Previous Angina Alters In-Hospital Outcome in TIMI 4
A Clinical Correlate to Preconditioning?
Background Ischemic preconditioning has been shown to reduce myocardial infarct size in experimental models, but its role in patients remains unclear. Angina before myocardial infarction reflects brief episodes of ischemia and may be a marker of preconditioning. As part of the Thrombolysis in Myocardial Infarction (TIMI) 4 study, we performed an analysis on the effect of a history of previous angina on in-hospital outcomes for patients with acute myocardial infarction.
Methods and Results Patients eligible for thrombolytic therapy were enrolled into the study. Data were collected from case report forms regarding previous history of angina, in-hospital outcome and 6-week follow-up. Two hundred eighteen patients had a history of previous angina at any time before acute myocardial infarction, and 198 patients did not have previous angina. Patients with any previous history of angina were less likely than with those without angina to experience in-hospital death (3% versus 8%) (P=.03), severe congestive heart failure (CHF) or shock (1% versus 7%, P=.006), or the combined end point of in-hospital death, severe CHF, or shock (4% versus 12%, P=.004). Moreover, patients with any history of angina were more likely to have a smaller creatine kinase (CK)-determined infarct size (119 versus 154 CK integrated units; P=.01) and were less likely to have Q waves on their ECG (57% versus 69%; P=.01). In the subset of patients who experienced angina within the 48 hours before infarction (compared with those who did not), there was a trend toward less likely in-hospital death (3% versus 6%; P=.09), a lower incidence of severe CHF or shock (1% versus 6% P=.008), a lower combined end point of death, CHF, or shock (3% versus 10%; P=.006), smaller infarct size assessed by CK (115 versus 151 CK units; P=.03), and a trend toward fewer Q-wave infarcts. However, patients with a history of previous angina did have a trend toward more recurrent ischemic pain. Of importance is that the beneficial in-hospital effects of previous angina were not dependent on angiographically visible coronary collaterals.
Conclusions Previous angina confers a beneficial effect on in-hospital outcome after acute myocardial infarction. The reasons for this benefit are uncertain, but one potential mechanism for this observation may be ischemic preconditioning.
Many experimental laboratories have shown that brief episodes of ischemia immediately before sustained coronary occlusion significantly reduce myocardial infarct size. This phenomenon has been termed “preconditioning” by Murry et al1 and has been demonstrated in dogs,1 2 rats,3 rabbits,4 5 and pigs.6 Recent clinical studies suggest that preconditioning may occur in patients with repetitive balloon inflations during angioplasty7 and with intermittent aortic cross-clamping during coronary artery bypass procedures.8 Whether preconditioning occurs in patients before acute myocardial infarction is not known, but a history of previous angina or angina occurring immediately before myocardial infarction might serve as a “marker” for patients who have experienced brief periods of ischemia (and therefore may have been “preconditioned”) before myocardial infarction. As there is no consensus in the literature on the consequences of preinfarction angina on in-hospital outcomes,9 10 11 12 13 14 15 we performed a retrospective analysis of the effect of a history of previous angina on in-hospital mortality, congestive heart failure (CHF), and/or shock and creatine kinase (CK)-determined infarct size in patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI) 4 trial.
The TIMI 4 study was designed to study patient outcome with three thrombolytic regimens for the treatment of acute myocardial infarction: anistreplase (APSAC), alteplase (recombinant tissue-type plasminogen activator [rTPA]), and the combination of these two drugs along with aspirin and heparin.16 An open-label run-in phase was first conducted with the combination arm in 34 patients. Inclusion criteria included all patients less than 80 years old who experienced at least 30 minutes of ischemic pain within 6 hours before entry to the study. An additional requirement was that the ECG show new ST-segment elevation of at least 0.1 mV in two contiguous leads. Coronary angiography was obtained at 90 minutes and 18 to 36 hours; a predischarge radionuclide ventriculogram and MIBI scan were obtained. Data were collected on the study forms regarding whether patients ever experienced angina before the qualifying episode of ischemic pain and, if they did, whether ischemic pain episodes occurred within 48 hours before randomization.
