CLINICAL RESEARCH: COMBINED GLYCOPROTEIN IIB/IIIA INHIBITORS AND FIBRINOLYTICS
Improved speed and stability of st-segment recovery with reduced-dose tenecteplase and eptifibatide compared with full-dose tenecteplase for acute st-segment elevation myocardial infarction
Matthew T. Roe, MD, MHS, FACC*,*,
Cynthia L. Green, PhD*,
Robert P. Giugliano, MD, SM, FACC ,
C. Michael Gibson, MD, FACC,
Kenneth Baran, MD ,
Mark Greenberg, MD ,
Sebastian T. Palmeri, MD||,
Suzanne Crater, ANP-C*,
Kathleen Trollinger, RN*,
Karen Hannan, MS*,
Robert A. Harrington, MD, FACC*,
Mitchell W. Krucoff, MD, FACC* INTEGRITI Investigators
* Duke Clinical Research Institute and Division of Cardiology, Duke Medical Center, Durham, North Carolina, USA
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
John Nasseff Heart Hospital, St. Paul, Minnesota, USA
Montefiore Medical Center, New York, New York, USA
|| Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
Manuscript received June 11, 2003;
revised manuscript received August 8, 2003,
accepted September 15, 2003.
* Reprint requests and correspondence: Dr. Matthew T. Roe, Duke Clinical Research Institute, P.O. Box 17969, Durham, North Carolina 27715, USA.
roe00001{at}mc.duke.edu
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Abstract
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OBJECTIVES: This sub-study of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial evaluated of the impact of combination reperfusion therapy with reduced-dose tenecteplase plus eptifibatide on continuous ST-segment recovery and angiographic results.
BACKGROUND: Combination therapy with reduced-dose fibrinolytics and glycoprotein IIb/IIIa inhibitors for ST-segment elevation myocardial infarction improves biomarkers of reperfusion success but has not reduced mortality when compared with full-dose fibrinolytics.
METHODS: We evaluated 140 patients enrolled in the INTEGRITI trial with 24-h continuous 12-lead ST-segment monitoring and angiography at 60 min. The dose-combination regimen of 50% of standard-dose tenecteplase (0.27 µg/kg) plus high-dose eptifibatide (2 boluses of 180 µg/kg separated by 10 min, 2.0 µg/kg/min infusion) was compared with full-dose tenecteplase (0.53 µg/kg).
RESULTS: The dose-confirmation regimen of reduced-dose tenecteplase plus high-dose eptifibatide was associated with a faster median time to stable ST-segment recovery (55 vs. 98 min, p = 0.06), improved stable ST-segment recovery by 2 h (89.6% vs. 67.7%, p = 0.02), and less recurrent ischemia (34.0% vs. 57.1%, p = 0.05) when compared with full-dose tenecteplase. Continuously updated ST-segment recovery analyses demonstrated a modest trend toward greater ST-segment recovery at 30 min (57.7% vs. 40.6%, p = 0.13) and 60 min (82.7% vs. 65.6%, p = 0.08) with this regimen. These findings correlated with improved angiographic results at 60 min.
CONCLUSIONS: Combination therapy with reduced-dose tenecteplase and eptifibatide leads to faster, more stable ST-segment recovery and improved angiographic flow patterns, compared with full-dose tenecteplase. These findings question the relationship between biomarkers of reperfusion success and clinical outcomes.
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Abbreviations and Acronyms
| | CTFC | = corrected TIMI frame count | | ECG | = electrocardiogram/electrocardiographic | | GP | = glycoprotein | | IMCL | = Ischemia Monitoring Core Laboratory | | INTEGRITI | = Integrilin and Tenecteplase in Acute Myocardial Infarction trial | | IRA | = infarct-related artery | | PCI | = percutaneous coronary intervention | | STEMI | = ST-segment elevation myocardial infarction | | TIMI | = Thrombolysis In Myocardial Infarction | | TMPG | = TIMI myocardial perfusion grade |
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Platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have emerged as a promising adjunctive reperfusion therapy for acute ST-segment elevation myocardial infarction (STEMI) when combined with reduced doses of fibrinolytics (termed "combination therapy"), given the central role of activated platelets in the pathophysiology of intracoronary thrombus formation after plaque rupture (1). Recent studies of combination therapy have shown favorable improvements in biomarkers that indicate early reperfusion success, including angiographic Thrombolysis In Myocardial Infarction (TIMI) flow grades and static ST-segment resolution (2–4). Subsequent large-scale clinical trials have shown lower frequencies of non-fatal recurrent ischemic events but have failed to demonstrate improved survival when combination pharmacologic reperfusion regimens were compared with full-dose fibrinolytic monotherapy (5,6). Although the impact of combination therapy before planned mechanical reperfusion with primary percutaneous coronary intervention (PCI) is currently being studied, these findings suggest that the impact of combination therapy on the timing and success of pharmacologic reperfusion in STEMI patients is not fully understood.
