Background Activation of platelets is central to the pathophysiologyof unstable angina. We studied whether inhibition of the finalcommon pathway for platelet aggregation with tirofiban, a nonpeptideglycoprotein IIb/IIIa receptor antagonist, would improve clinicaloutcome in this condition.
Methods In a double-blind study, we randomly assigned 3232 patientswho were already receiving aspirin to additional treatment withintravenous tirofiban or heparin for 48 hours. The primary endpoint was a composite of death, myocardial infarction, or refractoryischemia at 48 hours.
Results The incidence of the composite end point was 32 percentlower at 48 hours in the group that received tirofiban (3.8percent, vs. 5.6 percent with heparin; risk ratio, 0.67; 95percent confidence interval, 0.48 to 0.92; P=0.01). Percutaneousrevascularization was performed in 1.9 percent of the patientsduring the first 48 hours. At 30 days, the frequency of thecomposite end point (with the addition of readmission for unstableangina) was similar in the two groups (15.9 percent in the tirofibangroup vs. 17.1 percent in the heparin group, P=0.34). Therewas a trend toward a reduction in the rate of death or myocardialinfarction with tirofiban (a rate of 5.8 percent, as comparedwith 7.1 percent in the heparin group; risk ratio, 0.80; 95percent confidence interval, 0.61 to 1.05; P=0.11), and mortalitywas 2.3 percent, as compared with 3.6 percent in the heparingroup (P=0.02). Major bleeding occurred in 0.4 percent of thepatients in both groups. Reversible thrombocytopenia occurredmore frequently with tirofiban than with heparin (1.1 percentvs. 0.4 percent, P=0.04).
Conclusions Tirofiban was generally well tolerated and, as comparedwith heparin, reduced ischemic events during the 48-hour infusionperiod, during which revascularization procedures were not performed.The incidence of refractory ischemia and myocardial infarctionwas not reduced at 30 days, but mortality was lower among thepatients given tirofiban. Platelet inhibition with aspirin plustirofiban may have a role in the management of unstable angina.
Platelet activation and aggregation are central to the pathophysiologyof unstable angina. After plaque fissure or rupture, the activation,adherence, and aggregation of platelets may cause either nonocclusiveor occlusive thrombus formation.1 Pharmacologic antagonism ofthis process is thus an attractive strategy for antithrombotictherapy.
Aspirin therapy is standard in the management of unstable angina.The addition of heparin may reduce the incidence of refractoryangina and the likelihood of progression to myocardial infarction,2,3,4,5,6but the pharmacodynamic response to heparin is unpredictableand requires frequent measurement of the activated partial-thromboplastintime and appropriate adjustment of doses. Furthermore, ischemicevents may increase when heparin is stopped.7
Aspirin2,3,8,9 and ticlopidine10 inhibit platelet aggregationand have been shown to decrease the frequency of clinical events.Both drugs have lasting effects on platelet function, but theyprovide only partial inhibition of platelet aggregation at maximaldoses, which may not be adequate in acute ischemia, and theydo not inhibit the stimulation of platelet aggregation by thrombin.It is possible that more complete platelet inhibition may improvethe immediate clinical response. A potent, selective inhibitorof the final common pathway of platelet aggregation might thereforebe an important therapeutic advance.
Tirofiban (Aggrastat, Merck, White House Station, N.J.) is asmall, nonpeptide antagonist of the platelet glycoprotein IIb/IIIareceptor. By blocking the glycoprotein IIb/IIIa receptor, tirofibanblocks the essential final step in platelet aggregation —namely, the binding of plasma fibrinogen or von Willebrand factorto this activated membrane protein — thereby preventingcross-linking of platelets by the fibrinogen molecule. Tirofibanachieves a high degree of inhibition of platelet aggregationand prevents arterial thrombosis in animal models.11 The purposeof this trial was to compare intravenous tirofiban with intravenousunfractionated heparin for the treatment of unstable anginain patients receiving aspirin.
