Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

Schneeweiß, Sebastian; Seeger, John D.; Landon, Joan; Walker, Alexander M.

doi:10.1056/nejmoa0707571

Cited by 327 publications

(246 citation statements)

References 31 publications

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“…An example of this is seizure attacks in some patients. Aprotinin, a plasmin inhibitor in limited use in some countries, also suffers from a lack of specificity [1,5,6]. Several plasmin inhibitors being developed as antifibrinolytics include KDI-L17R [15] textilinin-1 [16] and cyclic peptidomimetics [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…A direct plasmin inhibitor, which is approved for use in only few countries, is aprotinin. Although useful, aprotinin, a Kunitz-type plasmin inhibitor, was withdrawn from the clinic in the U.S. due to its high risk of mortality and morbidity [5,6]. The two lysine analogs also suffer from significant adverse effects arising from their effects on the central GABA receptor, which provokes convulsive seizures [7].…”

Section: Introductionmentioning

confidence: 99%

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Plasmin Regulation through Allosteric, Sulfated, Small Molecules

et al. 2015

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Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%-100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

et al. 2015

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“…Premier's methodology and database, in which individualized severity-adjusted expected outcome parameters are calculated for each patient, are regularly used to evaluate mortality, costs, complications, morbidity, and resource utilization across a wide variety of patients and disease states [21,[24][25][26][27][28]. In this study, we focused on illnesses related to poisoning or toxic effects of drugs and demonstrated that inpatients primarily cared for by medical toxicologists, compared to patients primarily cared for by non-toxicologists and adjusted for predicted values, experienced significantly shorter hospital stays, generated lower costs, and suffered lower mortality.…”

Section: Discussionmentioning

confidence: 99%

Effect of a Medical Toxicology Admitting Service on Length of Stay, Cost, and Mortality Among Inpatients Discharged with Poisoning-Related Diagnoses

et al. 2014

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There are no published studies that have compared quality outcomes of hospitalized poisoned patients primarily under the care of physician medical toxicologists to patients treated by non-toxicologists. We hypothesized that inpatients primarily cared for by medical toxicologists would exhibit shorter lengths of stay (LOS), lower costs, and decreased mortality. Patients discharged in 2010 and 2011 from seven hospitals within the same health care system and greater metropolitan area with Medicare severity diagnosis-related groups for "poisoning and toxic effects of drugs" with and without major comorbidities or complications (917 & 918, respectively) were identified from a Premier® database. The database contained severity-weighted comparisons between expected and observed outcomes for each patient. Outcome parameters were differences between expected and observed LOS, cost, and percent mortality. These were then compared among groups of patients primarily admitted and cared for by (1) medical toxicologists at one hospital (Banner Good Samaritan Medical Center, BGS), (2) non-toxicologists at BGS, and (3) non-toxicologists at six other hospitals. Records of 3,581 patients contained complete data for assessment of at least one outcome measure. Patients cared for by medical toxicologists experienced favorable differences in LOS, costs, and mortality compared with other patient groups (p<0.001). If patients cared for by non-toxicologists had experienced similar differences in observed over expected values for LOS, cost, and mortality as those cared for by medical toxicologists, there would have been a median savings of 1,483 hospital days, $4.269 million, and a significant decrease in mortality during the 2-year study period. Differences between observed and expected LOS, cost, and mortality in patients primarily cared for by medical toxicologists were significantly better than in patients cared for by non-toxicologists, regardless of facility. These data suggest that significant reductions in patient hospital days, costs, and mortality are possible when medical toxicologists directly care for hospitalized patients.

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“…34 Instrumental variable methods or quasi-experimental designs can also be used to generate unbiased estimates in some situations. 23,35,36 Dose-response relationships can be tested to better assess the strength of the relationship between the preventive therapy and the outcome in question. Additionally, researchers can restrict the study to a population that is likely to be more homogenous with regard to health-seeking status to assess if there is a difference in result.…”

Section: Evaluating Study Design and Adjustment Methodsmentioning

confidence: 99%

Healthy User and Related Biases in Observational Studies of Preventive Interventions: A Primer for Physicians

2011

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The current emphasis on comparative effectiveness research will provide practicing physicians with increasing volumes of observational evidence about preventive care. However, numerous highly publicized observational studies of the effect of prevention on health outcomes have reported exaggerated relationships that were later contradicted by randomized controlled trials. A growing body of research has identified sources of bias in observational studies that are related to patient behaviors or underlying patient characteristics, known as the healthy user effect, the healthy adherer effect, confounding by functional status or cognitive impairment, and confounding by selective prescribing. In this manuscript we briefly review observational studies of prevention that have appeared to reach incorrect conclusions. We then describe potential sources of bias in these studies and discuss study designs, analytical methods, and sensitivity analyses that may mitigate bias or increase confidence in the results reported. More careful consideration of these sources of bias and study designs by providers can enhance evidence-based decision-making. P racticing clinicians face a substantial challenge when attempting to interpret data from observational studies that report the effects of prevention on patient health outcomes. Numerous high-profile descriptive studies of preventive screening tests, behaviors, and treatments have reported dramatically reduced mortality or improved health outcomes. However, many of these findings were later thrown into question when randomized controlled trials (RCTs) indicated contradictory results. In some cases, the flawed observational studies were the source of evidence for broad practice recommendations.1 While it would be a mistake to ignore all evidence from observational studies-there are many questions that will never be answered by RCTs-clinicians must be careful when interpreting observational studies demonstrating what seem to be surprisingly large beneficial effects of preventive therapy. With the investment of over $1 billion in comparative effectiveness research, clinicians will be faced with increasing volumes of complex results. Proper interpretation will require familiarity with a host of sources of bias in observational research. Bias results when features of a study's design lead to estimates that do not accurately reflect the relationship between the study variables. In this review, we explore a specific subset of these sources of bias-confounding in observational studies resulting from patient-level tendencies to engage in healthy behaviors or physician's perceptions of the health of patients. A recent body of research has emerged examining these sources of bias, and their effect on the interpretation of observational research findings. In this paper, we provide a brief review of observational studies that have appeared to reach incorrect conclusions due to healthy user and other related types of bias. We describe the sources of bias in these studies and discuss study designs, ...

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Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

Abstract: Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding.

Cited by 327 publications

References 31 publications

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

Effect of a Medical Toxicology Admitting Service on Length of Stay, Cost, and Mortality Among Inpatients Discharged with Poisoning-Related Diagnoses

Healthy User and Related Biases in Observational Studies of Preventive Interventions: A Primer for Physicians

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