Hal V. Barron

Sex-Based Differences in Early Mortality after Myocardial Infarction

Background There is conflicting information about whether short-term mortality after myocardial infarction is higher among women than among men after adjustment for age and other prognostic factors. We hypothesized that younger, but not older, women have higher mortality rates during hospitalization than their male peers. Methods We analyzed data on 384,878 patients (155,565 women and 229,313 men) who were 30 to 89 years of age and who had been enrolled in the National Registry of Myocardial Infarction 2 between June 1994 and January 1998. Patients who had been transferred from or to other hospitals were excluded. Results The overall mortality rate during hospitalization was 16.7 percent among the women and 11.5 percent among the men. Sex-based differences in the rates varied according to age. Among patients less than 50 years of age, the mortality rate for the women was more than twice that for the men. The difference in the rates decreased with increasing age and was no longer significant after the age ...

The volume of primary angioplasty procedures and survival after acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators.

BACKGROUND There is an inverse relation between mortality from cardiovascular causes and the number of elective cardiac procedures (coronary angioplasty, stenting, or coronary bypass surgery) performed by individual practitioners or hospitals. However, it is not known whether patients with acute myocardial infarction fare better at centers where more patients undergo primary angioplasty or thrombolytic therapy than at centers with lower volumes. METHODS We analyzed data from the National Registry of Myocardial Infarction to determine the relation between the number of patients receiving reperfusion therapy (primary angioplasty or thrombolytic therapy) and subsequent in-hospital mortality. A total of 450 hospitals were divided into quartiles according to the volume of primary angioplasty. Multiple logistic-regression models were used to determine whether the volume of primary angioplasty procedures was an independent predictor of in-hospital mortality among patients undergoing this procedure. Similar analyses were performed for patients receiving thrombolytic therapy at 516 hospitals. RESULTS In-hospital mortality was 28 percent lower among patients who underwent primary angioplasty at hospitals with the highest volume than among those who underwent angioplasty at hospitals with the lowest volume (adjusted relative risk, 0.72; 95 percent confidence interval, 0.60 to 0.87; P<0.001). This lower rate, which represented 2.0 fewer deaths per 100 patients treated, was independent of the total volume of patients with myocardial infarction at each hospital, year of admission, and use or nonuse of adjunctive pharmacologic therapies. There was no significant relation between the volume of thrombolytic interventions and in-hospital mortality among patients who received thrombolytic therapy (7.0 percent for patients in the highest-volume hospitals vs. 6.9 percent for those in the lowest-volume hospitals, P=0.36). CONCLUSIONS Among hospitals in the United States that have full interventional capabilities, a higher volume of angioplasty procedures is associated with a lower mortality rate among patients undergoing primary angioplasty, but there is no association between volume and mortality for thrombolytic therapy.

Use of Reperfusion Therapy for Acute Myocardial Infarction in the United States Data From the National Registry of Myocardial Infarction 2

BACKGROUND There is clear evidence that reperfusion therapy improves survival in selected patients with an acute myocardial infarction. However, several studies have suggested that many patients with an acute myocardial infarction do not receive this therapy. Whether this underutilization occurs in patients appropriate for such therapy remains unclear. METHODS AND RESULTS We examined the use of reperfusion therapy in patients with an acute myocardial infarction hospitalized at 1470 hospitals participating in the National Registry of Myocardial Infarction 2. We identified 84 663 patients who were eligible for reperfusion therapy as defined by diagnostic changes on the initial 12-lead ECG, presentation to the hospital within 6 hours from symptom onset, and no contraindications to thrombolytic therapy. Twenty-four percent of these eligible patients did not receive any form of reperfusion therapy (7.5% of all patients). When multivariate analyses were used, left bundle-branch block (odds ratio [OR]=0.22; 95% CI=0.20 to 0.24), lack of chest pain at presentation (OR=0.22; 95% CI=0.21 to 0.24), age >75 years (OR=0.40, 95% CI=0.36 to 0.43), female sex (OR=0.88, 95% CI=0.83 to 0.92), and various preexisting cardiovascular conditions were independent predictors that the patient would not receive reperfusion therapy. CONCLUSIONS Reperfusion therapy may be underutilized in the United States. Increased use of reperfusion therapy could potentially reduce the unnecessarily high mortality rates observed in women, the elderly, and other patient groups with the highest risk of death from an acute myocardial infarction.

Relationship of the TIMI Myocardial Perfusion Grades, Flow Grades, Frame Count, and Percutaneous Coronary Intervention to Long-Term Outcomes After Thrombolytic Administration in Acute Myocardial Infarction

Background—Although 90-minute TIMI flow grades (TFGs), corrected TIMI frame counts (CTFCs), and TIMI myocardial perfusion grades (TMPGs) have been associated with 30-day outcomes, we hypothesized that these indices would be related to long-term outcomes after thrombolytic administration. Methods and Results—As a substudy of the TIMI 10B trial (tissue plasminogen activator versus tenecteplase), 49 centers carried out 2-year follow-up. TIMI grade 2/3 flow (Cox hazard ratio [HR] 0.41, P =0.001), reduced CTFCs (faster flow, P =0.02), and an open microvasculature (TMPG 2/3) (HR 0.51, P =0.038) were all associated with improved 2-year survival. Rescue percutaneous coronary intervention (PCI) of closed arteries (TFG 0/1) at 90 minutes was associated with reduced mortality (P =0.03), and mortality trended lower with adjunctive PCI of open (TFG 2/3) arteries (P =0.11). In a multivariate model correcting for previously identified correlates of mortality (age, sex, pulse, left anterior descending coronary artery infarction, and any PCI during initial hospitalization), patency (TFG 2/3) (HR 0.32, P <0.001), CTFC (P =0.01), and TMPG 2/3 remained associated with reduced mortality (HR 0.46, P =0.02). Conclusions—Both improved epicardial flow (TFG 2/3 and low CTFCs) and tissue-level perfusion (TMPG 2/3) at 90 minutes after thrombolytic administration are independently associated with improved 2-year survival, suggesting complementary mechanisms of improved long-term survival. Although rescue PCI reduced long-term mortality, improved microvascular perfusion (TMPG 2/3) before PCI was also related to improved mortality independently of epicardial blood flow and the performance of rescue or adjunctive PCI. Further prospective trials are warranted to re-examine the benefit of early PCI with thrombolysis.

Association Between White Blood Cell Count, Epicardial Blood Flow, Myocardial Perfusion, and Clinical Outcomes in the Setting of Acute Myocardial Infarction A Thrombolysis In Myocardial Infarction 10 Substudy

BackgroundElevation of the white blood cell (WBC) count during acute myocardial infarction (AMI) is associated with adverse outcomes. We examined the relationship between the WBC count and angiographic findings to gain insight into this relationship.Results and MethodsWe evaluated data from 975 patients in the Thrombolysis In Myocardial Infarction (TIMI) 10A and 10B trials. Patients with a closed artery at 60 and 90 minutes had higher a WBC count than patients with an open artery (P =0.02). Likewise, the presence of angiographically apparent thrombus was associated with a higher WBC count (11.5±5.2×109/L, n=290, versus 10.7±3.5×109/L, n=648;P =0.008). In addition, a higher WBC count was associated with poorer TIMI myocardial perfusion grades (4-way P =0.04). Mortality rates were higher in patients with a higher WBC count (0% for WBC count 0 to 5×109/L, 4.9% for WBC count 5 to 10×109/L, 3.8% for WBC count 10 to 15×109/L, 10.4% for WBC count >15×109/L;P =0.03). The development of new congestive heart failure or shock was also associated with a higher WBC count (0% for WBC count 0 to 5×109/L, 5.2% for WBC count 5 to 10×109/L, 6.1% for WBC count 10 to 15×109/L, 17.1% for WBC count >15×109/L;P <0.001), an observation that remained significant in a multivariable model that adjusted for potential confounding variables (odds ratio 1.21, P =0.002). ConclusionsElevation in WBC count was associated with reduced epicardial blood flow and myocardial perfusion, thromboresistance (arteries open later and have a greater thrombus burden), and a higher incidence of new congestive heart failure and death. These observations provide a potential explanation for the higher mortality rate observed among AMI patients with elevated WBC counts and helps explain the growing body of literature that links inflammation and cardiovascular disease.

Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Participants in the National Registry of Myocardial Infarction 2

Numerous large clinical trials of thrombolytic therapy have shown impressive reductions in mortality associated with the use of thrombolytic agents in the setting of acute myocardial infarction. They have also consistently shown that thrombolysis imposes an excess risk for intracranial hemorrhage [1]. Although the incidence of intracranial hemorrhage associated with thrombolytic therapy is low, this complication is characterized by high fatality rates and substantial disability among survivors. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator (tPA) for Occluded Coronary Arteries (GUSTO-I) trial, intracranial hemorrhage rates were 0.46%, 0.57%, 0.70%, and 0.88% among patients treated with streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tPA, and combination therapy, respectively. Sixty percent of patients who had intracranial hemorrhage died, and another 25% were disabled [2]. The underuse of thrombolysis in special patient populations, such as elderly persons, is usually attributed to concerns about the risk for bleeding, particularly intracranial hemorrhage [3, 4]. These concerns often dominate decisions about the use of thrombolytic agents in eligible elderly patients with acute myocardial infarction despite the potential for substantial survival benefits from treatment [1]. In the GUSTO-I trial [5], 0.42% of patients younger than 75 years of age treated with streptokinase and 0.52% of those treated with accelerated tPA experienced a hemorrhagic stroke by 30 days of follow-up. Among patients older than 75 years of age, these values were 1.23% and 2.08%, respectively. Simoons and colleagues [6] combined information from a national registry of thrombolytic therapy with data from multiple thrombolytic trials to identify 150 patients who had had intracranial hemorrhage and compared them with 294 patients with acute myocardial infarction who received thrombolytic therapy but did not experience this outcome. After adjustment for other factors, including type of thrombolytic agent, body weight, and presence of hypertension on admission, patients older than 65 years of age were significantly more likely to experience intracranial hemorrhage (odds ratio, 2.2 [95% CI, 1.4 to 3.5]). Most information on the risk for intracranial hemorrhage associated with thrombolytic therapy in acute myocardial infarction derives from the experience of patients participating in clinical trials, in which stringent enrollment criteria are applied before thrombolytic therapy is administered [2, 7, 8]. The experience in the community setting has not been well described. The extent to which the clinician can extrapolate clinical trial data on the benefits and the risks of therapeutic interventions to the general practice setting is often unclear [9]. We used data from an ongoing national registry of patients who were hospitalized for acute myocardial infarction to determine the frequency of and risk factors for intracranial hemorrhage in patients treated with tPA, with particular focus on the relation between advancing age and this complication. Methods Data Sources The National Registry of Myocardial Infarction 2 (NRMI 2) was initiated in June 1994 as an ongoing registry of patients who received therapy for acute myocardial infarction at selected U.S. hospitals. The registry is supported by Genentech, Inc. (South San Francisco, California). From 1 June 1994 to 30 September 1996, 1484 U.S. hospitals contributed patients to NRMI 2. Participation in the registry is voluntary. Registry hospitals are substantially larger than nonparticipating U.S. hospitals: Twenty-seven percent of registry hospitals have more than 350 beds compared with 8% of nonregistry hospitals. In addition, registry hospitals are more likely than nonregistry hospitals to be certified by the Joint Commission on Accreditation of Health Care Organizations (99% compared with 77%); be affiliated with a medical school (36% compared with 17%); and have a coronary care unit (73% compared with 31%), a cardiac catheterization laboratory (72% compared with 23%), and a cardiac surgery program (39% compared with 11%). Registry hospitals are encouraged to enter consecutive patients who have had acute myocardial infarction, regardless of treatment or outcome. Approval for hospital participation in the registry may include review by the local institutional review board or human research subjects committee as dictated by local policy. A study coordinator at each participating hospital completes individual data collection forms for each study patient; these forms are forwarded to an independent central data collection center (ClinTrials Research, Inc., Lexington, Kentucky) for processing. Data on individual hospitals are confidential and are available only to the contributing hospital. Patients Patients in our study had had acute myocardial infarction documented according to local hospital criteria (usually cardiac enzyme levels or results of electrocardiography or coronary angiography). For the purpose of our study, patients were those enrolled in NRMI 2 who received tPA as the initial reperfusion strategy from 1 June 1994 to 30 September 1996. To be eligible for study inclusion, patients could not have been transferred to a participating registry hospital from any other hospital (registry or otherwise) in the context of management of the acute myocardial infarction event. In addition, study patients could not have received a second dose of any thrombolytic agent. As of 30 September 1996, NRMI 2 included 389 130 patients. Of these, 99 694 had received tPA as the initial reperfusion strategy; 26 370 of these patients had been transferred from another hospital for treatment of acute myocardial infarction. Of the remaining 73 324 patients, 2115 had received a second dose of a thrombolytic agent and 136 patients had missing information on age or sex. This left 71 073 patients in the study sample. The number of study patients contributed per registry hospital ranged from 1 to 311. Definitions The occurrence of primary intracranial hemorrhage was indicated on the registry data collection form, along with the date and time of onset of neurologic symptoms and whether computed tomography or magnetic resonance imaging (MRI) was performed to confirm the event. Events reported to have been confirmed by computed tomography or MRI were of principal interest in our study. The time between administration of tPA and intracranial hemorrhage was calculated. Sequelae of intracranial hemorrhage were characterized as death during hospitalization, residual deficit at discharge, or no residual deficit at discharge. The magnitude of the residual deficit was not classified. The reported intracranial hemorrhages and the circumstances surrounding them were not independently verified; information on these events was limited to that available on the data collection form provided by the participating hospitals. We characterized patients according to age (<65 years, 65 to 74 years, or 75 years), sex, and ethnicity (white, black, or other). Clinical characteristics included history of myocardial infarction, angina, congestive heart failure, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, stroke, diabetes mellitus, hypertension, hypercholesterolemia, and smoking. Systolic and diastolic blood pressure were characterized according to the first measurement recorded at hospital presentation. Likewise, Killip class was measured at presentation (no evidence of congestive heart failure, presence of rales or jugular venous distention, pulmonary edema, or cardiogenic shock) [10]. The study sample was stratified into quartiles according to body weight (measured in kg). The dose of tPA administered was categorized as less than 1.5 mg/kg or 1.5 mg/kg or more. These categories were based on manufacturer recommendations for tPA dosing [11]. (For patients weighing >67 kg, the maximum recommended total tPA dose is 100 mg [ 1.49 mg/kg]. Dosage adjustments based on weight are advised for patients weighing 67 kg or less.) Duration of tPA infusion was categorized as 90 minutes or less (accelerated tPA) or more than 90 minutes. We also characterized patients according to use of aspirin or intravenous heparin, which may be relevant to risk for bleeding. Statistical Analysis To assess comparability with a large clinical trial population, selected characteristics of our study sample were compared with those of patients who received accelerated tPA plus intravenous heparin in the GUSTO-I trial [5]. For our study sample, we evaluated the bivariate association between intracranial hemorrhage and selected demographic and clinical patient characteristics. These variables were used to develop stepwise multivariable logistic regression models with the occurrence of intracranial hemorrhage (confirmed by computed tomography or MRI) as the dependent variable. Patients with unknown values for any variable were excluded from multivariable analyses. The models were constructed with an entry significance level of P = 0.01 and an exit significance level of P = 0.05. Estimated odds ratios for the risk for intracranial hemorrhage, adjusted for all remaining variables, were obtained by using this model. Interactions between patient age and all other variables remaining in the final regression model were assessed. The goodness-of-fit criteria of Hosmer and Lemeshow were assessed for all models [12]. In addition, we calculated an area under the receiver-operating characteristic curve for each model [13]. All tests of statistical significance were two-tailed; a P value less than 0.05 was considered statistically significant. Multiple logistic regression analyses were performed by using the SAS PROC LOGISTIC procedure in SAS, version 6 (SAS Institute, Inc., Cary, North Carolina). The main-effects models were refit by using SAS PROC PHREG to control for potential int