We performed two series of statistical comparisons: (1) outcomes in patients with previous angina at any time before acute myocardial infarction versus patients without previous angina; and (2) outcomes in patients who did versus patients who did not experience angina within 48 hours of acute infarction. The history of previous angina was obtained during the recovery phase of acute myocardial infarction. In most patients, this was on days 2 to 4 after myocardial infarction. Populations were compared for demographics, history of previous myocardial infarction, coronary artery disease risk factors, antianginal drugs, infarct-related artery, and presence of multivessel coronary artery disease. The groups were compared for the following in-hospital end points: death, severe CHF (CHF is defined as the presence of rales that do not clear with coughing over more than half the lung fields), or cardiogenic shock, each occurring at least 24 hours after study drug initiation; the combined end point of death, severe CHF, or shock; the incidence of in-hospital reinfarction; TIMI flow grade (by coronary angiography); reocclusion of the infarct-related vessel determined from in-site evaluation of predischarge MIBI scan; recurrent ischemic pain; predischarge left ventricular ejection fraction assessed by radionuclide ventriculography; left ventricular ejection fraction in patients with and without previous myocardial infarction; and myocardial infarct size determined by total CK units integrated over the first 24 hours (and expressed as multiples of the upper limit of normal-hours as previously described17 ). To determine CK units, blood samples for CK were obtained at baseline and 8, 16, and 24 hours after enrollment, and measurements were assayed at each participating hospital. The values at each hospital were normalized by dividing the value by the upper limit of normal at that hospital. A trapezoidal “curve” of the CK values over the first 24 hours was constructed for each patient, and the area under the curve was calculated; the units of this value are “multiples of upper limit of normal-hours.”17 In addition, the groups were compared for the incidence of new Q-wave myocardial infarcts in the distribution of the original ST-segment elevation, time from onset of pain to initiation of thrombolytic therapy, and coronary collateral score using the following grading system: grade 0, no collaterals present−angiography fails to reveal evidence of collateral vessels; grade 1, minimal collaterals present−evidence of minimal to partial filling of the recipient artery; and grade 2, well-developed collaterals−evidence of collateral circulation with near-complete to complete filling of the recipient artery. Scoring of collaterals was performed in a blinded fashion by a core angiography laboratory.
Finally, the groups were compared at 6 weeks after infarction for events occurring after hospital discharge, including death, reinfarction, chronic CHF, unstable angina, hospitalization for cardiac events, coronary arteriography, angioplasty, and coronary artery bypass surgery.
All statistical analyses were carried out by Research Triangle Institute. χ2 analyses were used for comparing categorical data; t tests were used to compare continuous variables (age, left ventricular ejection fraction); and Wilcoxon two-sample tests were used to compare CK and time from onset of pain to thrombolysis. Logistic regression models were used to conduct analysis of outcome, adjusting for treatment and demographics.
Patients With Angina at Any Time Before Infarction
Table 1A⇓ summarizes the baseline characteristics for patients with versus those without a history of angina at any time before myocardial infarction. There was no difference in age or sex between patients with versus those without angina. Overall, there was a difference in the presence of angina by race, with Hispanics less likely to have angina. Patients with previous angina were more likely to have a history of previous myocardial infarction. As expected, patients with previous angina were more likely to be taking antianginal medicines (nitrates, β-blockers, calcium blockers) and aspirin. There was no difference in the distribution of the infarct-related artery among patients with versus those without angina. Patients with previous angina were more likely to have multivessel coronary artery disease on coronary angiography (68%) versus those without previous angina (55%; P=.01). There was no difference in the degree of stenosis of the infarct-related artery between patients with previous angina (78±1%) versus those without (80±1%; P=NS).
Table 1B⇓ shows the in-hospital outcomes. Interestingly, the time from onset of chest pain to initiation of thrombolysis was longer in patients with versus those without angina. This may indicate that if a patient is accustomed to having chest pain, it may take him or her longer to come to the hospital with the onset of the chest pain of myocardial infarction. Despite this longer time to thrombolysis and greater incidence of multivessel coronary artery disease, patients with a previous history of angina were less likely to experience in-hospital death than those without a previous history of angina (3% versus 8%; P=.03), were less likely to develop severe CHF or shock (1% versus 7%, P=.006), and were less likely to experience the combined end point of in-hospital death, severe CHF, or shock (4% versus 12%, P=.004). Patients with previous angina had smaller myocardial infarct size assessed by total CK units integrated over the first 24 hours (119 units with angina versus 154 without, P=.01) and had a lower incidence of Q-wave infarction as detected by ECG (57% versus 69%, P=.01). But of importance, patients with a history of angina did not have a greater collateral score than those without angina. In fact, there was a trend toward a lower collateral score (ie, fewer collaterals) in the angina group. To try to mimic the situation that might have been present before thrombolysis, we analyzed whether the subgroup who had not achieved reperfusion at 90 minutes (TIMI grade 0/1) had more collaterals if prior angina was present. The percentage of patients with collaterals in this group of patients was 28% with a history of prior angina versus 35% without angina. Thus, in our study, the presence of large epicardial collaterals was not better developed in patients with a history of angina, even when reperfusion did not occur. Overall, collaterals were present in 32% of patients with TIMI 0/1 flow versus 13% of those with TIMI 2/3 flow (P=.002).
