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Dr. Prediman K. Shah, Room 5347, Division of Cardiology, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
On behalf of my colleagues in the Scientific Program Committee, it is my honor and pleasure to present a few of the highlights among the scientific presentations at the annual Scientific Sessions of the American College of Cardiology, held in March to April 2003, in the category of Myocardial Infarction and Ischemia. I extend my sincere apologies to many fine colleagues whose interesting and important work could not be included in these highlights in view of time constraints.
Immediate reduction in acute myocardial infarction (MI) after implementation of a comprehensive smoke-free ordinance
This study was presented by Dr. Richard Sargent of St. Peter’s Hospital, Helena, Montana, at the Late Breaking Clinical Trials session. Several studies have shown that second-hand smoke increases the risk of fatal and non-fatal cardiac events by as much as 30%. Second-hand smoke rapidly induces endothelial dysfunction and creates a prothrombotic state through activation of platelets and platelet aggregation as well through induction of tissue factor. The goal of the study was to determine the impact of enactment of a smoke-free workplace and public place ordinance on the incidence of acute MI. A municipal ordinance was enacted on July 4, 2002, banning smoking in all public places, such as offices, restaurants, bars, and casinos, in Helena, Montana. In December 2002, the ordinance was suspended because of legal challenges. Investigators tracked all patients admitted to the St. Peter’s Hospital (the primary cardiac care center that serves 65,913 residents in Helena, Montana) with a primary or secondary diagnosis of acute MI at discharge, for six months after implementation of the smoke-free ordinance. Similar data were collected through chart review for a period of four years before the implementation of the ordinance. Investigators also collected data from hospital records of patients outside the Helena area that were not affected by the public ban on smoking. Investigators controlled for long-term trends and seasonal variation. The effect of smoking ban on the incidence of acute MI was examined using multilinear regression analysis. During an average six-month period before the enactment of the ordinance, approximately seven patients with acute MI were admitted per month to St. Peter’s Hospital, whereas during the average six months after the enactment of the smoking ban, the number of admissions for acute MI per month dropped to approximately three, representing a nearly 60% reduction (p = 0.02). In contrast, there was no significant change in the number of admissions for acute MI among people living outside the smoke-free ordinance zone. The important observations from this population-based study reinforce the relatively large and rapid benefits of implementing clean indoor air legislation on cardiovascular health, further confirming the adverse health impact of second-hand smoke. Therefore, this study provides data of considerable public health value.
Effect of glucose, insulin, and potassium (GIK) on 30-day mortality, infarct size, and ejection fraction in patients with acute MI undergoing primary percutaneous transluminal coronary angioplasty (PTCA)
The concept of GIK or the polarizing solution was introduced four decades ago by the Mexican cardiologist, Dimitri Sodi-Pallares, as an antiarrhythmic intervention with the putative mechanism of membrane stabilization. Since its original introduction 40 years ago, this form of treatment has also been evaluated for infarct size and mortality reduction in several small randomized trials which have yielded conflicting results, casting doubt on the efficacy of this intervention. In this study, presented by Iwan C. Van der Horst, investigators from the Netherlands examined the effect of intravenous GIK in combination with reperfusion therapy using primary PTCA on clinical outcome, left ventricular function (using radionuclide ventriculography) and infarct size (using cumulative release of the cardiac enzyme lactic dehydrogenase) in 940 patients with acute MI. Nearly half received a placebo (n = 464), and the other half received GIK (n = 476). Overall, there was no effect of GIK on mortality (4.8% vs. 5.8%; p = 0.5); however, in 856 patients without evidence of clinical left ventricular failure, the mortality was significantly lower with GIK compared with placebo (1.2% vs. 4.2%; p < 0.005). The prevalence of the highest quartile of infarct size was also significantly lower among GIK recipients (22% vs. 29%; p < 0.005), who also tended to have a lower prevalence of left ventricular dysfunction ejection fraction below 30% (13% vs. 17%; p = 0.2). This randomized trial has brought us full-circle back to GIK as a potentially low-cost, low-risk adjunctive intervention in a subset of patients with acute MI undergoing mechanical reperfusion. Although the results appear promising, more studies are warranted to confirm the results presented by these investigators.
The Aggrastat to Zocor (A to Z) trial
This late-breaking randomized clinical trial was sponsored by Merck and Company. It was presented by Dr. Michael Blazing of Duke University Medical Center (Durham, North Carolina). This study was designed in two parts. In part 1 of the study, the investigators compared the clinical outcome of 3,987 high-risk (with electrocardiogram changes or a positive biomarker) patients with acute coronary syndromes, all of whom were receiving aspirin and tirofiban (Aggrastat, a short-acting intravenous IIb/IIIa inhibitor), randomly allocated to weight-adjusted, unfractionated, intravenous heparin (UFH) or to subcutaneous injection of low-molecular-weight heparin enoxaparin at 1 mg/kg/12 h. The allocated heparin treatment was given for 120 h but could be stopped or switched at the discretion of the treating physician. Of the patients, 60% underwent coronary angiography during the hospital admission. The trial was designed as a non-inferiority trial comparing enoxaparin to UFH. The primary end point of death/MI/refractory ischemia occurred slightly more frequently in the UFH group, but this was not statistically significant (9.4% vs. 8.9%; p = 0.23). The overall results fulfilled the prespecified requirements to show that enoxaparin was not inferior to UFH. None of the subgroup analyses revealed any statistically significant differences between UFH and enoxaparin. Secondary end points, while showing a slight trend in favor of enoxaparin, were also not statistically significantly different between the two groups. There was a slight trend towards increased major plus minor bleeding with enoxaparin compared with UFH, but the differences, once again, were not statistically significant (3.1% vs. 2.2%; p = NS). Therefore, these overall results support the equivalence of UFH and enoxaparin in terms of benefits and risks in acute coronary syndrome patients. However, logistic advantages, in terms of feasibility for subcutaneous use, lack of need for dose adjustment, and monitoring with blood tests, would tend to favor enoxaparin over UFH. Part 2 of this trial, which compares early versus late initiation of simvastatin (Zocor) therapy, is likely to be presented later this year at the American Heart Association meetings in November 2003.