Predictors of door-to-balloon delay in primary angioplasty

In the treatment of acute myocardial infarction, delayed reperfusion therapy is associated with increased mortality. Predictors of delay have been described for fibrinolysis but not for primary percutaneous transluminal coronary angioplasty (pPTCA). Therefore, we studied 40,017 consecutive patients with acute myocardial infarction who underwent pPTCA in the National Registry of Myocardial Infarction between June 1994 and April 2000. Median door-to-balloon times were calculated, and factors independently associated with a delay of >120 minutes were determined by logistic regression. The median door-to-balloon time among all patients was 111 minutes (interquartile range 84 to 152). The proportion of patients with a delay of >2 hours was greater among those aged > or = 65 years (49% vs 41%), women (50% vs 42%), patients with contraindications to fibrinolysis (60% vs 41%), and those without chest pain on admission (61% vs 43%, all p <0.0001). Delay was also more common with transfer from another hospital (87% vs 38%), with presentation outside the hours of 8 A.M. to 4 P.M. (51% vs 38%), and in hospitals performing <49 pPTCAs/year (47% vs 41%, all p <0.0001). The strongest independent predictor of delay was hospital transfer, along with non-daytime presentation and low-volume centers. Older age, female sex, and non-white race were weaker predictors. Both patient and hospital factors are associated with delay in pPTCA after presentation. These findings may help design treatment algorithms to minimize delay, thus improving the survival benefit of pPTCA. These results may also help design trials of combination reperfusion strategies.

