Margaret Frederick

Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction : results of the thrombolysis in myocardial infarction -TIMI), phase II trial

OBJECTIVES To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events. DESIGN A multicenter, randomized, controlled trial. SETTING Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II). INTERVENTIONS Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy. MEASUREMENTS Patients were monitored for hemorrhagic events during hospitalization. MAIN RESULTS In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P less than 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose. CONCLUSIONS Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.

HLA-DRB1*1101: A Significant Risk Factor for Sarcoidosis in Blacks and Whites

Sarcoidosis is a granulomatous disorder of unknown etiology, associated with an accumulation of CD4+ T cells and a TH1 immune response. Since previous studies of HLA associations with sarcoidosis were limited by serologic or low-resolution molecular identification, we performed high-resolution typing for the HLA-DPB1, HLA-DQB1, HLA-DRB1, and HLA-DRB3 loci and the presence of the DRB4 or DRB5 locus, to define HLA class II associations with sarcoidosis. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled biopsy-confirmed cases (736 total) from 10 centers in the United States. Seven hundred six (706) controls were case matched for age, race, sex, and geographic area. We studied the first 474 ACCESS patients and case-matched controls. The HLA-DRB1 alleles were differentially distributed between cases and controls (P<.0001). The HLA-DRB1*1101 allele was associated (P<.01) with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% in whites. HLA-DRB1-F(47) was the amino acid residue most associated with sarcoidosis and independently associated with sarcoidosis in whites. The HLA-DPB1 locus also contributed to susceptibility for sarcoidosis and, in contrast to chronic beryllium disease, a non-E(69)-containing allele, HLA-DPB1*0101, conveyed most of the risk. Although significant differences were observed in the distribution of HLA class II alleles between blacks and whites, only HLA-DRB1*1501 was differentially associated with sarcoidosis (P<.003). In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis (DRB1*0401 for eye in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites). These studies confirm a genetic predisposition for sarcoidosis and present evidence for the allelic variation at the HLA-DRB1 locus as a major contributor.

Incidence and prognostic implications of heart block complicating inferior myocardial infarction treated with thrombolytic therapy: Results from TIMI II

OBJECTIVES The aim of this study was to determine the incidence and significance of second- or third-degree heart block among patients with inferior myocardial infarction treated with thrombolytic therapy. BACKGROUND Data from the prethrombolytic era suggest that heart block occurs in approximately 20% of patients with acute inferior myocardial infarction and is associated with a marked increase in mortality. Little is known about the incidence and prognostic implications of heart block among patients receiving thrombolytic therapy. METHODS We studied 1,786 patients with acute inferior myocardial infarction enrolled in the Thrombolysis in Myocardial Infarction (TIMI) II Trial who received recombinant tissue-type plasminogen activator (rt-PA) within 4 h of the onset of symptoms. RESULTS Heart block occurred in 214 patients (12%); 113 (6.3%) had heart block on presentation and 101 (5.7%) developed heart block in the 24 h after treatment with rt-PA. Patients with heart block at entry were slightly older and a greater proportion had cardiogenic shock. The 21-day mortality rate among patients with heart block at entry was 7.1% (8 of 113), compared with 2.7% (45 of 1,673) among patients without heart block at study entry (relative risk 2.6, p = 0.007). However, heart block was not independently associated with 21-day mortality after adjustment for other variables, including shock. Mortality and other adverse cardiac events in the following year were similar among patients with and without heart block. Among patients without heart block at study entry, coronary angiography among patients randomly assigned to coronary catheterization 18 to 48 h after admission revealed that the infarct-related artery was occluded in 28.2% (11 of 39) of patients who developed heart block versus 15.5% (112 of 723) of patients without heart block (p = 0.04). The 21-day mortality rate was increased among patients in whom heart block developed after thrombolytic therapy (9.9% [10 of 101] versus 2.2% [35 of 1,572] of patients without heart block, relative risk 4.5, p less than 0.001). Analysis of the increased mortality among patients who developed heart block suggests that mortality was due to severe cardiac dysfunction; no patient was considered to have died as a result of the heart block or its treatment. CONCLUSIONS Heart block is common among patients with inferior infarction given thrombolytic therapy and is associated with increased mortality. These clinical and anatomic data provide insight into the mechanism of heart block and increased mortality among such patients.

Frequency and significance of right ventricular dysfunction during inferior wall left ventricular myocardial infarction treated with thrombolytic therapy (results from the Thrombolysis in Myocardial Infarction [TIMI] II trial)☆

To determine the effect of thrombolytic therapy on the frequency of right ventricular (RV) dysfunction, and whether RV dysfunction is a risk factor for morbidity and mortality after discharge from the hospital, 1,110 patients in the Thrombolysis in Myocardial Infarction (TIMI) II trial with acute inferior wall left ventricular myocardial infarction were studied. RV dysfunction was defined as an RV wall motion abnormality on equilibrium radionuclide ventriculography performed a mean of 9 days after admission to the hospital. Fifty-eight patients (5%) had RV dysfunction. Baseline clinical characteristics among patients with and without RV dysfunction were similar. However, patients with RV dysfunction had a lower mean left ventricular ejection fraction (51.2 +/- 1.2% vs 55.5 +/- 0.3%; p < 0.001) and a greater frequency of in-hospital complications. Angiographic data from patients undergoing protocol catheterization 18 to 48 hours after hospital admission show that the infarct-related artery was more likely to be occluded in those with RV dysfunction (48% [15 of 31] vs 14% [68 of 495]; p < 0.001). There was no difference in the frequency of multivessel disease between the 2 groups. In patients with RV dysfunction in whom radionuclide ventriculography was repeated 6 weeks after hospital discharge, RV wall motion abnormalities persisted in only 18% (8 of 45). Mortality in the year after discharge was 3.5% (2 of 58) among patients with RV dysfunction compared with 1.7% (18 of 1,052; p = NS) among those without RV dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of treatment strategy on predischarge exercise test in the Thrombolysis in Myocardial Infarction (TIMI) II trial

Predischarge supine bicycle ergometry was used to assess persistent myocardial ischemia in postinfarction patients who received thrombolytic therapy and were randomized to an invasive versus conservative strategy in the Thrombolysis in Myocardial Infarction (TIMI) II trial. The frequency of ischemic responses in both strategies, and the 1-year prognostic importance of the different exercise test outcomes were examined. At 14 days, the percentage of patients with any adverse outcome (including death, presence of exercise-induced ST-segment depression, or inability to perform the exercise test) was 33.7% of 1,681 randomly assigned to the invasive strategy compared with 34.6% of 1,658 randomly assigned to the conservative strategy (p = 0.57). The 1-year mortality was greater in patients who did not perform the predischarge exercise test (7.7%) than in those who did (1.8%) (p < 0.001); the former were older, and a greater proportion were women, had a more frequent history of myocardial infarction, and more extensive coronary artery disease (p < 0.01 for each comparison). The 1-year mortality in patients with exercise-induced ST-segment depression or chest pain was only 1.4% (3 of 22) among those randomly assigned to the conservative strategy where coronary angiography and revascularization were recommended if the test result was abnormal (relative risk compared with those without ST-segment depression or chest pain 0.6; 99% confidence interval 0.1 to 2.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence and significance of ventricular tachycardia and fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: Results from the thrombolysis in myocardial infarction (TIMI) phaes II trial

Objectives. The purpese of this study was to determine the incidence of ventriculer tachycardia and fibrillation without hypotension or heart failure after treatment with recombinant tissue-type plasminogen activator (rt-PA), anatomic correlates of their development, the effect of immediate intravenous metoprolol on their occurrence and the outcome of patients with these arrhythmias. Background. Malignant arrhythmias after thrombolytic therapy have been reported to occur as a result of coronary reperfusion which is associated with reduced mortality in patients receiving thrombolytic therapy. Methods. We analysed data from 2,546 patients in the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial without congestive heart failure or hypotension during the 1st 24 h after study entry. Forty-nine patients (1.9%) developed sustained ventricular tachycardia or ventricular fibrillation within 24 h of study entry (group 1), and 2,497 patients (98.1%) did not (group 2). Results. Baseline characteristics and admission laboraratory values were similar in the two groups. In patients undergoing protocol angiography 18 to 48 h after rt-PA, the infarct-related artery was patent in a greater percent of group 2 patients (87% [1,015 of 1,169]) than group 1 patients (68% [15 of 22], P = 0.01), although angiography was performed less frequently in group 1 than in group 2. More group 1 than group 2 patients died within 21 days (20.4%) (1.6%, p < 0.001). For patients surviving to 21 days, there was no difference in mortality between patients in the two groups in the following year. Conclusions. Ventricular tachycardia and fibrillation are not markers for reperfusion after thrombolytic therapy. These arrhythmias are associated with occlusion, not patency, of the infarct-related artery. Early mortality is increased in patients who develop ventricular tachycardia and fibrillation, even in the absence of congestive heart failure and hypotension.

Effect of hard-drug use on CD4 cell percentage, HIV RNA level, and progression to AIDS-defining class C events among HIV-infected women.

