Conor F. Lundergan

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.

Randomized Comparison of Enoxaparin, a Low-Molecular-Weight Heparin, With Unfractionated Heparin Adjunctive to Recombinant Tissue Plasminogen Activator Thrombolysis and Aspirin Second Trial of Heparin and Aspirin Reperfusion Therapy (HART II)

Background—Adjunctive unfractionated heparin (UFH) during thrombolytic therapy for acute myocardial infarction (AMI) promotes the speed and magnitude of coronary artery recanalization and reduces reocclusion. Low-molecular-weight heparins offer practical and potential pharmacological advantages over UFH in multiple applications but have not been systematically studied as adjuncts to fibrinolysis in AMI. Methods and Results—Four hundred patients undergoing reperfusion therapy with an accelerated recombinant tissue plasminogen activator regimen and aspirin for AMI were randomly assigned to receive adjunctive therapy for at least 3 days with either enoxaparin or UFH. The study was designed to show noninferiority of enoxaparin versus UFH with regard to infarct-related artery patency. Ninety minutes after starting therapy, patency rates (thrombolysis in myocardial infarction [TIMI] flow grade 2 or 3) were 80.1% and 75.1% in the enoxaparin and UFH groups, respectively. Reocclusion at 5 to 7 days from TIMI grade 2 or 3 to TIMI 0 or 1 flow and TIMI grade 3 to TIMI 0 or 1 flow, respectively, occurred in 5.9% and 3.1% of the enoxaparin group versus 9.8% and 9.1% in the UFH group. Adverse events occurred with similar frequency in both treatment groups. Conclusions—Enoxaparin was at least as effective as UFH as an adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.

End-systolic volume index at 90 to 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality. The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I Angiographic Investigators

BACKGROUND Left ventricular remodeling is an important sequela of myocardial infarction (MI). Although remodeling occurs soon after MI, the effect of early left ventricular dilatation on outcome is not established and may be useful for early risk stratification. We assessed whether end-systolic volume index (ESVI) at 90 to 180 minutes into thrombolytic therapy for MI is associated with adverse outcomes. METHODS AND RESULTS In the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I study, 41021 patients with evolving MI received one of four thrombolytic regimens. At 90 or 180 minutes into reperfusion therapy, 1300 patients underwent left ventriculography. ESVI was measured and correlated with adverse outcomes: 30-day and 1-year mortality and in-hospital congestive heart failure, shock, and reinfarction. Clinical variables were also tested in a stepwise logistic regression analysis to determine predictors of left ventricular dilatation. ESVI was directly related to all adverse outcomes with univariate analysis. ESVI of > or = 40 mL/m2 was independently associated with mortality (adjusted odds ratio [95% confidence interval]: 30-day, 3.4 [2.0 to 5.9]; 1-year, 4:1 [2.6 to 6.2], both P < .001). Male sex, prior angina or MI, weight of < 70 kg, heart rate of > or = 80 bpm, systolic blood pressure of < 110 mm.Hg, and anterior infarction were independent predictors of an ESVI of > or = 40 mL/m2. CONCLUSIONS Left ventricular ESVI early into reperfusion therapy for MI strongly predicts adverse outcomes, including early and late mortality. The study establishes the role of very early left ventricular dilatation on outcome in MI and may be useful in identifying high-risk patients who might benefit from aggressive treatment, including the early use of ACE inhibitors.

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.

Gender and acute myocardial infarction : Is there a different response to thrombolysis ?