Continuous monitoring of ST-segment resolution is a quantitative biomarker developed to comprehensively evaluate the speed, quality, and stability of reperfusion in patients presenting with STEMI (7,8). Because continuous ST-segment monitoring has been shown to predict recovery of left ventricular function and clinical outcomes more reliably than TIMI flow grades, this biomarker may better characterize the potential benefits of combination therapy for STEMI (9–12).
Therefore, we performed a continuous ST-segment monitoring sub-study as part of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial to quantify the speed, stability, and quality of ST-segment recovery with reduced-dose tenecteplase combined with the GP IIb/IIIa inhibitor eptifibatide, compared with full-dose tenecteplase monotherapy without eptifibatide, and to determine how these findings correlated with angiographic measures of reperfusion success.
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Methods
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Patient selection and treatment.
All patients presenting to U.S. sites participating in the INTEGRITI trial were eligible for inclusion in the continuous ST-segment monitoring sub-study. Patients at Canadian and European sites were not eligible for inclusion, given resource limitations and logistical challenges related to training and equipping sites outside of the U.S. Inclusion criteria for the main INTEGRITI trial included presentation within 6 h of the onset of ischemic chest pain lasting for at least 30 min, persistent ST-segment elevation in two or more contiguous electrocardiographic (ECG) leads, and age 18 to 75 years (13). Exclusion criteria have been published previously.
All patients received aspirin and unfractionated heparin. Treatment with tenecteplase plus eptifibatide was randomly assigned based on the phase of the trial. During the dose-finding phase, patients were assigned to receive varying doses of both reduced-dose tenecteplase plus eptifibatide in two sequential parts (13). The combination of half-dose tenecteplase (0.27 mg/kg) and high-dose eptifibatide (180-µg/kg bolus, 2.0-µg/kg/min infusion; second 180-µg/kg bolus 10 min later) emerged as the most promising regimen from the dose-finding phase and was compared with full-dose tenecteplase monotherapy in the dose-confirmation phase.
Coronary angiography and PCI.
All patients underwent coronary angiography within 60 min (range 55 to 75 min) after administration of the tenecteplase bolus, with the primary end point of the trial being TIMI flow grade in the infarct-related artery (IRA). Angiograms were reviewed in a blinded core laboratory, according to methods previously published (13). The angiographic parameters analyzed included TIMI flow grade, corrected TIMI frame count (CTFC), and TIMI myocardial perfusion grade (TMPG). After angiography, PCI was permitted at the discretion of the investigator. Post-PCI angiography was recommended to assess the impact of PCI on angiographic parameters of reperfusion success, but it was not mandated.
ST-segment monitoring.
The ST-segment monitoring was performed with RZ-152 12-lead integrated-circuit ST-segment monitors (Northeast Monitoring, Boston, Massachusetts) that acquired and archived a standard 12-lead ECG every 60 s and a continuous three-lead Holter rhythm strip every 60 s. Patients were monitored for 24 h beginning at the time of enrollment in the main INTEGRITI trial. Continuous ECG data were not accessible to the clinical care teams at the enrolling sites. Digital ECG data on 32-megabyte flashcards were analyzed at the Ischemia Monitoring Core Laboratory (IMCL) at Duke Clinical Research Institute (Durham, North Carolina).
All studies were analyzed according to the standard methods of the IMCL. All analyses were done in blinded manner as to treatment assignments and other clinical information. Analysis of the ST-segment variables started at the onset of treatment with tenecteplase and continued for 24 h. Detailed definitions of IMCL standard parameters for ST-segment recovery analysis have been published previously (8,14–16). Patients with technical inadequacies that obscured ST-segment monitoring, such as ECG tracing artifacts or transient left bundle branch block, were excluded.