Patients with previous angina did have a nonsignificant trend toward more recurrent ischemic pain (30% versus 22%; P=.10).
Overall predischarge left ventricular ejection fraction was 52.2% in those with versus 50.8% in those without previous angina. Left ventricular ejection fraction in patients with prior myocardial infarction was greater in patients with previous angina (51.8%) than in those without previous angina (44.3%; P=.05).
Six-week follow-up data are given in Table 1C⇓. There were no significant differences in any of these parameters between patients with versus those without previous angina.
Of patients experiencing previous angina, 29.4% received alteplase, 33.5% received anistreplase, and 37.2% received both (P=.028). Because of this difference in study drug distribution, Table 1D⇓ shows logistic regression analysis models for death and severe CHF or shock adjusted for both thrombolytic treatment assignment and demographics. After adjustment, these end points continued to differ between angina and nonangina groups.
Because the use of antianginal medicines might have contributed to better in-hospital outcome in patients with previous angina, we also analyzed in-hospital end points of patients with versus without previous angina for the subgroup not taking antianginal medication or aspirin (Table 1E⇓). Despite the smaller sample size and loss of statistical power, there was still a lower incidence of death and combined end point of death, CHF, or shock in patients with previous angina. Total integrated CK value tended to be lower in patients with angina than in those without (140 versus 160), but this difference no longer achieved statistical significance.
Patients With Angina Within 48 Hours of Infarction
Table 2A⇓ shows demographic characteristics for patients with versus those without ischemic pain that occurred within 48 hours of myocardial infarction. Women were more likely than men to have angina in the 48 hours before infarction. Patients with angina within 48 hours of infarct were again more likely to be on antianginal drugs and aspirin. They were also more likely to have multivessel coronary artery disease (69%) than were patients without angina within 48 hours (57%; P=.02). There was no difference in the degree of stenosis of the infarct-related artery between patients with angina within 48 hours (78±1%) and those without (79±1%; P=NS).
Table 2B⇓ summarizes the in-hospital end points. As in the previous analysis, patients with previous angina within 48 hours had a longer time from onset of pain to thrombolysis. However, there was a trend toward less in-hospital death in patients with versus without angina within 48 hours (3% versus 6%; P=.09). Patients with angina within 48 hours had a lower incidence of severe CHF or shock than those without angina (1% versus 6%; P=.008). Patients with prior angina had a lower combined end point of death or CHF or shock (3% versus 10%; P=.006). There was no difference in left ventricular ejection fraction between the groups. Myocardial infarct size was 115 total CK units in patients with previous angina versus 151 in those without (P=.03). There was also a trend toward a lower incidence of Q-wave infarction in patients with prior angina. Surprisingly, however, patients with angina within 48 hours of infarction were less likely to have collaterals present (9%) than were those without angina (23%; P=.01).
Six-week follow-up data on patients with angina within 48 hours are given in Table 2C⇓. Aside from two deaths in the angina group, there were no differences between the two populations.
There was an equal distribution of thrombolytic treatment assignment among patients with angina within 48 hours of infarct, with 32.3% receiving alteplase, 33.6% receiving anistreplase, and 34.2% receiving both drugs. Table 2D⇓ shows that adjusting for treatment assignment did not alter the in-hospital outcomes for patients with angina versus for patients without recent angina.
Table 2E⇓ summarizes in-hospital events for the subset of patients not on antianginal drugs or aspirin. As in the previous analysis, the incidence of death and the combined end points of death or CHF or shock were lower in patients with previous angina. There was a trend toward smaller infarct size in patients with previous angina, but this did not achieve statistical significance.
Table 3⇓ shows major in-hospital end point data for patients who had a positive history of previous angina but either did or did not have angina within the 48 hours before the myocardial infarction. There were no significant differences in end points between these two groups.
