but no significant difference was observed when celecoxib was compared with naproxen. In the RA subgroup, comparisons of celecoxib versus ibuprofen and celecoxib versus naproxen for the risk of major adverse CV events revealed HRs of 1.06 (95% CI 0.69-1.63) and 1.22 (95% CI 0.78-1.92), respectively. In the OA subgroup, comparisons of celecoxib versus ibuprofen for the risk of GI events showed an HR of 0.68 (95% CI 0.51-0.91), and a comparison of celecoxib versus naproxen showed an HR of 0.73 (95% CI 0.55-0.98). Duplicate comparisons in patients with RA revealed HRs of 0.48 (95% CI 0.22-1.07) and 0.54 (95% CI 0.24-1.24), respectively. In patients with OA, a comparison of celecoxib versus ibuprofen for the risk of renal events showed an HR of 0.58 (95% CI 0.40-0.82). In patients with RA, celecoxib treatment was associated with significantly lower mortality compared with naproxen treatment (HR 0.47, 95% CI 0.25-0.88). CONCLUSION Treatment with celecoxib at approved dosages conferred a similar or lower risk of CV, GI, and renal adverse events compared with treatment with ibuprofen or naproxen in patients with OA and patients with RA

Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial

In patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu