Samuel W. Greenhouse

A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial ☆

OBJECTIVES The study evaluated the efficacy and safety of a short-acting reduced-dose fibrinolytic regimen to promote early infarct-related artery (IRA) patency during the inherent delay experienced by infarct patients referred for angioplasty as the principal recanalization modality. BACKGROUND Previous approaches using long-acting, full-dose thrombolytic infusions rarely showed benefit, but they did increase adverse event rates. METHODS Following aspirin and heparin, 606 patients were randomized to a 50-mg bolus of recombinant tissue-type plasminogen activator (rt-PA) (alpha half-life 4.5 min) or to placebo followed by immediate angiography with angioplasty if needed. The end points included patency rates on catheterization laboratory (cath lab) arrival, technical results when PTCA (percutaneous transluminal coronary angioplasty) was performed, complication rates, and left ventricular (LV) function by treatment assignment and time to restored patency following angioplasty. RESULTS Patency on cath lab arrival was 61% with rt-PA (28% Thrombolysis in Myocardial Infarction trial [TIMI]-2, 33% TIMI-3), and 34% with placebo (19% TIMI-2, 15% TIMI-3) (p = 0.001). Rescue and primary PTCA restored TIMI-3 in closed arteries equally (77%, 79%). No differences were observed in stroke or major bleeding. Left ventricular function was similar in both treatment groups, but convalescent ejection fraction (EF) was highest with a patent IRA (TIMI-3) on cath lab arrival (62.4%) or when produced by angioplasty within an hour of bolus (62.5%). However, in 88% of angioplasties, the delay exceeded 1 h: convalescent EF 57.3%. CONCLUSIONS Tailored thrombolytic regimens compatible with subsequent interventions lead to more frequent early recanalization (before cath arrival), which facilitates greater LV function preservation with no augmentation of adverse events.

Extended Mortality Benefit of Early Postinfarction Reperfusion

Background —Reperfusion therapy for myocardial infarction, understood to reduce mortality by preserving left ventricular function, was initially expected to provide increasing benefits over time. Surprisingly, large controlled thrombolysis trials demonstrated maximum benefit at 4 to 6 weeks with no subsequent increased treatment advantage. Such studies, however, compared groups by assigned treatment, not physiological effectiveness. Methods and Results —We calculated 2-year survival differences among 2431 myocardial infarction patients according to early infarct artery patency and outcome left ventricular ejection fraction using Kaplan-Meier curves. Hazard ratios for significant survival determinants were derived from Cox regression models. Two-year vital status (minimum, 688 days) was determined in 2375 patients (97.7%). A substantial mortality advantage for early complete reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3) and for preserved ejection fraction occurred beyond 30 days. The unadjusted hazard ratio for the TIMI 3 group compared with lesser grades at 30 days was 0.57 (95% confidence interval [CI], 0.35 to 0.94) and 30 days to ≥688 days was 0.39 (95% CI, 0.22 to 0.69). Consequently, early TIMI 3 flow was associated with approximately a 3 patient per 100 mortality reduction the first month with an additional 5 lives per 100 from 30 days to 2 years. For ejection fraction >40% compared with ≤40%, the unadjusted hazard ratio was 0.25 (95% CI, 0.16 to 0.37) at 30 days and 0.22 (95% CI, 0.15 to 0.33) after 30 days through 2 years (lives saved, ≈9 and 11 per 100, respectively). Conclusions —Successful reperfusion and myocardial salvage produce significant mortality benefits that are amplified beyond the initial 30 days.

Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: The GUSTO-I angiographic experience

OBJECTIVE This study sought to determine whether the recovery of regional and global left ventricular function is reduced in elderly patients despite successful thrombolytic therapy for acute myocardial infarction. Comparisons were made between elderly (> or = 75 years old, n = 47) and adult (< 75 years old, n = 434) patients enrolled in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) angiographic trial who underwent catheterization at 90 min and 5 to 7 days after thrombolysis and who had an open infarct-related artery with Thrombolysis in Myocardial Infarction (TIMI) grade 2 to 3 flow at both times. BACKGROUND The morbidity and mortality of acute myocardial infarction is increased in elderly patients, presumably because of multiple adverse coexistent baseline variables. However, functional recovery after thrombolysis has not been characterized in the elderly. METHODS Ejection fraction, end-systolic volume index, infarct and noninfarct zone contractile function (SD/chord) and infarct extent (number of chords) were determined. RESULTS At 90 min, elderly patients with an open infarct-related artery had decreased infarct zone contractile function (-2.8 +/- 0.2 vs. -2.3 +/- 0.1 SD/chord in adults, p < or = 0.05) and a greater extent of injury (26.0 +/- 2.6 vs. 20.7 +/- 0.8 chords in adults, p < or = 0.05). At 5- to 7-day follow-up ventriculography, ejection fraction was reduced, and end-systolic volume index was significantly increased in elderly patients compared with adults. The severity of regional wall motion dysfunction in the infarct zone was also greater in the elderly than in adults at 5- to 7-day follow-up (-2.6 +/- 0.2 vs. -1.9 +/- 0.1 SD/chord, respectively, p < or = 0.005). Non-infarct zone contractile function at 90-min ventriculography was similar in both groups. Despite a patent infarct-related artery at 90-min, the 30-day mortality rate in the elderly remained elevated (17.8%) compared with that of adults (4%) (p < or = 0.0001). Elderly patients were predominantly female and had a higher prevalence of hypertension, multivessel coronary disease, previous infarction, anterior infarctions and later time to treatment (between 3 and 6 h) than adults. However, age > or = 75 years remained an independent determinant by multivariable regression analysis of 1-week postinfarction end-systolic volume index, regional left ventricular dysfunction (p = 0.02 and p < or = 0.008, respectively) and 30-day mortality (p < or = 0.0001). CONCLUSIONS Elderly patients had increased damage in the infarct zone and had persistently increased mortality despite sustained infarct-related artery patency after successful thrombolysis. Although the causes are probably multifactorial, a more rapid progression of ischemic injury or a blunted postreperfusion recovery appears to contribute to the poorer outcomes in elderly patients.