Methods
Study Population
The study population consisted of patients who presented withischemic symptoms of unstable angina. The study included 128sites in 25 countries and was conducted from March 1994 to October1996. All patients gave written informed consent. A data andsafety monitoring committee reviewed data on safety and efficacyand performed two interim analyses, as specified in the protocol.
Eligible patients were those who had their most recent episodeof chest pain at rest or accelerating chest pain within 24 hoursof randomization. Coronary artery disease had to be manifestedby one of the following three sets of signs: (1) electrocardiographicevidence of myocardial ischemia in two contiguous leads duringan episode of chest pain with new, persistent, or transientST-segment depression of 0.1 mV or more (0.08 second after theJ point); new, persistent, or transient T-wave inversion; ortransient ST-segment elevation (lasting less than 20 minutes)of 0.1 mV or more; (2) elevated cardiac-enzyme levels consistentwith the occurrence of non–Q-wave myocardial infarction;or (3) a history of myocardial infarction, percutaneous revascularizationmore than six months earlier, coronary surgery more than onemonth earlier, a positive exercise stress test or dipyridamole(or adenosine) nuclear stress test, or narrowing of at least50 percent of the luminal diameter of a major coronary arteryon a previous arteriogram.
Patients were retrospectively classified as having non–Q-waveinfarction if the creatine kinase level exceeded twice the normalvalue or if the level of the creatine kinase MB fraction (CK-MB)was above normal within the first 24 hours, in the absence ofa new infarction. Patients were excluded if they had receivedthrombolytic therapy within the previous 48 hours or had allergyto or intolerance of heparin; a serum creatinine level above2.5 mg per deciliter (221 µmol per liter); an active bleedingdisorder; a history of gastrointestinal bleeding; hematuria;a positive fecal occult-blood test; known coagulopathy; a plateletdisorder or a history of thrombocytopenia; persistent systolicblood pressure above 180 mm Hg, diastolic blood pressure above110 mm Hg, or both, at the time of enrollment; a history ofhemorrhagic cerebrovascular disease or an active intracranialpathologic process; a history of cerebrovascular disease ortransient ischemic attack within the previous year; a majorsurgical procedure within the previous month; active pepticulceration within the previous 3 months; or an invasive procedurewithin 14 days before enrollment that would substantially increasethe risk of hemorrhage.
Study Design
The Platelet Receptor Inhibition in Ischemic Syndrome Management(PRISM) trial was a randomized, double-blind study. All patientsreceived aspirin (300 to 325 mg daily) before randomizationand for 48 hours after randomization, and thereafter at thediscretion of the physician, unless its use was contraindicated.Patients randomly assigned to tirofiban therapy received a loadingdose of 0.6 µg per kilogram of body weight per minutefor 30 minutes, followed by 0.15 µg per kilogram per minutefor 47.5 hours. An intravenous 5 percent dextrose solution wasalso given as placebo for heparin. Patients randomly assignedto heparin therapy received a 5000-unit intravenous bolus followedby an infusion of 1000 units per hour for 48 hours and an intravenousnormal-saline placebo for tirofiban.
The heparin infusion was adjusted at 6 and 24 hours by an investigatorwho was not blinded to treatment assignment but was not directlyinvolved in patient care, using a standard nomogram to maintainthe activated partial-thromboplastin time at twice the controlvalue. For patients receiving a placebo for heparin, "dummy"instructions for the adjustment of the infusion were provided.Angiography and revascularization in the first 48 hours werediscouraged. It was recommended that the blinded infusions bestopped if revascularization was performed.
Dose Selection and Concurrent Treatment
On the basis of dose-finding studies with tirofiban,12 the loadingand maintenance infusion should rapidly have achieved a medianinhibition in vitro of turbidimetric platelet aggregation mediatedby adenosine diphosphate (5 µM) of more than 90 percent,with more than 70 percent inhibition of platelet aggregationmaintained throughout the infusion in more than 95 percent ofthe patients.12
Other medications (except nonsteroidal antiinflammatory agents,ticlopidine, and warfarin) could be prescribed.