OBJECTIVES This study sought to 1) determine the effect of gender on early and late infarct-related artery patency and reocclusion after thrombolytic therapy for acute myocardial infarction; 2) examine the effect of gender on left ventricular function in response to injury/reperfusion; and 3) assess the independent contribution of gender to early (30-day) mortality after acute myocardial infarction. BACKGROUND Women have a higher mortality rate than men after myocardial infarction. However, the effect of gender on infarct-related coronary artery patency and left ventricular response to injury/reperfusion have not been fully defined in the thrombolytic era. METHODS Patency rates and global and regional left ventricular function were determined in patients at 90 min and 5 to 7 days after thrombolytic therapy for acute myocardial infarction. The effect of gender on infarct-related artery patency and left ventricular function was determined. Thirty-day mortality differences between women and men were compared. RESULTS Women were significantly older and had more hypertension, diabetes, hypercholesterolemia, heart failure and shock. They were less likely to have had a previous myocardial infarction, history of smoking or previous bypass surgery. Ninety-minute patency rates (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) in women and men were 39% and 38%, respectively (p = 0.5). Reocclusion rates were 8.7% in women versus 5.1% in men (p = 0.14). Women had more recurrent ischemia than men (21.4% vs. 17.0%, respectively, p = 0.01). Ninety-minute ejection fraction and regional ventricular function were clinically similar in women and men with TIMI 2 or 3 flow (ejection fraction [mean +/- SD]: 63.4 +/- 6% vs. 59.4 +/- 0.7%, p = 0.02; number of chords: 21.4 +/- 0.9 vs. 21.0 +/- 1.9, p = 0.7; SD/chord: -2.4 +/- 08 vs. -2.4 +/- 0.2, p = 0.9, respectively). No clinically significant differences in left ventricular function were noted at 5- to 7-day follow-up. Women had a greater hyperkinetic response than men in the noninfarct zone (SD/chord: 2.4 +/- 0.2 vs. 1.7 +/- 0.1, p = 0.005). The 30-day mortality rate was 13.1% in women versus 4.8% in men (p < or = 0.0001). After adjustment for other clinical and angiographic variables, gender remained an independent determinant of 30-day mortality. CONCLUSIONS Women do not differ significantly from men with regard to either early infarct-related artery patency rates or reocclusion after thrombolytic therapy or ventricular functional response to injury/reperfusion. Gender was an independent determinant of 30-day mortality after acute myocardial infarction.

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.

Clinical predictors of early infarct-related artery patency following thrombolytic therapy : Importance of body weight, smoking history, infarct-related artery and choice of thrombolytic regimen : The GUSTO-I experience

OBJECTIVES The purpose of this study was to determine patient characteristics that are a priori predictors of early infarct related artery patency following thrombolytic therapy, and to provide a paradigm which may identify patients who would be most likely to achieve restoration of normal (TIMI 3) coronary flow in response to thrombolytic therapy. BACKGROUND Restoration of infarct-related artery perfusion in acute myocardial infarction is necessary for preservation of ventricular function and mortality reduction. Clinical variables that are a priori predictors of early patency with currently available thrombolytic regimens have not been fully characterized. METHODS The probability of early infarct-related artery patency (TIMI 3 flow) was determined by multivariable logistic regression. We determined a reduced (parsimonious) model for predicting early (90 min) infarct-related artery patency (TIMI grade 3) based on data from 1,030 patients in the GUSTO-I Angiographic study. RESULTS Predictors of 90 min TIMI 3 flow are use of an accelerated t-PA regimen (vs. streptokinase containing regimens) (chi2=39.1; p < or = 0.0001), infarct related artery (RCA/Lcx vs. LAD) (chi2=12.7; p=0.0004), body weight (chi2=10.3; p=0.001) and history of smoking (chi2=7.4; p=0.007). Time from symptom onset to treatment was not significant (p=0.71). CONCLUSIONS The efficacy of currently available thrombolytic regimens is chiefly dependent on choice of thrombolytic regimen, body weight, infarct-related coronary artery and smoking history. Clinical variables alone correctly predict a priori TIMI 3 flow in the infarct-related artery 64% of the time. Patients with body weights greater than 85 kg are at a significant disadvantage with regard to achieving successful thrombolysis compared to those with lesser body weights.

