Faculty Bibliography

BACKGROUND: Evidence-based medications (EBM) are underused in older patients despite potentially larger absolute benefits. Little is known about factors influencing prescribing in the elderly with acute coronary syndromes. METHODS: Among the 15,904 patients from the Sibrafiban vs aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes (SYMPHONY) and second SYMPHONY trials, we examined the rates of use of EBM according to age (< 75 or > or = 75 years, and 3 subgroups of 5 year increments among patients > or = 75 years). RESULTS: Ninety-day mortality increased with age (< 75 years, 1.3%; > or = 75 to < 80 years, 4.4%; > or = 80 to < 85 years, 6.0%; > or = 85 years, 9.6%). Compared with subjects < 75 years (n = 14,043), acute EBM use was lower among patients > or = 75 years (n = 1794): aspirin (83% vs 85%), heparin (73% vs 78%), and beta-blockers (70% vs 76%). Similarly, discharge use of beta-blockers (69% vs 76%) and statins (28% vs 40%) was lower, although this was not the case for angiotensin-converting enzyme inhibitors (44% vs 41%). These patterns persisted among eligible patients. Beyond the age of 75 years, EBM use was not further influenced by age except for statins and angiotensin-converting enzyme inhibitors, which were used less frequently in those > or = 85 years. Among patients aged > or = 75 years, prediction for use of each EBM in multivariable modeling was modest (C indices, approximately 0.7); except for statins, increasing age did not predict lower EBM use. CONCLUSIONS: Despite higher mortality risk, EBM use was lower among older patients even considering eligibility. Among those aged > or = 75 years, age was no longer the major factor predicting EBM use. The modest C indices suggest other factors are associated with prescribing, underscoring the need for treatment algorithms and quality assurance measures in older patients

BACKGROUND: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin. OBJECTIVE: To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. METHODS: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX-2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non-fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF). RESULTS: In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib. CONCLUSIONS: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis-generating study.

Previous studies of non-ST-segment elevation acute coronary syndromes (NSTE ACSs) complicated by heart failure (HF) have focused primarily on patients with left ventricular systolic dysfunction defined by an ejection fraction (EF) <40%. Little is known about HF with preserved systolic function (EF >/=40%) in the NSTE ACS population. We identified high-risk patients with NSTE ACS (ischemic electrocardiographic changes and/or positive cardiac markers) from the CRUSADE quality improvement initiative who had an EF recorded and who had information on HF status. Management and outcomes were analyzed and compared based on the presence or absence of HF and whether left ventricular EF was >/=40%. Of 94,558 patients with NSTE ACS, 21,561 (22.8%) presented with signs of HF, and most had HF with preserved systolic function (n = 11,860, 55%). Mortality rates were 10.7% for HF/systolic dysfunction, 5.8% for HF/preserved systolic function, 5.7% for no HF/systolic dysfunction, and 1.5% for no HF/preserved systolic function. Use of guideline-recommended medical therapies and interventions was frequently significantly lower in those with HF regardless of EF compared with those without HF, except for use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In conclusion, NSTE ACS complicated by HF with preserved systolic function is common and associated with a 2.3-fold higher mortality compared with NSTE ACS without HF or systolic dysfunction. Guideline-recommended therapies and interventions are under-utilized in patients with NSTE ACS and HF, with and without preserved systolic function, compared with those without HF

Aims Previous studies suggested haemodynamic benefits and, possibly, mortality reduction with the use of nitric oxide synthase (NOS) inhibition in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). We assessed preliminary efficacy and safety of four doses of l-n-monomethyl-arginine (l-NMMA), a non-selective NOS inhibitor, in patients with AMI complicated by CS despite an open infarct-related artery. Methods and results Patients (n = 79) were randomly assigned to a bolus and 5 h infusion of placebo or 0.15, 0.5, 1.0, or 1.5 mg/kg of l-NMMA. The primary outcome measure was absolute change in mean arterial pressure (MAP) at 2 h. Fifteen minutes after study drug initiation, mean change in MAP was -4.0 mmHg in the placebo group and 5.8 (P = 0.02), 4.8 (P = 0.02), 5.1 (P = 0.07), and 11.6 (P < 0.001) mmHg in the four l-NMMA groups, respectively (all vs. placebo). Mean change in MAP at 2 h was -0.4, 4.4, 1.8, -4.1, and 6.8 mmHg in the placebo and four l-NMMA groups, respectively (all P = NS). Conclusion l-NMMA resulted in modest increases in MAP at 15 min compared with placebo but there were no differences at 2 h

