Improved In-Hospital Outcomes in Acute Coronary Syndromes (Unstable Angina/Non-ST Segment Elevation Myocardial Infarction) Despi

The optimal approach to the management of acute coronary syndromes (ACS), including unstable angina (UA) and non-ST segment myocardial infarction (STEMI), continues to evolve. These patients comprise a heterogenous population with varying degrees of risk of death and recurrent cardiac ischemic events. Tailoring pharmacologic and interventional strategy based on to an individual’s specific risk profile provides the most benefit to patients with the greatest propensity for subsequent cardiovascular events, and conserves scarce economic and medical resources. Risk stratification using The Thrombolysis In Myocardial Infarction (TIMI) Risk Score has been shown to effectively predict prognosis in patients with ACS with a previous generation of medical and interventional therapy.1 However, the impact of newer antiplatelet and antithrombotic therapies for ACS such as low molecular weight heparin (LMWH) and glycoprotein IIb/IIIa inhibitors (GPI) coupled with contemporary interventional techniques, such as the increased utilization of intracoronary stenting, in different patient populations with ACS adjusted by TIMI Risk Score has not been the subject of previous clinical trials. Retrospective application of TIMI Risk Score in patients with ACS predicted responsiveness to low-molecular weight heparin (LMWH), but this has not been tested prospectively.2 In addition, the efficacy of GPI in preventing in-hospital major adverse cardiac events (MACE) in a patient population adjusted for risk using TIMI risk scores has not been examined. Thus, this study sought to assess the temporal effect of changing medical therapies and interventional techniques on MACE in two different populations of patients with ACS with similar TIMI Risk Scores. Methods The baseline demographics, clinical profiles, and in-hospital adverse events of all patients with ACS admitted to a single large university medical center from January 1, 1998 to December 31, 1998 (Group 1998) was compared to all patients presenting from January 1, 2000 to December 31, 2000 (Group 2000) using a prospectively collected database. ACS was defined as patients who presented with unstable angina or non-ST segment elevation myocardial infarction, and specifically excluded patients with ST segment elevation MI. Group 1998 represents the comparator group, characterized by the clinical demographics and treatment options available for patients with ACS prior to the widespread utilization of LMWH and GPI, and onset of routine use of intracoronary stenting. Group 2000 represents the study group, characterized by clinical demographics and treatment options available for patients with ACS after the increased utilization of LMWH, GPI, and includes the routine use of intracoronary stenting. In this institution, the LMWH that was administered was enoxaparin (1 mg/kg subcutaneously every 12 hours), and the GPI agents included tirofiban (0.4 mcg/kg/minute intravenous (IV) bolus followed by 0.1 mcg/kg/minute) or abciximab (0.25 mg/kg IV bolus followed by 0.125 mcg/kg/minute). No ACS patients in these time frames were excluded. Interventional and clinical cardiology databases were developed on site that collects over 800 data elements using a PARADOX platform (Borland International, Scotts Valley, California). The data elements were designed to be compatible with the American College of Cardiology-National Cardiovascular Database Registry,3 as well as collecting numerous additional data elements. The data collection and adjudication of various events was determined by dedicated research nurses using standard definitions. To assure data quality, a research nurse screens yearly at least 10% of all procedures at random, and evaluates all cases for accuracy and completeness. The primary endpoints were the occurrence of in-hospital major adverse cardiac events (MACE), which included death, MI, or recurrent angina. Death was defined as any in hospital mortality, regardless of cause. MI was defined as: 1) a total creatine kinase concentration more than twice the upper limit of normal and an above normal concentration of creatine kinase MB (at least 5% of total creatine kinase), an increase in the serum troponin (cTnI) level above the 99th percentile of a normal control group; or 2) new Q waves of more than 0.04 seconds in at least two contiguous leads. A diagnosis of infarction after percutaneous coronary intervention was made if the total creatine kinase concentration increased to three times the upper limit of normal and at least 50% above the previous baseline value. A diagnosis of a new MI in a patient with a non-ST elevation MI was defined as: 1) new Q waves of more than 0.04 seconds in at least 2 contiguous leads; 2) an increase in the creatine kinase-MB of at least 50% above the previous value (i.e. a re-elevation of cardiac markers).4 These cardiac biomarkers were collected consistently and similarly between 2 periods. Recurrent angina was defined as one of the following: angina at rest lasting at least 5 minutes that was associated with new ST segment depression or elevation (>= 1 mm), or with T wave inversions, in two contiguous electrocardiographic leads that prompted a decision to urgently perform an unplanned coronary revascularization procedure. This definition of recurrent angina is the same one that was used in the two major trials which evaluated the use of enoxaparin in acute coronary syndromes.5,6 The