Safety
A complete physical examination, laboratory evaluation, andelectrocardiography were performed at base line and at 24, 48,and 72 hours. Bleeding was defined according to the criteriaof the Thrombolysis in Myocardial Infarction trial,13 with majorbleeding defined as a decrease in the hemoglobin level of 50g per liter, intracranial hemorrhage, or cardiac tamponade,and minor bleeding defined as a decrease in the hemoglobin levelof more than 30 g per liter from an identified site, spontaneousgross hematuria, hematemesis, or hemoptysis.
Clinical Efficacy
The primary end point was a composite of death, myocardial infarction,or refractory ischemia at the end of the 48-hour infusion. Asecondary end point was death, myocardial infarction, or refractoryischemia at seven days. Patients were followed for 30 days,and the composite end point (with the addition of readmissionfor unstable angina) and its components were analyzed in a predefinedexploratory analysis.
Refractory ischemia was defined as recurrent anginal chest painwith ischemic ST-T changes (new ST-segment depression or elevationof at least 0.1 mV or T-wave inversion in two contiguous leads)lasting 20 minutes or more, or two or more episodes lastingat least 10 minutes each within a 1-hour period, despite fullmedical therapy. Such therapy generally included an infusionof nitroglycerin plus use of a beta-blocker or calcium-channelblocker at a dosage adjusted according to the heart rate andblood pressure. The definition of refractory ischemia also includedhemodynamic instability attributed to ischemia, as evidencedby pulmonary edema (new rales over one third of the lung fieldsor tachypnea lasting more than 30 minutes), systolic blood pressurebelow 95 mm Hg that was not related to medication, or a needfor inotropic agents.
Myocardial infarction after randomization was defined as typicalchest pain with new ST-T changes, new pathologic Q waves (lastingmore than 0.03 second), or both, accompanied by an increasein the serum creatine kinase level to more than twice the normalvalue. In patients who had non–Q-wave myocardial infarctionat enrollment, new infarction was defined as an increase inthe creatine kinase level to 50 percent or more above the valuein the preceding sample and more than twice the normal value.All deaths during the first 30 days were recorded. All potentialend points were reviewed and adjudicated by a three-member,blinded end-points committee made up of cardiologists who werenot involved in the study. Consensus was required for verificationof an end point.
Statistical Analysis
The primary end point was analyzed with use of Cox regressionanalysis to calculate risk ratios and 95 percent confidenceintervals. Prespecified subgroups included patients who weretaking heparin and aspirin before randomization and those withelectrocardiographic evidence of ischemia. The secondary endpoint and the components of the composite end points were analyzedin the same manner. Other data were analyzed with Fisher's exacttest. Continuous variables are presented as means ±SD.Significance was indicated by a P value below 0.05, except forthe analysis of the primary end point, in which a P value below0.047 was required to correct for the two interim analyses bythe data and safety monitoring committee.
The trial was designed with a sample size of 2000 patients,which provided 80 percent power to detect a 30 percent reductionin the incidence of the primary end point from 14.3 percentin the heparin group to 10.0 percent in the tirofiban group.At the time of the second interim analysis, after approximately1350 patients had completed the study, the combined rate ofclinical events comprised by the primary end point in the twogroups combined was lower than expected. Because of this, thesteering committee and the data and safety monitoring committeerecommended an increase in the sample size in order to provideadequate power to detect a 35 percent reduction in clinicalevents in the tirofiban group.
Results
A total of 3232 patients were randomly assigned to treatment(1616 in each group). There were no significant differencesin base-line characteristics or use of medications (Table 1).Seventy percent of the patients had documented evidence of previouscoronary artery disease, and 75 percent had an abnormal base-lineelectrocardiogram with ST-segment depression (31.5 percent),T-wave inversion (51.4 percent), or transient ST-segment elevation(7.3 percent). Evidence of non–Q-wave myocardial infarctionwas present in 24.2 percent of patients assigned to tirofibanand 25.5 percent of those assigned to heparin.