Primary ST-segment recovery parameters were analyzed during the 24-h period of monitoring, based on the single ECG lead with maximal ST-segment deviation before the onset of ST-segment recovery. The degree of ST-segment elevation in the most deviated ECG lead was continuously assessed before ST-segment recovery occurred. Time to stable ST-segment recovery was defined as the time from the onset of lytic therapy to the beginning of a period of  50% recovery from previous peak ST-segment levels in the most deviated lead, lasting 4 h without further ST-segment evolution (100 µV). Recurrent ischemia was defined as either early cyclic flow or late ST-segment re-elevation. Cyclic flow (early recurrent ischemia) was defined as ST-segment re-elevation of 150 µV after a period of 50% recovery from previous peak ST-segment levels in the most deviated lead, but before stable ST-segment recovery. Late ST-segment re-elevation (late recurrent ischemia) was defined as either ST-segment re-elevation of 150 µV in the most deviated lead occurring after stable ST-segment recovery or persistent ST-segment elevation 6 h after the onset of therapy (i.e., 6 h time to stable ST-segment recovery). The quality of reperfusion was defined by the percentage of ST-segment recovery at the time of steady-state ST-segment recovery relative to the previous absolute peak ST-segment level. For the purposes of this protocol, this was assessed as a continuous variable at the onset of stable ST-segment recovery at 6 h after the start of lytic therapy relative to the previous absolute peak ST-segment level (if onset of stable ST-segment recovery was >6 h). The quality of reperfusion was also assessed as a dichotomous variable (presence or absence of >50% recovery from the previous peak levels) at 30, 60, 90, 120, and 180 min after lytic therapy. The combination of speed, stability, and quality of reperfusion was measured as the area under the ST-segment deviation versus the time trend curve during the first 3 h after the start of lytic therapy.
Statistical analysis and power calculation.
The primary hypothesis was that combination therapy with tenecteplase and eptifibatide would shorten the time to stable ST-segment recovery, compared with full-dose tenecteplase monotherapy. The secondary hypothesis was that combination therapy with tenecteplase and eptifibatide would: 1) decrease the frequency of recurrent ischemia denoted by cyclic flow patterns and late ST-segment re-elevation; 2) improve the quality of reperfusion as assessed by the percent ST-segment recovery from previous peak levels (continuous and dichotomous measures); and 3) reduce the overall injury pattern as assessed by the ST-segment deviation trend curve area.
The time of stable ST-segment recovery was collected for all patients with analyzable ECG data. Group comparisons for continuous variables were performed with the two-sample t test, Wilcoxon rank-sum test, or log-rank test for censored data. A comparison of discrete variables was performed with the likelihood ratio chi-square test or Fisher exact text.
This study was powered to achieve statistical significance for the comparison of treatment groups with regard to the time from treatment until stable ST-segment recovery. The sample-size estimates are based on ST-segment recovery data pooled from previous acute myocardial infarction clinical trials that made a comparison between patients who received a GP IIb/IIIa inhibitor combined with a fibrinolytic agent (combination therapy) and patients who only receiving fibrinolytics (15,16). Using the pooled ST-segment recovery data, the sample size of 134 patients was computed assuming that combination therapy would decrease the median time until stable ST-segment recovery by 30% in the treatment group (hazard ratio 1.67). The overall sample size was increased by 15% (n = 158) to account for patients in whom ECG data could not be analyzed. The sample-size calculation was performed using alpha = 0.05 (two-sided) and beta = 0.20 (power 80%). Because there was no control group in the dose-finding phase, sample-size calculations were made with the assumption that more patients would be enrolled in the combination therapy group than in the tenecteplase monotherapy group.
Patients who received combination therapy in the dose-confirmation phase were analyzed separately and also combined with those from the dose-finding phase for comparisons with patients who received full-dose tenecteplase monotherapy in the dose-confirmation phase.
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Results
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Treatment details.
