Reperfusion therapy for acute myocardial infarction: observations from the National Registry of Myocardial Infarction 2

The National Registry of Myocardial Infarction 2 (NRMI-2) provides a unique opportunity to evaluate the practice patterns among participating cardiology and emergency medicine departments involved in the care of patients with acute myocardial infarction. The data from NRMI-2 suggest that almost 1/3 of all non-transfer-in and non-transfer-out patients are eligible for reperfusion therapy. Furthermore, of those patients who are clearly eligible for reperfusion therapy, 24% are not given this proven therapy. Specifically, women, the elderly, patients without chest pain on presentation, and those patients at highest risk for in-hospital mortality were least likely to be treated with reperfusion therapy. The reason for underuse of reperfusion therapy may in part reflect a concern for adverse bleeding events associated with the use of thrombolytic therapy. The data from NRMI-2 also suggest that patients with contraindications to thrombolysis may be very appropriate for primary angioplasty. Realizing the full potential benefits of reperfusion therapy in terms of reduced cardiovascular morbidity and mortality will require that clinical practice patterns be aligned more closely with the recommended national guidelines, which are based on extensive clinical trial data that show the benefit of reperfusion therapy in a wide range of patients with acute myocardial infarction. By using observational databases, such as the NRMI-2, which describe how clinical care is administered in nonclinical trial settings, we can continually monitor our progress and initiate changes to ensure that patients are given access to the many therapies that have been shown to improve their quality of life and survival

Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening Against the Flap Site of HIV Protease

Molecular docking is a powerful tool used in drug discovery and structural biology for predicting the structures of ligand–receptor complexes. However, the accuracy of docking calculations can be limited by factors such as the neglect of protein reorganization in the scoring function; as a result, ligand screening can produce a high rate of false positive hits. Although absolute binding free energy methods still have difficulty in accurately rank-ordering binders, we believe that they can be fruitfully employed to distinguish binders from nonbinders and reduce the false positive rate. Here we study a set of ligands that dock favorably to a newly discovered, potentially allosteric site on the flap of HIV-1 protease. Fragment binding to this site stabilizes a closed form of protease, which could be exploited for the design of allosteric inhibitors. Twenty-three top-ranked protein–ligand complexes from AutoDock were subject to the free energy screening using two methods, the recently developed binding energy analysis method (BEDAM) and the standard double decoupling method (DDM). Free energy calculations correctly identified most of the false positives (≥83%) and recovered all the confirmed binders. The results show a gap averaging ≥3.7 kcal/mol, separating the binders and the false positives. We present a formula that decomposes the binding free energy into contributions from the receptor conformational macrostates, which provides insights into the roles of different binding modes. Our binding free energy component analysis further suggests that improving the treatment for the desolvation penalty associated with the unfulfilled polar groups could reduce the rate of false positive hits in docking. The current study demonstrates that the combination of docking with free energy methods can be very useful for more accurate ligand screening against valuable drug targets

Applicability of percutaneous transluminal coronary angioplasty to patients with recombinant tissue plasminogen activator mediated thrombolysis

To test the utility and safety of percutaneous transluminal coronary angioplasty (PTCA) after recombinant tissue plasminogen activator (t-PA), we performed the procedure in all suitable candidates with acute myocardial infarction (MI) who had successful t-PA mediated coronary thrombolysis. Twenty consecutive patients with MI received t-PA after coronary angiographic conformation of total occlusion. Successful recanalization with t-PA was achieved in 13 patients, leaving a residual obstruction of 84 ± 6% in the nine patients for whom PTCA was attempted at a mean of 21.6 h. Success was achieved in seven patients, leading to a residual lesion of 29 ± 7%. In the two patients for whom PTCA was unsuccessful, total reocclusion occurred prior to the attempt despite therapy with heparin, aspirin, dipyridamole, and nifedipine. All PTCA procedures were uncomplicated. Serial two-dimensional echocardiography at 10 days, compared to admission, demonstrated infarct zone wall motion index improvement in the patients with successful PTCA (group A, 0.83 ± 0.36 to 1.46 ± 0.49) as compared to the 13 patients without thrombolysis or successful PTCA (group B, 0.61 ± 0.26 to 0.66 ± 0.39), (P < 0.05). One patient of group A sustained a massive stroke at 2 weeks after hospital discharge. In the remaining six patients, follow-up exercise testing and/or coronary arteriography demonstrated a negative treadmill test and/or patent infarct vessel, respectively. After successful PTCA, no patient had clinical signs of reocclusion, reinfarction, postinfarction angina, or congestive heart failure. At 9.4 ± 2 months, all six patients are asymptomatic and have returned to work. Thus, sequential PTCA after t-PA can be performed safely and successfully in patients with MI and this approach may be associated with improved regional function and a favorable post-MI course.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38212/1/1810110402_ftp.pd

Acute ischemic heart disease and interventional cardiology: a time for pause

BACKGROUND: A major change has occurred in the last few years in the therapeutic approach to patients presenting with all forms of acute coronary syndromes. Whether or not these patients present initially to tertiary cardiac care centers, they are now routinely referred for early coronary angiography and increasingly undergo percutaneous revascularization. This practice is driven primarily by the angiographic image and technical feasibility. Concomitantly, there has been a decline in expectant or ischemia-guided medical management based on specific clinical presentation, response to initial treatment, and results of noninvasive stratification. This 'tertiarization' of acute coronary care has been fuelled by the increasing sophistication of the cardiac armamentarium, the peer-reviewed publication of clinical studies purporting to show the superiority of invasive cardiac interventions, and predominantly supporting (non-peer-reviewed) editorials, newsletters, and opinion pieces. DISCUSSION: This review presents another perspective, based on a critical reexamination of the evidence. The topics addressed are: reperfusion treatment of ST-elevation myocardial infarction; the indications for invasive intervention following thrombolysis; the role of invasive management in non-ST-elevation myocardial infarction and unstable angina; and cost-effectiveness and real world considerations. A few cases encountered in recent practice in community and tertiary hospitals are presented for illustrative purposes The numerous and far-reaching scientific, economic, and philosophical implications that are a consequence of this marked change in clinical practice as well as healthcare, decisional and conflict of interest issues are explored. SUMMARY: The weight of evidence does not support the contemporary unfocused broad use of invasive interventional procedures across the spectrum of acute coronary clinical presentations. Excessive and unselective recourse to these procedures has deleterious implications for the organization of cardiac health care and undesirable economic, scientific and intellectual consequences. It is suggested that there is need for a new equilibrium based on more refined clinical risk stratification in the treatment of patients who present with acute coronary syndromes