Table 1. Base-Line Demographic Characteristics of the Patients.
Tirofiban was infused for a mean of 45.6±8.7 hours andheparin for 45.9±8.1 hours. The rate of use of concomitantmedications during this time was similar in the two groups;70.9 percent of patients treated with tirofiban were takingbeta-blockers, as compared with 72.0 percent of those treatedwith heparin; for long-acting nitrates, the comparable figureswere 87.9 percent and 89.4 percent, and for calcium-channelblockers, 46.3 percent and 47.8 percent. One patient assignedto the tirofiban group and four assigned to the heparin groupreceived abciximab after the blinded infusions were stopped.
During the first 48 hours, 5.7 percent of patients underwentangiography, 1.9 percent underwent percutaneous revascularization,and 0.5 percent underwent coronary-artery surgery. Tirofibanhad no significant effect on the activated partial-thromboplastintimes, as shown in Figure 1. On average, satisfactory prolongationof the activated partial-thromboplastin time was achieved byadjustment of the heparin infusions.
Figure 1. Mean (±SD) Activated Partial-Thromboplastin Time during the Blinded 48-Hour Infusion in Patients Receiving Tirofiban or Heparin.
At 48 hours, the incidence of the composite end point was significantlylower in the tirofiban group than in the heparin group (riskratio, 0.67; 95 percent confidence interval, 0.48 to 0.92; P=0.01)(Table 2). Both refractory ischemia and myocardial infarctionwere approximately a third less frequent than in the heparingroup. At the time of verified episodes of refractory ischemia,61 percent of patients were receiving intravenous nitroglycerin,39.4 percent were receiving oral or topical nitrates, 69.8 percentwere receiving beta-blockers, and 45.4 percent were receivingcalcium-channel blockers. Open-label therapy with heparin wasbegun at 48 hours in 31.4 percent of the tirofiban group and32.6 percent of the heparin group.
Table 2. Clinical Events at 48 Hours, 7 Days, and 30 Days.
At seven days, the composite end point had been reached in 10.3percent of the tirofiban group and 11.2 percent of the heparingroup (P=0.33) (Table 2). At 30 days the composite end pointhad occurred in 15.9 percent of the tirofiban group and 17.1percent of the heparin group (P=0.34) (Table 2). The rate ofdeath or myocardial infarction was 5.8 percent in the tirofibangroup, as compared with 7.1 percent in the heparin group (riskratio, 0.80; 95 percent confidence interval, 0.61 to 1.05; P=0.11).Death was significantly less common in the tirofiban group thanin the heparin group (2.3 percent vs. 3.6 percent; risk ratio,0.62; 95 percent confidence interval, 0.41 to 0.93; P=0.02).Figure 2 shows 30-day mortality, with early separation of thecurves and an increase in the absolute difference in mortalityto 1.3 percentage points.
Figure 3. Risk Ratio of the Composite End Point of Death, Myocardial Infarction, or Refractory Ischemia within 48 Hours, According to Demographic and Clinical Characteristics.
In the first 30 days, angiography was performed in 62.0 percentof the patients. Percutaneous revascularization was performedin 21.6 percent of the patients randomly assigned to heparinand 21.3 percent of those randomly assigned to tirofiban. Stentingwas performed in 34.0 percent of percutaneous revascularizationprocedures. Coronary surgery was performed in 16.5 percent ofthe patients assigned to heparin and 18.1 percent of those assignedto tirofiban.
Patients were selected for medical management, percutaneousrevascularization, or coronary surgery in part on the basisof their response to the study therapy. Table 3 shows the 30-dayoutcomes in relation to medical therapy and revascularizationprocedures. For patients who were treated with medical therapyalone, the rate of death or myocardial infarction was reducedfrom 6.2 percent in the heparin group to 3.6 percent in thetirofiban group (risk ratio, 0.58; 95 percent confidence interval,0.38 to 0.87; P<0.01).