In vitro and animal studies suggest that cocaine and heroin increase HIV replication and suppress immune function, whereas epidemiologic studies are inconclusive regarding their effect on HIV infection progression. The authors prospectively examined the association between illicit-drug use and 4 outcome measures (CD4 cell percentage, HIV RNA level, survival to class C diagnosis of HIV infection, and death) in a national cohort of HIV-infected women. Women enrolled between 1989 and 1995 were followed for 5 years and repeatedly interviewed about illicit (“hard”)–drug use. Up to 3 periodic urine screens validated self-reported use. Outcomes were compared between hard-drug users (women using cocaine, heroin, methadone, or injecting drugs) and nonusers, adjusting for age, antiretroviral therapy, number of pregnancies, smoking, and baseline CD4 cell percentage. Of 1148 women, 40% reported baseline hard-drug use during pregnancy. In multivariate analyses, hard-drug use was not associated with change in CD4 cell percentage (P = 0.84), HIV RNA level (P = 0.48), or all-cause mortality (relative hazard = 1.10; 95% confidence interval, 0.61–1.98). Hard-drug users did, however, exhibit a higher risk of developing class C diagnoses (relative hazard = 1.65; 95% confidence interval, 1.00–2.72), especially herpes, pulmonary tuberculosis, and recurrent pneumonia. Hard-drug–using women may have a higher risk for nonfatal opportunistic infections.

Selective versus routine predischarge coronary arteriography after therapy with recombinant tissue-type plasminogen activator, heparin and aspirin for acute myocardial infarction

To ascertain whether predischarge arteriography is beneficial in patients with acute myocardial infarction treated with recombinant tissue-type plasminogen activator (rt-PA), heparin and aspirin, the outcome of 197 patients in the Thrombolysis in Myocardial Infarction (TIMI) IIA study assigned to conservative management and routine predischarge coronary arteriography (routine catheterization group) was compared with the outcome of 1,461 patients from the TIMI IIB study assigned to conservative management without routine coronary arteriography unless ischemia recurred spontaneously or on predischarge exercise testing (selective catheterization group). The two groups were similar with regard to important baseline variables. During the initial hospital stay, coronary arteriography was performed in 93.9% of the routine catheterization group and 34.7% of the selective catheterization group (p less than 0.001), but the frequency of coronary revascularization (angioplasty or coronary artery bypass surgery) was similar in the two groups (24.4% versus 20.7%, p = NS). Coronary arteriograms showed a predominance of zero or one vessel disease (stenosis greater than or equal to 60%) in both groups (routine catheterization group 73.1%, selective catheterization group 61.3%). During the 1st year after infarction, rehospitalization for cardiac reasons and the interim performance of coronary arteriography were more common in the selective catheterization group (37.9% versus 27.6%, p = 0.007 and 28.6% versus 11.6%, p less than 0.001, respectively); however, the interim rates of death, nonfatal reinfarction and performance of coronary revascularization procedures were similar. At the end of 1 year, coronary arteriography had been performed one or more times in 98.9% of the routine catheterization group and 59.4% of the selective catheterization group (p less than 0.001), whereas death and nonfatal reinfarction had occurred in 10.2% versus 7.0% (p = 0.10) and 8.6% versus 9.0% (p = 0.87), respectively. Because the selective coronary arteriography policy exposes about 40% fewer patients to the small but finite risks and inconvenience of the procedure without compromising the 1 year survival or reinfarction rates, it seems to be an appropriate management strategy.

Morbidity and mortality during the first two years of life among uninfected children born to human immunodeficiency virus type 1-infected women: the women and infants transmission study.

Objective: We evaluated morbidity and mortality during the first 2 years of life among children born to human immunodeficiency virus-(HIV) type 1-infected women enrolled in the Women and Infants Transmission Study (WITS) during an 11-year period (1990–2001). Design and Methods: As part of WITS, evaluations were performed at birth and at 1, 2, 4, 6, 9, 12, 18 and 24 months of age. Growth, hospitalization and the incidence of clinical disease were assessed regularly. Results: Data regarding 1118 children born to HIV-infected women (955 HIV-uninfected children and 163 HIV-infected children) were analyzed. Fewer changes in the caretaker of the child and fewer in utero exposures to drugs, tobacco and alcohol occurred in the latter periods of the study (all P values for time trend analyses <0.01). The percentages of HIV-uninfected children with poor weight gain (44 of 767; 5.7%), short stature (32 of 703; 4.5%) and wasting (27 of 792; 3.4%) were higher than expected for the general population. Two or more changes in caretaker were associated with all growth deficiencies except wasting, and fetal exposure to tobacco was associated with height abnormalities. Anemia was common and was associated with receipt of zidovudine prophylaxis. Morbidity and mortality decreased during the study period. For the uninfected children, a decrease in class A events (Kaplan-Meier rates: group 1, 22.3%; group 2, 6.8%; group 3, 4.2%; P < 0.001) and class C events and death (Kaplan- Meier event rates: group 1, 2.0%; group 2, 1.7%; group 3, 0.2%; P = 0.062) during the first 2 years of life account for the differences in the curves over time. Conclusions: During an 11-year period, morbidity and mortality during the first 24 months of life decreased substantially for children born to HIV-infected women.

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.