The major findings of the present study were that in-hospital death, the incidence of severe CHF or shock, the combined end point of death or severe CHF or shock, myocardial infarct size assessed by total CK units integrated over the first 24 hours, and presence of Q waves on the ECG were lower for patients with a history of angina before myocardial infarction compared with those without previous angina. In patients with a history of previous infarction, those with angina had a greater ejection fraction than those without previous angina. In general, benefits in in-hospital outcome were seen both for patients who had a history of angina at any time before infarction and those reporting angina within 48 hours of infarction. In patients with any history of angina, having angina within 48 hours before infarction did not appear to confer additional benefit.
Of interest is that these beneficial effects on in-hospital outcome were not dependent on better epicardial coronary collateral arteries as assessed by coronary angiography. In fact, there was a trend for the degree of collateralization to be less in patients with a history of any previous angina compared with those without angina. In addition, the percentage of patients with visible epicardial coronary collaterals was significantly less in patients who experienced angina within 48 hours of infarction versus those who did not experience angina during this time. However, we cannot exclude the possibility that patients with angina had developed intramural and/or microscopic collateral vessels that could not be visualized by angiography. We also do not have data on the status of the infarct-related artery or coronary collaterals before reperfusion, and this remains a limitation of our study. However, even in patients without successful reperfusion, collaterals were not more well developed in those with a history of previous angina.
The analyses revealed that the beneficial effects of previous angina on in-hospital outcome were not solely dependent on the use of antianginal medicines. Not surprisingly, patients who have angina are more likely to be taking β-blockers, nitrates, calcium blockers, and aspirin−agents that, in at least some experimental models, have been shown to have cardioprotective effects in the setting of acute myocardial infarction. We observed that previous angina was associated with reduced in-hospital mortality and the combined end point of death or CHF or shock even in patients not receiving antianginal drugs or aspirin. In addition, there was a nonsignificant trend for CK-determined infarct size to be lower in patients with versus those without angina in this subset not treated with antianginal medications. Nevertheless, we cannot entirely rule out the possibility that the greater use of antianginal drugs and aspirin with angina before myocardial infarction contributed at least in part to the better in-hospital outcomes of patients with prior angina.
A history of previous angina did have one potentially deleterious consequence. There was a nonsignificant trend for patients with angina to demonstrate recurrent ischemia after infarction. This observation is perhaps not surprising, as it suggests that patients who experience a myocardial infarction and have previously had angina are more likely to emerge from the infarction with recurrent ischemia. This observation also might be explained by the presence of more multivessel coronary artery disease in patients with previous angina.
Potential Mechanisms of Cardioprotection by Previous Angina
Although there is debate in the cardiology literature regarding the consequences of previous angina before myocardial infarction, some studies have concluded that previous angina has some protective properties. Specifically, Hirai et al9 observed that patients who experienced angina for more than 1 week before coronary occlusion had higher left ventricular ejection fractions and better wall motion in the infarct-related zone compared with patients without angina. The authors concluded, however, that this improvement in left ventricular function was a secondary consequence of increased collateral perfusion in patients with previous angina. Matsuda et al18 and Cortina et al19 also reported better preservation of left ventricular function in patients with a history of angina before myocardial infarction. In the study of Matsuda et al, this was not due to increased collaterals whereas in the study by Cortina et al, collaterals appeared to play a role. Some studies have suggested that patients with prior angina have more collaterals,20 but results have not been consistent.18 In our study, patients with previous angina did not have more collaterals, and this was even true in patients whose collaterals were graded in the setting of a lack of reperfusion at 90 minutes.
Muller et al10 showed that patients with a history of angina for more than 1 week before acute myocardial infarction had a lower rate of reocclusion after thrombolysis and a nonsignificant trend toward lower in-hospital mortality (4.6% versus 7.2%). Several factors were implicated to play a role in the benefit of prior angina, including enhanced collateralization, ischemic preconditioning, prior antianginal medicines, or intrinsic differences in the thrombolytic systems between the two groups. Finally, in a preliminary report, Ottani et al11 described smaller infarct sizes (determined by CK) and a smaller number of hypokinetic segments (assessed by left ventricular angiography) in patients with prodromal angina within 24 hours of the onset of myocardial infarction, and they postulated that prodromal angina may have preconditioned these infarcts. The findings of our study would, in general, support the observations of these previous studies,9 10 11 18 19 although in-hospital benefits in our analysis did not appear to be explained by increased epicardial collateral perfusion or solely by prior use of antianginal medicines. In addition, our study showed benefits on multiple in-hospital end points.