Table 3. Clinical Events within 30 Days, According to Treatment Strategy.
Safety
Major bleeding was infrequent (Table 4) and did not differ infrequency between the groups. Intracranial hemorrhage occurredin two patients in the heparin group and in one in the tirofibangroup in whom it was possibly related to a fall before hospitalization.Thrombocytopenia (defined as a platelet count below 90,000 percubic millimeter) occurred more frequently with tirofiban thanwith heparin (1.1 percent vs. 0.4 percent, P=0.04). The plateletcounts returned to normal over a period of several days afterthe cessation of the study-drug infusions, without any otherclinical sequelae.
The glycoprotein IIb/IIIa receptor antagonists are potent plateletinhibitors that have been shown to prevent thrombotic complicationsassociated with percutaneous revascularization.14,15,16,17,18Patients with unstable angina have the pathophysiology of anunstable atherosclerotic plaque with superimposed platelet depositionand are at risk for thrombotic complications, which can triggerrecurrent ischemia, myocardial infarction, or death. We thereforecompared a new platelet glycoprotein IIb/IIIa receptor antagonist,tirofiban, directly with unfractionated heparin, an active control,in patients with unstable angina who were receiving aspirintherapy.
The combined incidence of death, myocardial infarction, or refractoryangina in high-risk patients with unstable angina remains highdespite treatment with aspirin, heparin, and antianginal agents.19,20,21The highest event rates occur in patients with recent chestpain and ST-segment changes.19,20,22 In this study, 75 percentof the patients had electrocardiographic changes indicativeof ischemia at randomization. The incidence of death, myocardialinfarction, or refractory ischemia in the heparin group was5.6 percent at 48 hours; the incidence of death, myocardialinfarction, refractory ischemia, or readmission for unstableangina was 17.1 percent at 30 days.
This trial demonstrates that a combination of aspirin and intravenoustirofiban is associated with a lower rate of ischemic eventsduring the infusion than aspirin plus heparin, in the absenceof invasive procedures, in patients with unstable angina ornon–Q-wave myocardial infarction. Tirofiban was also beneficialin the prespecified subgroups. At 30 days, mortality was 36percent lower with tirofiban than with heparin (P=0.02). Forpatients treated with medical therapy alone, the rate of deathor myocardial infarction was reduced by 42 percent (P<0.01).Tirofiban was generally well tolerated, and bleeding was infrequentand similar in frequency in the two groups.
We chose 48 hours as the time to evaluate the primary end pointin this trial in order to determine the efficacy of tirofibanduring the period of infusion, unconfounded by percutaneousrevascularization. In the period after the cessation of thestudy-drug infusion, physicians performed angiography and revascularizationas appropriate, without restrictions imposed by the protocol.Some of the initial benefit observed during the administrationof the drug was lost after the infusion was stopped. There wasno effect on refractory ischemia at seven days, and the riskratio for myocardial infarction in the tirofiban group becameless favorable (it changed from 0.64 to 0.84). However, theeffect on survival became greater in absolute terms with longerfollow-up, so that at 30 days, mortality was significantly lower(1.3 percentage points lower) in the tirofiban group than inthe heparin group.
The end point of refractory ischemia was chosen to avoid confoundingassociated with revascularization procedures, which may be performedbecause of anatomical findings rather than to alleviate symptoms.In an international trial, even when it is prespecified thatearly revascularization is to be performed only for symptom-relatedreasons, the results may still be confounded by variations ininterpretation. In addition, revascularization procedures maythemselves be associated with myocardial infarction independentlyof the efficacy of a drug.18 In this trial, refractory ischemiawas strictly defined, and classification of this end point wasperformed by a blinded end-points committee. If refractory ischemiadevelops, the risk of subsequent morbidity and death increasessubstantially.23,24,25 A 1993 study reported a ninefold incidenceof infarction and an eightfold incidence of death in patientswith refractory ischemia, as compared with those without thiscondition.23 By decreasing the incidence of refractory ischemiafrom that in patients treated with heparin, tirofiban had aneffect on events that might otherwise have required revascularization.