Early Use of Glycoprotein IIb/IIIa Inhibitors in Non-ST-Elevation Acute Myocardial Infarction Observations From the National Registry of Myocardial Infarction 4

OBJECTIVES We sought to identify patient and hospital features associated with early glycoprotein (GP) IIb/IIIa inhibitor therapy for non-ST-elevation (NSTE) myocardial infarction (MI) and to relate this treatment to in-hospital outcomes. BACKGROUND Glycoprotein IIb/IIIa inhibitors have improved outcomes in randomized trials of NSTE MI, leading national treatment guidelines to recommend their use. Their actual use, safety, and effectiveness have not been well characterized beyond trial populations. METHODS We studied 60,770 patients with NSTE MI treated between July 2000 and July 2001 at 1,189 hospitals in a U.S. registry. Using logistic regression, we identified patient and hospital features associated with GP IIb/IIIa inhibition within 24 h after presentation. We also compared outcomes by early treatment versus no treatment after adjusting for patient and hospital characteristics and treatment propensity. RESULTS Only 25% of eligible patients received early GP IIb/IIIa therapy. Elderly patients, women, minority patients, and those without private insurance received such therapy less often than their counterparts. Treated patients had lower unadjusted in-hospital mortality (3.3% vs. 9.6%, p < 0.0001) remaining significantly lower after adjustment for patient risk, treatment propensity, and hospital characteristics (adjusted odds ratio, 0.88; 95% confidence interval, 0.79 to 0.97). Hospitals that adopted early GP IIb/IIIa inhibition more rapidly also had lower adjusted mortality rates than those slower to adopt such therapy. CONCLUSIONS Glycoprotein IIb/IIIa inhibitor therapy appears to be underused in early management of NSTE MI patients. Because this therapy is associated with better outcomes, it represents a target for quality improvement.

The association between white blood cell count and acute myocardial infarction mortality in patients ≥65 years of age: findings from the cooperative cardiovascular project

OBJECTIVES The purpose of the study was to examine the association between white blood cell (WBC) count on admission and 30-day mortality in patients with acute myocardial infarction (AMI). BACKGROUND Elevations in WBC count have been associated with the development of AMI and with long-term mortality in patients with coronary artery disease. However, the relationship between WBC count and prognosis following AMI is less clear. METHODS Using the Cooperative Cardiovascular Project database, we evaluated 153,213 patients > or = 65 years of age admitted with AMI. RESULTS An increasing WBC count is associated with a significantly higher risk of in-hospital events, in-hospital mortality and 30-day mortality. Relative to those patients in the lowest quintile, patients in the highest quintile were three times more likely to die at 30 days (10.3% vs. 32.3%; p < 0.001). After adjustment for confounding factors, WBC count was found to be a strong independent predictor of 30-day mortality (odds ratio = 2.37; 95% confidence interval 2.25 to 2.49, p = 0.0001 for the highest quintile of WBC count). CONCLUSIONS White blood cell count within 24 h of admission for an AMI is a strong and independent predictor of in-hospital and 30-day mortality as well as in-hospital clinical events. Although the mechanism of the association remains speculative, the results of this study have important clinical implications for risk-stratifying patients with AMI.

Relation Between Hospital Intra-Aortic Balloon Counterpulsation Volume and Mortality in Acute Myocardial Infarction Complicated by Cardiogenic Shock

Background—Increasing evidence suggests an inverse relationship between outcome and the total number of invasive cardiac procedures performed at a given hospital. The purpose of the present study was to determine if a similar relationship exists between the number of intra-aortic balloon counterpulsation (IABP) procedures performed at a given hospital per year and the in-hospital mortality rate of patients with acute myocardial infarction complicated by cardiogenic shock. Methods and Results—We analyzed data of 12 730 patients at 750 hospitals enrolled in the National Registry of Myocardial Infarction 2 from 1994 to 1998. The hospitals were divided into tertiles (low–, intermediate–, and high–IABP volume hospitals) according to the number of IABPs performed at the given hospital per year. The median number of IABPs performed per hospital per year was 3.4, 12.7, and 37.4 IABPs at low-, intermediate-, and high-volume hospitals, respectively. Of those patients who underwent IABP, there were only minor differences in baseline patient characteristics between the 3 groups. Crude mortality rate decreased with increasing IABP volume: 65.4%, lowest volume tertile; 54.1%, intermediate volume tertile; and 50.6%, highest volume tertile (P for trend <0.001). This mortality difference represented 150 fewer deaths per 1000 patients treated at the high IABP hospitals. In the multivariate analysis, high hospital IABP volume for patients with acute myocardial infarction was associated with lower mortality (OR=0.71, 95% CI=0.56 to 0.90), independent of baseline patient characteristics, hospital factors, treatment, and procedures such as PTCA. Conclusions—Among the myocardial infarction patients with cardiogenic shock who underwent IABP placement, mortality rate was significantly lower at high–IABP volume hospitals compared with low–IABP volume hospitals.