One potential mechanism that explains the results of our study is ischemic preconditioning. Ischemic preconditioning is the process in which brief episodes of ischemia before a sustained period of coronary occlusion reduce myocardial infarction size; this phenomenon has been observed in nearly all experimental models tested.1 2 3 4 5 Although the precise mechanism of this phenomenon remains unresolved, it appears to be related to stimulation of adenosine A1 receptors and opening of ATP-dependent potassium channels.4 21 22 Activation of ATP-dependent potassium channels results in a shorter action potential duration and a decrease in calcium flux, which may have an energy-sparing effect on the myocardium. Brief ischemia at 24 hours before sustained coronary occlusion has also been shown to reduce infarct size and may be related to expression of heat shock protein.23 This delayed protection implies that the heart may become more resistant to prolonged ischemia even when this dose of brief ischemic preconditioning occurred at a remote previous time. The mechanism whereby heat shock and expression of heat shock proteins provide longer protection of the heart is still under investigation. Thus, it appears that brief periods of ischemia provide endogenous protection to the heart.
Although preconditioning has been studied exhaustively in the experimental laboratory, information regarding the clinical existence or importance of this phenomenon is limited. Deutsch and coworkers7 have provided evidence of apparent endogenous protection during serial angioplasty procedures: they observed that a second angioplasty balloon inflation was associated with less anginal intensity, less ST-segment deviation, and reduced production of myocardial lactate. Subsequent angioplasty studies have recently confirmed this initial observation.24 25 Recently, Yellon et al8 explored the issue of whether intermittent aortic cross-clamping during coronary artery bypass surgery might protect or precondition the heart. They observed that 3-minute episodes of intermittent aortic cross-clamping prevented intramyocardial ATP depletion during a subsequent 10-minute period of cross-clamping. Their observation provides direct support of the concept that the human heart can be preconditioned.
Our results also imply that ischemic preconditioning may occur in patients. However, we are somewhat limited in how preinfarction ischemia is documented. Precise quantification of ischemic episodes (both anginal and silent) would require ambulatory ECG monitoring.26 Thus, in the present study, previous angina can be considered only a marker of patients more likely to have had episodes of brief ischemia sometime before infarction.
Previous Angina Does Not Provide Sustained Benefit
Although our study revealed that previous angina improved in-hospital outcome, no benefit was observed once patients left the hospital. In fact, some studies have found that a history of previous angina before infarction either provided no benefit or worsened the long-term outcome. Behar et al12 concluded that a history of previous angina was associated with increased in-hospital mortality and 5-year mortality. Karagounis et al13 reported that regional wall motion abnormalities and ejection fraction were similar in patients with versus those without previous angina before myocardial infarction. However, in our study, ejection fraction was improved only in the subgroup of patients with previous myocardial infarction who had prior angina, not in those who did not. Ruocco et al14 observed in the TIMI Phase II trial that antecedent angina identified patients at increased risk for recurrent in-hospital chest pain and recurrent infarction at 1 year. In some respects this is similar to the present study, in that we also found a trend toward more recurrent ischemic pain in patients with previous angina. Barbash et al27 observed that prior angina in a thrombolytic trial was associated with a longer hospital stay, a higher incidence of bypass surgery, increased in-hospital death, and a higher 6-month mortality rate. However, in contrast to our study, patients with antecedent angina were older, had a higher rate of hypertension, and had more heart failure at baseline−all factors that might mediate outcome.
Pierard et al28 observed that patients with angina before myocardial infarction had in-hospital mortality rates that were similar to those of patients without infarction but that 3-year posthospital mortality was higher in those with a previous history of angina than in those without. In their study patients with previous angina were older and were more likely to present with left ventricular failure and bundle-branch block. Of note, they were also more likely to present with a non–Q-wave infarction, a finding that was similar to our observation as well as that of Harper et al29 and Behar et al.12
The reason for the differences among these trials is not clear but may include the fact that some studies described patients from the prethrombolytic era.15 29 It would be unlikely for ischemic preconditioning to be protective in the absence of reperfusion. In canine studies, preconditioning does not reduce infarct size if the duration of sustained ischemia is prolonged beyond 60 to 90 minutes.2 In this regard, recent retrospective analysis of the MILIS Study, a large prethrombolytic trial of acute myocardial infarction, showed that previous angina did not confer in-hospital protection (Kloner et al, unpublished observation). A second issue is that in some of the studies, baseline conditions such as age, presentation of heart failure on admission, and hypertension differed between angina and nonangina groups. Finally, the protection afforded by previous angina may be short lived. Results from the present study suggest that previous angina confers an early protective effect on acute myocardial infarction in the hospital setting but not in the subsequent weeks after discharge, perhaps due to the presence of more multivessel disease in patients with previous angina.