Evolution of Early TIMI 2 Flow After Thrombolysis for Acute Myocardial Infarction

BACKGROUND Patients with early Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow after thrombolysis appear to have outcomes similar to thrombolytic failures. To evaluate the origin and evolution of early TIMI 2 flow, we examined early and late angiographic and ventriculographic data from the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-1) angiographic study. METHODS AND RESULTS Of the 914 patients with both 90-minute and 5- to 7-day catheterizations, 278 patients had TIMI grade 2 flow at 90 minutes. At follow-up, 188 (67%) had improved to TIMI grade 3 flow. At 90 minutes, patients with TIMI grade 2 flow had greater infarct vessel narrowing and a significantly greater incidence of thrombus than patients with TIMI grade 3 flow. At the 5- to 7-day follow-up, patients whose flow had improved from TIMI grade 2 at 90 minutes to grade 3 flow at follow-up had larger-caliber vessels (minimum luminal diameter, 0.99 +/- 0.47 versus 0.84 +/- 0.48 mm; P = .03) and a lower incidence of visible thrombus (26% versus 38%, P = .04) than those with persistent TIMI grade 2 flow. These patients also had a higher mean ejection fraction (57.5 +/- 14.1% versus 52.8 +/- 12.9%, P = .02) and better infarct zone wall motion (-2.1 +/- 1.5 versus -2.6 +/- 1.3 SD per chord, P = .01) at the 5- to 7-day follow-up. Patients in whom flow improved from TIMI grade 2 at 90 minutes to TIMI grade 3 by 5 to 7 days had significantly better left ventricular function than patients with persistent TIMI grade 0, 1, or 2 flow and constituted a group whose left ventricular function was intermediate between those who had no reperfusion (TIMI grades 0 and 1) and those whose reperfusion was complete (TIMI grade 3). CONCLUSIONS These data suggest that incomplete clot lysis plays a significant role in the pathogenesis of TIMI grade 2 flow. Furthermore, early TIMI grade 2 flow may be sufficient to provide prolonged myocyte viability, which will further recover if flow normalizes.

Early angiography cannot predict postthrombolytic coronary reocclusion: Observations from the GUSTO angiographic study☆

OBJECTIVES The purpose of this study was to determine whether early qualitative or quantitative angiographic features can predict reocclusion after initially successful coronary thrombolysis. BACKGROUND Although both the benefits of early reperfusion and the consequences of subsequent reocclusion after thrombolysis for acute myocardial infarction have been well described, efforts to describe angiographic markers of lesions at high risk for reocclusion have produced conflicting results. The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) angiographic trial provides the opportunity to examine these relations in the largest single, prospective patient cohort studied to date. METHODS We studied 559 patients undergoing follow-up angiography at 90 min and 5 to 7 days after thrombolysis in the GUSTO trial. Patients received one of four thrombolytic regimens: 1) streptokinase with intravenous heparin; 2) streptokinase with subcutaneous heparin; 3) accelerated-dose recombinant tissue-type plasminogen activator (rt-PA) with intravenous heparin; or 4) a combination of streptokinase and conventionally dosed rt-PA with intravenous heparin. Qualitative variables examined at 90-min angiography included Thrombolysis in Myocardial Infarction (TIMI) flow grade, visible thrombus and lesion morphology. Quantitative variables included percent diameter stenosis, percent area stenosis, minimal lumen diameter and lesion length. The study contained a power > 0.85 to detect clinically important differences in percent diameter stenosis, percent area stenosis and minimal lumen diameter between the groups with subsequent reocclusion and sustained patency at the p = 0.05 level. RESULTS At follow-up, 33 patients (5.9%) had reocclusion. The reocclusion rate for patients with early TIMI grade 2 flow was 6.3% versus 5.6% for TIMI grade 3 flow (p = NS). When the group with reocclusion was compared with the group with continued patency, there were no differences in presence of early visible thrombus, complex lesion morphology, percent diameter stenosis, percent area stenosis, minimal lumen diameter or lesion length. CONCLUSIONS Our findings demonstrate that neither qualitative nor quantitative angiographic variables at 90 min after initiation of thrombolytic therapy can be used to predict subsequent coronary reocclusion.

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.