This study compared the effect of tirofiban with that of heparinin patients who were already receiving aspirin therapy. A similarcomparison was undertaken in the Platelet Receptor Inhibitionin Ischemic Syndrome Management in Patients Limited by UnstableSigns and Symptoms (PRISM-PLUS) study,26 with the addition ofa third study group in which patients received aspirin, tirofiban,and heparin. At the first interim analysis, the data and safetymonitoring committee recommended stopping the trial in the groupgiven tirofiban without heparin, to which 345 patients had beenassigned, because of an increase in deaths at day 7 (4.6 percent,as compared with 1.1 percent in the group that received onlyheparin). This decision did not take into account statisticaladjustment for multiple comparisons. There was no adverse effectin terms of the other end points of refractory ischemia andmyocardial infarction, which share a common pathophysiology,and there was no significant increase in deaths at 48 hours(0.6 percent, vs. 0.3 percent in the heparin group) or at 30days (6.1 percent vs. 4.0 percent). At six months, mortalitywas similar in the group assigned to heparin and that assignedto tirofiban (6.9 percent vs. 7.2 percent).
The PRISM-PLUS patients differed from the study population inthe current PRISM trial in several ways, including the incidenceof ST-segment depression on the electrocardiogram obtained atrandomization (58.5 percent in PRISM-PLUS vs. 31.5 percent inour study). In addition, approximately 70 percent of the patientsin PRISM-PLUS were receiving intravenous heparin at the timeof randomization. It is therefore possible that heparin rebound,which has been reported to increase the incidence of ischemicevents (including death) in the presence of aspirin up to 61/2 days after the cessation of heparin therapy, could haveoccurred when these patients were randomly assigned to receiveaspirin plus tirofiban.27
The findings in the discontinued group in PRISM-PLUS were thereforenot consistent with those of our study, which included almostfive times as many patients as were in the tirofiban-only groupin PRISM-PLUS. The most likely explanation for these resultsis chance, but an effect of heparin rebound cannot be excluded.
As an indirect inhibitor of thrombin, heparin inhibits a differentpart of the clotting system from that affected by tirofiban.Since early inhibition of platelets may be important in preventingthrombus formation in the arterial circulation, tirofiban mayhave advantages over heparin in the treatment of clinical syndromesrelated to arterial plaque disruption and early thrombotic processes.Heparin has a number of limitations, including the need forrepeated measurements of activated partial-thromboplastin timeand the fact that its anticoagulant effect is unpredictableand varies markedly with the patient's age, sex, weight, smokingstatus, renal function,28 and antithrombin III activity. Noevidence of clinical rebound was noted in this study when thetirofiban infusion was stopped.
This study confirms the central role of platelets in the acutecoronary syndrome of unstable angina. Aspirin plus tirofibanwas effective in reducing the incidence of acute ischemic eventsduring the infusion, in the absence of revascularization procedures,as compared with heparin, an active control. This study doesnot make clear whether patients would benefit more if tirofibanwere administered for longer than 48 hours. Future studies mightuse a short-acting, intravenous glycoprotein IIb/IIIa receptorantagonist to stabilize the condition of the patients in theshort term, with long-term oral therapy to maintain or enhancethis effect. Another possibility is the use of tirofiban incombination with low-molecular-weight heparins, which can beadministered subcutaneously for long-term therapy.
* The investigators and centers participating in the trial arelisted in the Appendix. Professor White, as chairman of thestudy, assumes full responsibility for the overall content andintegrity of the manuscript.
Source Information
Address reprint requests to Professor Harvey White at the Cardiology Department, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand.