A total of 199 (92%) of the 217 patients enrolled at U.S. sites in the main INTEGRITI trial were included in the ST-segment monitoring sub-study, and 13 patients who did not receive at least one of the medications assigned during randomization were excluded from the sub-study. Of the remaining 186 patients, the continuous ST-segment monitor was successfully hooked up in 156 patients (84%), and ST-segment monitoring data were analyzable in 140 (90%) of them. The reasons for non-analyzable ST-segment monitoring data in 16 patients included development of bundle branch block, technical artifacts, late hookup times, or a short duration of monitoring that precluded assessment of ST-segment recovery. The median (interquartile) time from administration of the tenecteplase bolus to monitor hookup was –0.02 min (–7.0 to 13.0). The median duration of ST-segment monitoring was 23.8 h (23.4 to 24.0).
Patient characteristics.
Baseline characteristics were similar across treatment groups for patients enrolled in the ST-segment monitoring sub-study (Table 1). Patients in that sub-study underwent immediate PCI after baseline angiography more frequently than the overall study cohort (71.5% vs. 58.8%).
ST-segment recovery analyses.
ST-segment recovery parameters showed a trend toward an improvement with combination therapy across the dosing regimens used in the dose-finding and dose-confirmation phases (Table 2). When patients treated with the dose-confirmation/combination therapy regimen (n = 68) were compared directly to patients who were treated with full-dose tenecteplase (n = 41), combination therapy was associated with a faster median time to steady-state ST-segment recovery, an improved percentage of patients achieving steady-state ST-segment recovery by 2 h, a smaller median ST-segment curve area, and less recurrent ischemia. When continuously updated ST-segment recovery was analyzed at several static time points, modest trends were present for greater ST-segment recovery at 30, 60, and 90 min with the dose-confirmation/combination therapy regimen as compared with full-dose tenecteplase (Table 3).
Angiographic results.
Angiographic results at 60 min demonstrated trends toward improvements in TIMI flow grades, CTFC, and TMPG across the dosing regimens used in the dose-finding and dose-confirmation phases, as compared with full-dose tenecteplase (Table 4). After 60-min angiography, immediate PCI was performed in more patients treated with full-dose tenecteplase (Table 1). However, post-PCI angiography was performed in only 57.6% (19 of 33 patients) versus 56.6% (30 of 53) versus 48.9% (23 of 47) of patients who underwent PCI across the three treatment groups (full-dose tenecteplase vs. dose-finding regimen vs. dose-confirmation regimen, respectively; as shown in Tables 1 and 2). The frequency of TIMI flow grade 2 or 3 after PCI in patients in whom angiography was performed was 89.5% versus 100% versus 95.6%, whereas the frequency of TMPG 2 or 3 was 52.6% versus 65.5% versus 65.2% in the respective dosing groups.
Clinical outcomes.
Despite a higher incidence of mortality in patients treated with the dose-finding regimen of 50% or 75% of the standard tenecteplase dose with intermediate doses of eptifibatide (180-µg/kg, 90-µg/kg double-bolus regimen), the number of events and sample sizes were small, and there were no significant differences in clinical outcomes among the dosing groups (Table 5). ST-segment recovery parameters correlated with the risk of adverse clinical outcomes (e.g., composite of death, re-infarction, severe congestive heart failure, cardiogenic shock, and urgent repeat revascularization through 30 days) as the time to stable ST-segment recovery was faster and the percentage of patients with stable ST-segment recovery at 2 h was greater in patients who did not experience an adverse outcome (Table 6). Conversely, patients with adverse outcomes had a greater frequency of late ST-segment re-elevation.
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Discussion
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We have demonstrated faster, more stable ST-segment recovery with the combination of reduced-dose tenecteplase and high-dose eptifibatide compared with full-dose tenecteplase. Favorable trends in the ST-segment recovery parameters analyzed in this study also correlated with improved angiographic parameters of reperfusion success and clinical outcomes—a finding that further demonstrates that rapid, stable reperfusion sufficient to restore oxygen and nutrient delivery to the myocardium is the key mechanistic step for the successful treatment of STEMI (17). However, these results also highlight the differential treatment effect of combination therapy on biomarkers of reperfusion success compared with clinical outcomes (2,3,5,6,13,18).
ST-segment recovery analyses.