Efficacy of a novel P-selectin antagonist, rPSGL-Ig, for reperfusion therapy in acute MI: the RAPSODY trial
P-selectin is an adhesion molecule that interacts with its ligand P-selectin glycoprotein ligand (PSGL) and mediates the endothelium-leukocytes and platelets-leukocytes interaction. It has been implicated in thrombosis as well as so-called “reperfusion injury.” Reperfusion injury is a putative and highly controversial concept that implicates reperfusion as a source of myocardial damage through the release of oxygen-free radicals and leukocyte-plugging of microvasculature. In experimental studies, a recombinant inhibitor of P-selectin, rPSGL-Ig, has been shown to facilitate thrombolysis, reduce reocclusion, and attenuate “reperfusion injury.” This dose-finding randomized clinical trial, conducted in 598 ST-segment elevation type acute MI patients receiving tissue plasminogen activator for reperfusion therapy within 6 h of onset of symptoms, was designed to determine if rPSGL-Ig would improve the speed of ST-segment resolution (as a surrogate for facilitation of thrombolysis) and reduce infarct size. Three different doses of intravenous rPSGL-Ig (5 mg, 25 mg, 75 mg) were compared with placebo. Continuous ST-segment monitoring was used to assess reperfusion; infarct size was measured by sestamibi single photon emission computed tomography imaging on day 7; and left ventricular ejection fraction was determined by radionuclide ventriculography on day 30. Clinical outcome was monitored for six months. The study was supported by Wyeth Pharmaceuticals and presented by Jean-Francois Tanguay of the Montreal Heart Institute (Montreal, Quebec, Canada). The study failed to show any significant effect of any dose of rPSGL-Ig on infarct size, ejection fraction, and stroke/death/MI at 30 or 180 days. Furthermore, and contrary to expectation, there was a significant prolongation of time to ST-segment resolution with increasing doses of rPSGL-Ig (p = 0.008). Therefore, this study failed to show any benefit with adjunctive use of a novel P-selectin antagonist, and adds to a large body of clinical trial data (conducted at an astronomical expense) that have failed to show any benefit from any intervention designed to address the so-called “reperfusion injury” despite promising preclinical findings. These observations continue to question the very existence of so-called “reperfusion injury,” as suggested by elegant experimental studies of William Ganz at Cedars Sinai Medical Center (Los Angeles, California) reported several years ago.
Regional angiogenesis with vascular endothelial growth factor (VEGF): the RAVE trial
The concept of therapeutic angiogenesis for relief of ischemia, using angiogenic growth factor gene transfer, first pioneered by the late Dr. Jeffrey Isner, continues to be explored despite inconsistent and conflicting results. The RAVE trial was a double-blind, randomized, placebo-controlled trial to assess the safety and efficacy of locally administered adenovirus-mediated VEGF-121 (Ad-VEGF-121) gene transfer for unilateral peripheral vascular disease in patients with severe disabling intermittent claudication. The study was presented by Dr. Sanjay Rajagopalan of the University of Michigan (Ann Arbor, Michigan). Twenty local and ipsilateral intramuscular injections of either low dose or high dose of Ad-VEGF-121 were compared with placebo injections in 105 patients with severely symptomatic peripheral vascular disease confined to one lower extremity. The primary end point was safety and peak walking time at 12 weeks after randomization. Secondary end points included ankle-brachial index and peak walking time at 26 and 52 weeks.
The Ad-VEGF-121 therapy resulted in a dose-dependent increase in leg edema (nearly 30% at high dose) without any excess of cellulitis or liver function abnormalities. However, Ad-VEGF-121, at any dose, failed to produce any significant improvement over placebo in the primary end point. Placebo-treated patients showed a 20% increase in peak walking time at 12 weeks, which was not significantly different from the 30% and 20% increases experienced by low- and high-dose gene therapy recipients, respectively. Similarly, there was no significant difference in secondary end points or any other quality-of-life measures between placebo and gene therapy recipients. These results from the largest placebo-controlled adenoviral gene transfer trial in cardiovascular disease to date were quite disappointing, adding to the uncertainty of this seemingly biologically plausible and promising approach for refractory organ ischemia. The lack of beneficial effects may have been due to an inadequate dose of Ad-VEGF-121, limited transcription of the therapeutic gene, and/or limited duration of gene transcription, which has been a problem with adenoviral vectors. Whether better vectors, different angiogenic growth factors, or different delivery systems will ultimately allow realization of the promise of angiogenic gene therapy remains an open question for now.
- American College of Cardiology Foundation
- Immediate reduction in acute myocardial infarction (MI) after implementation of a comprehensive smoke-free ordinance
- Effect of glucose, insulin, and potassium (GIK) on 30-day mortality, infarct size, and ejection fraction in patients with acute MI undergoing primary percutaneous transluminal coronary angioplasty (PTCA)
- The Aggrastat to Zocor (A to Z) trial
- Efficacy of a novel P-selectin antagonist, rPSGL-Ig, for reperfusion therapy in acute MI: the RAPSODY trial
- Regional angiogenesis with vascular endothelial growth factor (VEGF): the RAVE trial