In summary, previous angina in the TIMI 4 study resulted in a lower incidence of in-hospital death, severe heart failure or shock, and smaller CK-determined infarct size. These beneficial effects occurred despite a longer time to receive thrombolytic therapy and more multivessel coronary artery disease in the angina groups. These beneficial effects were not dependent on angiographically visible epicardial coronary collateral blood vessels or solely on the use of antianginal medication. One potential explanation of these benefits is that previous angina preconditions the human heart.
Study Chairman’s Office
Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Study chairman, Eugene Braunwald, MD; coinvestigator, Christopher P. Cannon, MD; project director, Carolyn H. McCabe, BS.
Data Coordinating Center
Research Triangle Institute, Research Triangle Park, NC. Principal investigator, W. Kenneth Poole, PhD; study/data coordinator, Betty K. Hastings; statisticians, Vicki Davis, DrPH, Barbara Alexander, MSPH, Rebecca Perritt, MS; systems analyst, David Myers, PhD; research associate, Sandra McGuire.
Angiographic Core Laboratory
Beth Israel Hospital, Boston, Mass. Coprincipal investigators, C. Michael Gibson, MS, MD, Donald S. Baim, MD; coinvestigators, Robert N. Piana, MD, Jeffrey A. Breall, MD, Stacy F. Davis, MD, Kathleen A. Mansour, MD; research coordinator, Margaret Flatley.
Biochemistry Core Laboratories
MB isoforms: The Methodist Hospital, Baylor College of Medicine, Houston, Tex. Principal investigator, Peter Puleo, MD; coinvestigators, Robert Roberts, MD, Denise Mayer, MTASCP, Leah White, MLT. MM isoforms: Washington University, St Louis, Mo. Principal investigator, Dana Abendschein, PhD; coinvestigators, Burt E. Sobel, MD; Lea Doerr Bullock, MS.
Drug Distribution Center
VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM. Pharmacist, Cindy Colling, RPh, MS; study coordinator, Jenine Peterson, BS; coinvestigator, Mike R. Sather, MS, FASHP.
Myocardial Infarction Confirmation Core Laboratory
St Louis University, St Louis, Mo. Principal investigator, Bernard R. Chaitman, MD; coinvestigators, Debbie Kargl, BA, Bonpei Takase, MD, Beaver Tamesis, MD; research coordinator, Karen Stocke, BS, MBA.
Hematology Core Laboratory
Brigham and Women’s Hospital, Boston, Mass. Principal investigator, Joseph Loscalzo, MD, PhD; research coordinator, Dorinda George, AB.
Radionuclide Core Laboratory
Yale University School of Medicine, New Haven, Conn. Coprincipal investigators, Barry L. Zaret, MD, Frans J.T. Wackers, MD; research coordinator, Michael McMahon, CTNM.
Data and Safety Monitoring Board
Lewis Becker, MD, Joel Karliner, MD, Sheryl Kelsey, PhD, Charles Rackley, MD, Sanford Shattil, MD; ex-officio members, Eugene Braunwald, MD, W. Kenneth Poole, PhD.
Morbidity and Mortality Classification Committee
Chairman, Daniel J. Diver, MD. Members, Christopher P. Cannon, MD, Ferdinand Leya, MD, Donald Palisaitis, MD, Leroy Rabbani, MD.
Clinical Centers (in the Order of the Number of Patients Enrolled)
Beth Israel Hospital, Boston, Mass. Principal investigators, Daniel J. Diver, MD; coinvestigators, Jeffrey A. Breall, MD, Clifford Berger, MD; research coordinator, Susan Marble, RN. Satellite center: Emerson Hospital, Concord, Mass. Principal investigator, Steve Herson, MD; coinvestigator, Richard Daum, MD; research coordinator, Gail Carey, RN.
Alta Bates Medical Center, Berkeley, Calif. Principal investigator, Robert M. Greene, MD; research coordinators, Eileen Healy, RN, Vickie Perry, RN.