TIMI Risk Score was utilized to estimate risk by based on 7 predictor variables: age > 65 years, two or more episodes of rest angina in the last 24 hours, at least 3 risk factors for coronary artery disease, prior coronary stenosis of >= 50%, ST deviation on EKG, prior aspirin use, and elevated cardiac enzymes.1 Statistical analysis. Results are presented as mean ± SD. Group comparisons for continuous variables were made using T-test or Mann-Whitney test as appropriate. Chi-Square Test or Fisher’s Exact Test was used to compare categorical values. Stepwise logistic regression with the log odds of MACE as outcome was used for multivariate analysis and was used to adjust for TIMI Risk score. Significant interactions between TIMI Score and other predictors were tested. All tests were two-tailed, and a p-value Patient population. A total of 563 patients with ACS in 1998, and 614 patients in 2000 were compared. Comparing Groups 1998 and 2000, there were no differences in the mean age > 65 years (40.1% vs. 37.8%; p = 0.437). Group 1998 had less hypertension (63.9% vs. 75.1%; p Medical treatment. Variations in medical treatment were noted between the two groups. Comparing Groups 1998 and 2000, there was no difference in the prior use of aspirin (50.8% vs. 50.7%; p = 0.984), and a trend towards a decreased use of beta-blockers within 24 hours (56.6% vs. 32.2%; p = 0.060). A significant decrease in the use of intravenous nitrates (31.1% vs. 17.8%; p TIMI risk score variables. There was no significant difference between the mean TIMI Risk Score of Group 1998 compared to the Group 2000 (2.90 ± 1.52 vs. 2.91 ± 1.52; p = 0.968). The frequency of each of the individual variables comprising the TIMI Risk Score is shown in Table 1. Comparing Groups 1998 and 2000, there were no differences in the mean age > 65 years (40.1% vs. 37.8%; p = 0.437), the number of patients with coronary stenosis >50% (32.0% vs. 29.5%; p = 0.194), or with prior use of aspirin (50.8% vs. 50.3%; p = 0.984) respectively. However, there was a greater incidence of elevated cardiac enzymes (43.8% vs. 28.6%; p = 3 traditional cardiovascular risk factors (66.0% vs. 83.5%; p Coronary angiography/pecutaneous coronary intervention. There was no significant difference between the rates of coronary angiography in patients with ACS in 1998 compared to 2000 (48.7% (274/563) vs. 46.4% (285/614); p = 0.448). Although the frequency of percutaneous coronary intervention in those patients with ACS who underwent cardiac catheterization in 1998 compared to 2000 was similar (49.3% [135/274] vs. 45.6% [130/285]; p = ns), there was a statistically significant increase in the utilization of intracoronary stenting (46.6% [63/135] vs. 64.6% [84/130]; p = 0.005) during the coronary intervention (Table 3). Frequency of in-hospital major adverse cardiac events. Importantly, there was a reduction of frequency of MACE over time comparing Group 1998 and Group 2000 (9.1% vs. 2.8%; p Multivariate analysis. Logistic regression analysis showed that the use of LMWH was associated with a trend towards reduction in the risk of in-hospital adverse cardiac events (OR 0.3, 95% CI 0.08, 1.35; p = 0.067). After adjustment for the TIMI Risk Score using multivariate analysis, use of GPI was associated with a decrease in MACE, and a significant interaction was found between GPI utilization and TIMI Risk Score, with the greatest benefit derived from administration to those patients at highest risk (p = 0.01). Discussion The current study suggests that despite similar TIMI Risk Scores, in-hospital outcomes in patients with ACS have improved over time, and this change was associated with the greater use of newer antiplatelet and antithrombotic therapies such as GPI and LMWH, and the increased utilization of intracoronary stenting. This study also suggests that the TIMI Risk Score is a valuable tool in assessing differences and similarities in two patient populations studied at different times, and that patient groups with similar TIMI Risk Scores may have comparable risk even though the individual items of the risk profile vary significantly. Patients with unstable angina and non-ST segment elevation myocardial infarction comprise a heterogenous population with varying propensities for major ischemic complications.7–9 The development of various clinical risk models has assisted in classification of patients with acute coronary syndromes into low, moderate, and high-risk groups.10–13 The TIMI Risk Score is a simple prognostication scheme that categorizes the patient’s risk of death, non-fatal myocardial infarction, and severe recurrent ischemia requiring urgent revascularization within 2 weeks of presentation based on 7 clinical variables.1 The TIMI Risk Score was developed using the database of the Thrombolysis in Myocardial Infarction (TIMI) 11B Trial and validated using the TIMI 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE) Trial, which predates the widespread use of GPI and routine intracoronary stenting. Furthermore, no prior study has used the TIMI Risk Score to adjust for the varying temporal differences in two groups of patients with ACS over time. The impact of newer antiplatelet therapies for acute coronary syndromes such as GPI and low LMWH and routine use of intracoronary stents in-hospital MACE in patients with similar TIMI Risk Scores was the primary objective of this study. LMWH has several potential clinical advantages compared to unfractionated heparin due to more stable, reliable bioavailability and anticoagulant effect, ease