CONTEXT: Cardiogenic shock complicating acute myocardial infarction (MI) remains a common and lethal disorder despite aggressive use of early revascularization. Systemic inflammation, including expression of inducible nitric oxide synthase (NOS) and generation of excess nitric oxide, is believed to contribute to the pathogenesis and inappropriate vasodilatation of persistent cardiogenic shock. Preliminary, single-center studies suggested a beneficial effect of NOS inhibition on hemodynamics, renal function, and survival in patients with cardiogenic shock. OBJECTIVE: To examine the effects of an isoform-nonselective NOS inhibitor in patients with MI and refractory cardiogenic shock despite establishment of an open infarct artery. DESIGN, SETTING, AND PATIENTS: International, multicenter, randomized, double-blind, placebo-controlled trial (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock [TRIUMPH]) with planned enrollment of 658 patients at 130 centers. Participants were enrolled between January 2005 and August 2006 when the study was terminated early. INTERVENTION: Tilarginine (L-N(G)-monomethylarginine [L-NMMA]), 1-mg/kg bolus and 1-mg/kg per hour 5-hour infusion, vs matching placebo. MAIN OUTCOME MEASURES: The primary outcome was 30-day all-cause mortality among patients who received study medication. Secondary outcomes included shock resolution and duration, New York Heart Association (NYHA) functional class at 30 days, and 6-month mortality. RESULTS: Enrollment was terminated at 398 patients based on a prespecified futility analysis. Six-month follow-up was completed in February 2007. There was no difference in 30-day all-cause mortality between patients who received tilarginine (97/201 [48%]) vs placebo (76/180 [42%]) (risk ratio, 1.14; 95% confidence interval, 0.92-1.41; P = .24). Resolution of shock (133/201 [66%] tilarginine vs 110/180 [61%] placebo; P = .31) and duration of shock (median, 156 [interquartile range, 78-759] hours tilarginine vs 190 [100-759] placebo; P = .16) were similar. At 30 days a similar percentage of patients had heart failure (48% tilarginine vs 51% placebo; P = .51) with a similar percentage of those patients in NYHA class I/II (73% tilarginine vs 75% placebo; P = .27). After 6 months mortality rates were similar in the 2 groups (58% tilarginine vs 59% placebo; hazard ratio, 1.04; 95% confidence interval, 0.79-1.36; P = .80). CONCLUSIONS: Tilarginine, 1-mg/kg bolus and 5-hour infusion, did not reduce mortality rates in patients with refractory cardiogenic shock complicating MI despite an open infarct artery. Early mortality rates in this patient group are high. Further research is needed to develop effective therapies for patients with cardiogenic shock following acute MI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00112281

We sought to assess the microbiologic profile of patients with suspected sepsis who participated in the SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK? (SHOCK) trial, a randomized controlled trial of early coronary revascularization in patients with cardiogenic shock complicating acute myocardial infarction. A protocol-mandated SEPSIS form was completed prospectively for 54 patients (18%) with fever or leukocytosis suggestive of sepsis. These patients were divided further into those with positive (n = 40) or negative (n = 14) culture results. The predominant pathogen isolated in patients with positive culture results was Staphylococcus aureus (32%), followed by Klebsiella pneumoniae and Pseudomonas aeruginosa. Patients with both positive and negative culture results had longer median durations of mechanical ventilation (p <0.001 and p = 0.02), intra-aortic balloon pump (IABP) support (p = 0.074 and p = 0.021), and hospital stay (p <0.001 and p = 0.048) than controls. Sepsis was predicted by both duration of IABP support (p = 0.007) and use of multiple central catheters (p = 0.026). In conclusion, clinical sepsis is common after cardiogenic shock complicating acute myocardial infarction, particularly in patients who received prolonged IABP support or had multiple central catheters