Resolution of ST-segment elevation is a simple, non-invasive biomarker that correlates with recanalization of the epicardial IRA, successful restoration of myocardial tissue perfusion, and a lower risk of mortality (19–21). Although frequently reported as measured between two serial static ECGs, analysis of static ST-segment resolution provides only a "snapshot" assessment of reperfusion that does not characterize the continuum of reperfusion (21,22). In contrast, continuous analysis of ST-segment recovery characterizes the entire process of reperfusion, and ST-segment recovery parameters correlate directly to preservation of left ventricular mechanical function, early re-infarction, and mortality (9–12,23). Even though continuous ST-segment monitoring analyses have demonstrated improved speed and stability of reperfusion with combination therapy, these findings did not translate into improved survival in large-scale trials evaluating pharmacologic combination reperfusion regimens (5,6,15,16,24).
Biomarker arrays.
Use of a single biomarker, such as static or continuous ST-segment resolution or angiography alone, may be a limited approach to evaluating promising new reperfusion regimens. Other biomarkers of reperfusion success, including infarct size measurements with technetium-99m sestamibi single-photon emission computed tomography, provide complementary information to ST-segment resolution, but missing or uninterpretable data in  10% to 20% of patients limit the predictive capabilities of individual biomarkers (2,4,13,22,25). Furthermore, correlations between individual biomarkers such as ST-segment resolution and angiography have not been thoroughly investigated, so the relative utility of single biomarkers for comprehensively describing the speed and quality of reperfusion remains unclear. Studies that have used multiple, simultaneous biomarkers suggest that biomarker arrays may be the most effective approach for the initial clinical evaluation of new therapies for STEMI, by both enhancing information content and retrieval and overcoming the loss of data that occurs when individual biomarkers are used (26–28). However, the therapeutic success of new reperfusion regimens has not yet been tested with biomarker arrays, so strategies will need to be developed to determine the optimal number and combination of disparate biomarkers that best define "successful" reperfusion and most accurately correlate with the impact of a given therapy on mortality (29). Thus, biomarker arrays may be most useful in early phase I and II trials to assess the biologic activity of new reperfusion regimens and in mechanistic sub-studies of phase III trials to provide pathophysiologic underpinnings for the clinical outcomes results.
Combination reperfusion therapy.
Despite the limitations of using biomarkers to evaluate combination therapy, mechanistic studies suggest that combination therapy may offer several potential advantages for the treatment of STEMI patients. The ST-segment resolution analyses have demonstrated that early reperfusion during the typical "door-to-balloon" time that precedes primary PCI (30 to 90 min) is enhanced with combination therapy (3,4,13,24). Because mortality is substantially lower when normal epicardial flow is re-established in the IRA before primary PCI is performed and combination therapy reduces angiographic thrombus burden in the infarct vessel, intensified pharmacologic therapy before planned primary PCI may "facilitate" primary PCI by enhancing recanalization of the IRA before PCI, improving procedural outcomes, and enhancing myocardial salvage (30–34).
Notwithstanding the potential advantages of a facilitated pharmacologic and mechanical approach for the treatment of STEMI patients, this study and another continuous ST-segment monitoring study have both shown that combination therapy is associated with a higher rate of late ST-segment re-elevation compared with full-dose fibrinolytic monotherapy (24). Because late ST-segment shifts correlate with higher mortality, these findings are concerning and suggest that rebound ischemia may occur after discontinuation of the heparin or GP IIb/IIIa inhibitor infusion (11). A previous study has demonstrated increased thrombin generation and activity after discontinuation of heparin following full-dose fibrinolytic therapy, but eptifibatide attenuated the risk of rebound ischemia after heparin discontinuation in patients with non–ST-segment elevation acute coronary syndromes (35,36). Nonetheless, precipitants for recurrent ischemia in relation to the type and duration of medication regimens used with combination therapy have not been investigated. Thus, the benefits of improved early IRA reperfusion with combination therapy may be partially mitigated by late recurrent ischemia, but further studies are needed to delineate the causes of recurrent ischemia after combination therapy and to determine how recurrent ischemia influences clinical outcomes.
Study limitations.