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Appendix
The principal investigators of the PRISM Study Group, listedin alphabetical order according to country, are as follows (thenumbers of patients enrolled in each country are shown in parentheses):Argentina (121) — O. Bazzino; Australia (89) — P.Aylward and A. Hains; Austria (29) — J. Slany and K. Steinbach;Belgium (67) — F. Van de Werf and C. Vrints; Brazil (68)— O. Coelho and J. Ramires; Canada (154) — P. Bogaty,J. Boudreault, J. Diodati, D. Gossard, S. Kouz, P. Laramee,M. Lemay, S. Maillette, and P. Théroux; Colombia (72)— R. Botero; Costa Rica (4) — M. Arce; Finland (44)— J. Heikkila; France (86) — D. Danchin and S. Weber;Germany (129) — E.P. Kromer, F.J. Neumann, and C. Nienaber;Greece (84) — D. Katritsis and N. Papazaglou; Israel (85)— J. Benhorin, D. David, and D. Tzivoni; Italy (13) —M. Guazzi; Mexico (68) — R. Moguel and J. Verdejo; theNetherlands (72) — J. Bonnier and C. DeZwaan; New Zealand(137) — A.W. Hamer and H.D. White; Norway (51) —M. Aarones, K. Arvesen, E. Fossum, B. Henestam, and A. Rollag;Portugal (20) — V. Ribeiro; South Africa (212) —P. Commerford, P. Landless, J. Marx, and H. Weich; Spain (82)— P. Ancillo, J. Caturla, E. Civeira, J. Ferrero, J. Figueras,R. Ginestal, and M. Ruano; Sweden (129) — L. Erhardt andC. Sylven; Switzerland (86) — T. Luscher and T. Moccetti;United Kingdom (383) — P. Adams, A.A.J. Adgey, N. Buller,R. Canepa, S. Furniss, R. Greenbaum, J. Hall, K. Jennings, J.Kooner, R. Levy, D. Lipkin, M. Noble, and M. Rothman; UnitedStates (947) — D. Abrahamson, F. Aguirre, J. Ambrose,H.V. Anderson, J. Anderson, R. Arora, J. Babb, S. Bhasin, N.Bittar, R. Botti, M. Bowles, A. Brown, M. Cohen, H. Colfer,W. Daley, D. Dawley, R. Detrano, P. Eisenberg, N. Farhat, D.Faxon, M. Frey, S. Friedman, N. Goldschlager, A. Gradman, F.Gutierrez, C. Hattemer, H. Herrmann, J. Hochman, N. Israel,J. Kiernan, M. Koren, J. Kramer, F. Ling, J. Mehta, F. Mody,S. Mohiuddin, A. Nafziger, R. Nair, A. Niederman, T. Palabrica,S. Rodriguez, R. Rosenson, J. Rutherford, J. Schmedtje, P.K.Shah, S. Sharma, S. Smith, T. Smitherman, M. Stillabower, P.Tierstein, D. Vaughan, D. Waters, P. Weinstock, M. Williams,S. Yakubov, and R. Zoble; Steering Committee — H.D. White(chairman), M. Cohen, N.S. Kleiman, K.H. Lipschutz (projectstatistician), F.L. Sax (Merck Research Laboratories), P.K.Shah, and F. Van de Werf; Data and Safety Monitoring Committee— J. Cairns (chairman), M. Espeland (statistician), G.FitzGerald, M. Verstraete, W.D. Weaver, and D.O. Williams; End-PointsCommittee — M. Cohen, L.S. Dreifus, J. Nasmith, and M.Runge; Merck Research Laboratories — F.L. Sax, W. Grossman,and S.M. Snapinn (statistician); Merck medical program coordinators— M. Bremer, V. Frame, J. Hutnyan, J.T. Lappe, M. Sergio,and A. Thornton.
Management of Non–Q-Wave Myocardial Infarction
Bedell S. E., Graboys T. B., Ravid S., Thompson R. C., Roe M. T., Bowen T. E., Topol E. J., Huitink J. M., Bax J. J., Boden W. E., O'Rourke R. A., Crawford M. H.
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N Engl J Med 1998;
339:1395-1398, Nov 5, 1998.
Correspondence
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