Relationship of Infarct Artery Patency and Left Ventricular Ejection Fraction to Health-Related Quality of Life After Myocardial Infarction The GUSTO-I Angiographic Study Experience

BackgroundPost–myocardial infarction global ejection fraction and infarct-related artery patency might be expected to be associated with health-related quality-of-life (HRQOL) outcomes, but this association has not been previously shown. The GUSTO-I Angiographic Study cohort 2-year follow-up afforded an examination of such potential relationships. Methods and ResultsA total of 1848 patients (87.7% response rate) who were enrolled in the GUSTO-I Angiographic Study were contacted for a telephone interview regarding their current HRQOL (physical function, psychological well-being, perceived health status, and social function) 2 years after MI. In multivariable models, left ventricular ejection fraction (EF) was significantly related to physical (P =0.021) and social (P =0.014) function, psychological well-being (P =0.042), and perceived health status (P =0.024). Infarct-related artery patency was not directly related to any HRQOL outcome. A decreasing EF was predictive of poorer outcomes in each HRQOL dimension. Men consistently had better outcomes in all HRQOL dimension with the exception of perceived health status. Increasing age was predictive of poorer outcomes in all dimensions of HRQOL except for psychological well-being where the inverse occurred; younger patients experienced greater depression, anxiety and worry than their older counterparts. The presence of comorbidities increased the likelihood of worse outcomes in all dimensions. ConclusionsThis is the first study to demonstrate a significant relationship between EF and long-term HRQOL outcomes. This advantage in left ventricular function preservation should be added to the mortality advantage when considering the impact of treatment strategies for myocardial infarction.

Estimating a Common Relative Risk: Application in Equal Employment

Abstract To analyze hiring data in equal employment cases, the available positions should be stratified in accordance with the qualifications needed for the jobs. It is then necessary to combine the results of each stratum to obtain an overall test of equal hiring rates. Furthermore, a summary measure, which compares the hiring rate of a minority applicant to that of a majority one, is then estimated. Indeed, the relative risk measure is used by the government in assessing an employment practice for possible discriminatory impact. Sometimes reliable data on the applicants is unavailable, but an accurate estimate of the minority fraction, πi, of qualified persons in the appropriate labor market is obtainable from census or other external data. Usually the number of hires, t i, in each occupation is small relative to the number of applicants, which itself is a small fraction of the large external pool of qualified persons. Then the number of minority hires, x i, in each occupation can be regarded as a binom...

A selection of Mantel's contributions to laboratory research

Nathan Mantel served as a statistician in the National Cancer Institute of the NIH for more than 25 years. During this period he was a consultant to many laboratory investigators, epidemiologists, clinicians and incidentally statisticians. These consultant activities in the design and analysis of data led to many of the research problems that he was engaged in as an independent investigator. Among these were many contributions to quantitative methods in laboratory research. This report discusses six such issues.

A diffusion process approximation approach to restricted sequential tests with early stopping

Modified restricted sequential plans with the potential for early stopping and expected stopping times close to those of the SPRT are given for testing binomial distributions.These plans are based upon the conditional probability of rejecting the null hypothesis given the accumulated data. A normal diffusion process approximation to the binomial random walk is used to obtain the conditional probabilities at each stage of the trial and thusdetermine an acceptance boundary for the null hypothesis. Plans derived using the diffusion process are compared with plans obtained by an exact method in terms of error probabilities and stopping time distributions. Some limiting relationships are also examined.

The Joint Asymptotic Distribution of the Maximum Likelihood and Mantel-Haenszel Estimators of the Common Odds Ratio in k 2 x 2 Tables

The Mantel-Haenszel (MHE) and Maximum Likelihood (MLE) estimators of an assumed common odds ratio in the analysis of several (k) 2x2 tables are usually found to be quite close. This suggests their joint asymptotic distribution should have a high correlation. Since the MLE cannot be obtained as an explicit function of the observations, we instead utilize an asymptotically equivalent surrogate for the MLE enabling us to find a large sample representation for the two estimators from which we obtain their joint asymptotic distribution. This is found for both the uncondtional and conditional likelihoods, under the assumption that k is fixed and the sample sizes within each table approach infinity.