Despite the measurable benefits of combination therapy on ST-segment recovery, several limitations were present in this analysis. First, the sample size was limited (n = 140), so a larger study is needed to confirm these results. Second, monitors were not placed on approximately 20% of patients enrolled at sub-study sites, and data were non-analyzable in an additional 8% of patients who were monitored. Strategies for improving data capture and quality with continuous ST-segment monitoring have already been developed since the completion of this study, producing analyzable rates >90%. Third, the time to treatment from symptom onset varied among patients and may have influenced the degree of ST-segment elevation identified during monitoring, but we continuously analyzed the degree of peak ST-segment elevation before recovery to account for the evolution of ST-segment elevation after the initial ischemic insult and the onset of ST-segment monitoring relative to the timing of symptoms. Furthermore, the median time to treatment from symptom onset was almost identical in the three treatment groups. Fourth, the majority of patients analyzed in this study had non-anterior infarcts, so the treatment effect of combination therapy may have been underestimated with the large proportion of smaller infarcts. Fifth, although approximately 75% of patients underwent early PCI after 60-min angiography in the various dosing groups, the differential contributions of combination pharmacologic therapy and early PCI on ST-segment recovery and angiographic parameters of reperfusion success could not be accurately determined, given the non-randomized use of PCI in the treatment arms, the non-randomized use of eptifibatide during PCI in patients treated initially with full-dose tenecteplase, and the lack of postprocedural angiographic data in almost half the patients who underwent PCI. Finally, Canadian and European sites utilized PCI after angiography in fewer patients, compared with U.S. sites, so exclusion of these sites from the continuous ST-segment monitoring sub-study may have further biased the results.
Conclusions.
Combination therapy with reduced-dose tenecteplase and high-dose eptifibatide appears to be a promising reperfusion regimen for the treatment of acute STEMI. Larger studies and studies of patients with larger infarcts are needed to determine if the enhanced speed and stability of ST-segment recovery and improved angiographic flow patterns demonstrated with this combination therapy regimen will translate into improved clinical outcomes.
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Footnotes
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This study was funded from research grants from Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, and Schering-Plough Research Institute, Kenilworth, New Jersey.
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M. Albertal, F. Cura, J. Thierer, M. Trivi, A. G. Escudero, L. T. Padilla, and J. A. Belardi
Time to Stable ST-Segment Recovery Following Primary Angioplasty is Predictive of Regional Wall Motion Score and Clinical Outcome
Angiology,
October 1, 2010;
61(7):
638 - 642.
[Abstract]
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J. D.E. Haeck, K. T. Koch, L. Bilodeau, R. J. Van der Schaaf, J. P.S. Henriques, M. M. Vis, J. Baan Jr, A. C. Van der Wal, J. J. Piek, J. G.P. Tijssen, et al.
Randomized Comparison of Primary Percutaneous Coronary Intervention With Combined Proximal Embolic Protection and Thrombus Aspiration Versus Primary Percutaneous Coronary Intervention Alone in ST-Segment Elevation Myocardial Infarction: The PREPARE (PRoximal Embolic Protection in Acute myocardial infarction and Resolution of ST-Elevation) Study
J. Am. Coll. Cardiol. Intv.,
October 1, 2009;
2(10):
934 - 943.
[Abstract]
[Full Text]
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M. Albertal, F. Cura, A. G. Escudero, L. T. Padilla, J. Thierer, M. Trivi, J. A Belardi, and PREMIAR InvestigatorsBelardi
Relationship Between Collateral Circulation and Successful Myocardial Reperfusion in Acute Myocardial Infarction: A Subanalysis of the PREMIAR Trial
Angiology,
October 1, 2008;
59(5):
587 - 592.
[Abstract]
[PDF]
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Part 5: Acute Coronary Syndromes
Circulation,
November 29, 2005;
112(22_suppl):
III-55 - III-72.
[Full Text]
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G. W. Stone, J. Webb, D. A. Cox, B. R. Brodie, M. Qureshi, A. Kalynych, M. Turco, H. P. Schultheiss, D. Dulas, B. D. Rutherford, et al.
Distal Microcirculatory Protection During Percutaneous Coronary Intervention in Acute ST-Segment Elevation Myocardial Infarction: A Randomized Controlled Trial
JAMA,
March 2, 2005;
293(9):
1063 - 1072.
[Abstract]
[Full Text]
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B. S. Wiggins and S. Spinler
Antiplatelet and Antithrombin Therapy for Early Management of Acute Coronary Syndromes
Journal of Pharmacy Practice,
October 1, 2004;
17(5):
347 - 369.
[Abstract]
[PDF]
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Abstract
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