Cedars-Sinai Medical Center, Los Angeles, Calif. Principal investigator, Prediman K. Shah, MD; coinvestigator, Bojan Cercek, MD; research coordinator, Adrian Mirea, MD.
University of Miami/Jackson Memorial Hospital, Miami, Fla. Principal investigator, Raphael F. Sequeira, MD; coinvestigator, Alan Fernandez, MD; research coordinator, Denise A. Francoeur, RN.
Loyola University Hospital, Maywood, Ill. Principal investigator, Ferdinand Leya, MD; research coordinator, Rosita Picchi, RN.
Brigham and Women’s Hospital, Boston, Mass. Principal investigator, James M. Kirshenbaum, MD; coinvestigator, Christopher P. Cannon, MD; research coordinators, Deborah Bates-Riordan, RN, JD, Paul Sedgwick, RN.
Ohio State University, Columbus, Ohio. Principal investigator, Raymond D. Magorien, MD; coinvestigators, Gregory Eaton, MD, James Peterson, MD; research coordinator, Jenny Sharp-Wilmer, RN.
Robert Wood Johnson Medical School, New Brunswick, NJ. Principal investigator, Sebastian T. Palmeri, MD; coinvestigators, Abel E. Moreyra, MD, Maryhelen Hosler, RN; research coordinator, Laurie Casazza, RN.
Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec. Principal investigator, Vincent Dangoisse, MD; coinvestigator, Guy Proulx, MD; research coordinator, Jackie Dangoisse.
University of Missouri (Columbia). Principal investigator, Greg C. Flaker, MD; coinvestigators, Robert Myers, MD, Richard Webel, MD, John Bartolozzi, MD; research coordinator, Kathy Belew, RN. Satellite center: Lake of the Ozarks General Hospital, Osage Beach, Mo. Principal investigator, T.W. Garrison, Jr, MD; research coordinators, Mary Cope, RN, Roland Vize, RN.
Baystate Medical Center, Springfield, Mass. Principal investigator, Marc J. Schweiger, MD; coinvestigators, Mark Porway, MD, John Joelson, MD, Thomas Marantz, MD, Alan Wiseman, MD; research coordinator, Deborah Warwick, RN.
Kaiser Permanente Medical Center, Los Angeles, Calif. Principal investigator, Peter R. Mahrer, MD; research coordinators, Joni Noceda, RN, Judy Fletcher, RN.
Hospital of the Good Samaritan, Los Angeles, Calif. Principal investigator, Thomas L. Shook, MD; coinvestigators, Steven Burstein, MD, David S. Cannom, MD, Ray V. Matthews, MD, Robert A. Kloner, MD, PhD; research coordinator, Lucille Junio, RN, Carolyn Gray, RN, BSN.
LDS Hospital, University of Utah (Salt Lake City). Principal investigator, Jeffrey L. Anderson, MD; coinvestigators, Labros Karagounis, MD, Miguel Gomez, MD; research coordinator, Ann Allen, BS.
Hôpital du Sacre Coeur de Montreal, Montreal, Quebec. Principal investigator, Donald Palisaitis, MD; coinvestigators, James Nasmith, MD, Joseph M. Ruggio, MD; research coordinators, Ginette Gaudette, RN, Jocelyne Fouquette, RN.
SUNY Health Science Center at Stony Brook. Principal investigator, Peter F. Cohn, MD; coinvestigators, Stephen Vlay, MD, John Dervan, MD, Praveer Jain, MD; research coordinator, Linda Olson-Vlay, RN.
University of Ottawa Heart Institute, Ottawa, Canada. Principal investigator, Louise A. Laramee, MD; coinvestigators, Richard F. Davies, MD, Ian G. Stiell, MD; research coordinators, Ann Baker, RN, Colette Favreau, RN.
This study was supported by a grant from SmithKline Beecham, Philadelphia, Pa.
Reprint requests to Robert A. Kloner, MD, PhD, Professor of Medicine, University of Southern California, Heart Institute Research Department, Hospital of the Good Samaritan, 616 S Witmer, Los Angeles, CA 90017.
The guest editor was Dr Myron L. Weisfeldt, Columbia Presbyterian Medical Center, New York, N.Y.
↵1 A list of participants is given in “Appendix.”
- Received April 29, 1994.
- Accepted August 2, 1994.
- Copyright © 1995 by American Heart Association
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