of subcutaneous administration, higher anti-Xa activity, decreased sensitivity to platelet factor 4, and lower rates of thrombocytopenia.14 The ESSENCE Trial5 and TIMI 11B Trial6 showed a significant 15–20% relative risk reduction in the combined endpoint of death, myocardial infarction and recurrent ischemia in patients with ACS who received LMWH compared to unfractionated heparin at 14 days. Likewise, GPI have been evaluated in the setting of both high risk and low risk patients with acute coronary syndromes undergoing percutaneous coronary interventions and have shown a significant relative reduction in adverse cardiac events ranging from 22–56% at 30 days.15–17 The suggested mechanisms for the early clinical benefit of GPI in ACS is through inhibition of platelet aggregation by blocking the final common pathway at the glycoprotein receptor, with reduction in distal embolization of platelet aggregates and prevention of subsequent myocardial infarction.18 The baseline characteristics of the patients enrolled in our study were similar to the clinical profile and demographics of other large randomized trials involving patients with ACS.5,6,15,16 The lack of a difference in the mean TIMI Risk Score between Group 1998 and Group 2000 implies a similar overall risk profile between these two cohorts. However, a significant difference in the MACE rate between Group 1998 and Group 2000 was noted, with a corresponding increase in utilization of stenting and antithrombotic and antiplatelet therapy. Consequently, the difference in MACE appeared due, in large part, to the differences in use of LMWH and GPI and increased utilization of intracoronary stenting. These findings were supported by subsequent multivariate analysis. There were no significant differences between the two groups in terms of the utilization of other standard medical therapies for ACS such as aspirin and beta- blockers. Although there was a decrease in the utilization of intravenous nitrates and trend towards less use of beta blockers from 1998 to 2000, this difference was most likely due to case selection, and rather than account for the findings, actually magnifies the potential beneficial effects of LMWH and GPI in decreasing the observed MACE rate over this time period. The use of intravenous unfractionated heparin decreased from 1998 to 2000, which is consistent with the increasing use of LMWH and GPI seen during this time period. Furthermore, the mean TIMI Risk Score of 3 in both groups in our study reflect a generally higher risk population, which in other studies, benefited from a more aggressive pharmacologic and interventional approach.2,19 There was a significantly higher rate of ST segment depression on admission in 2000 compared to 1998, and this has been shown to correlate with a higher incidence of multivessel and left main disease, and likewise benefit from a more aggressive interventional approach.20 The lower incidence of elevated cardiac biomarkers in 2000 compared to 1998 also suggests that there may have been a treatment effect as a result of increased utilization of GPI and LMWH. The ability to diagnose recurrent MI depends on the reliable collection of cardiac biomarkers. In this study, these cardiac biomarkers were collected consistently and similarly between 2 periods. The significant difference in MACE between the patients treated in 1998 and 2000 was largely driven by differences in rates of recurrent angina, without significant differences in death and myocardial infarction. Recurrent angina was prospectively defined as angina associated with electrocardiographic changes that prompted unplanned urgent coronary revascularization, and was the same definition that was used in the ESSENCE5 and TIMI11B6 Trials. These two major trials comparing unfractionated heparin and LMWH in ACS, similar to this current study, showed a difference in the composite endpoints of death, MI, and recurrent angina that was almost wholly due to differences in recurrent angina alone. However, this lack of a benefit of LMWH in ACS in terms of the “harder” endpoints, such as death and MI, may be due, in part, to lack of statistical power since a meta-analysis21 suggests that treatment with LMWH may be associated with a significant reduction in death and serious cardiac ischemic events. In our study, logistic regression analysis showed that the use of LMWH was associated with a reduction in the risk of in-hospital adverse cardiac events. Furthermore, after adjustment for the TIMI Risk Score using multivariate analysis, use of GPI was associated with an improved outcome with the greatest benefit derived from administration to those patients at highest risk. Thus, this study supports the concept that those patients with higher risk profiles based on the TIMI Risk Score benefit in terms of in-hospital MACE with the use of these newer antiplatelet and antithrombotic agents.2 However, the results of this study were based on retrospective analysis, and thus unmeasured confounding variables cannot be excluded. Whether an early invasive approach coupled with a combination of LMWH and GPI could further improve outcomes is currently under investigation. Conclusions Despite similar TIMI Risk Scores, the in-hospital outcomes of patients with acute coronary syndromes have improved over time. This improvement is associated with the greater use of newer antiplatelet and antithrombotic therapies such as GPI and LMWH and increased utilization of intracoronary stenting.

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