Harvey D. White

Difference in countries' use of resources and clinical outcome for patients with cardiogenic shock after myocardial infarction: results from the GUSTO trial

BACKGROUND Use of aggressive and invasive interventions is more common in the USA than in other countries. We have compared use of resources for patients with cardiogenic shock after myocardial infarction in the USA and in other countries, and assessed the association between use of resources and clinical outcomes. METHODS We analysed data for patients with cardiogenic shock after myocardial infarction who were enrolled in the GUSTO-I trial (1891 treated in the USA, 1081 treated in other countries). Patients were randomly assigned combinations of streptokinase, heparin, and accelerated tissue-plasminogen activator (t-PA), then decisions about further interventions were left to the discretion of the attending physician. The interventions included in our analysis were: pulmonary-artery catheterisation, cardiac catheterisation, intravenous inotropic agents, ventilatory support, intra-aortic balloon counterpulsation (IABP), percutaneous transluminal coronary angioplasty (PTCA), and coronary bypass graft surgery (CABG). The primary outcome measure was death from any cause at 30 days of follow-up. FINDINGS Patients who were treated in the USA were significantly younger than those treated elsewhere (median 68 [IQR 59-75] vs 70 [62-76], p < 0.001), a smaller proportion had anterior infarction (49 vs 53%, p < 0.001), and they had a shorter time to treatment (mean 3.1 vs 3.3 h, p < 0.001). Aggressive diagnostic and therapeutic procedures were used more commonly in the USA than in the other countries: cardiac catheterisation (58 vs 23%); IABP (35 vs 7%); right-heart catheterisation (57 vs 22%); and ventilatory support (54 vs 38%). 483 (26%) of the patients treated in the USA underwent PTCA, compared with 82 (8%) patients in other countries. Patients who underwent revascularisation had better survival in all countries. Adjusted 30-day mortality was significantly lower among patients treated in the USA than among those treated elsewhere (50 vs 66%, p < 0.001). The difference in mortality remained at 1 year-56% of patients treated in the USA died versus 70% of patients treated elsewhere (hazard ratio 0.69 [95% CI 0.63-0.75], p < 0.001). INTERPRETATION 30-day and 1-year mortality was significantly lower among patients treated in the USA than among those treated in other countries. This difference in mortality may be due to the greater use of invasive diagnostic and therapeutic interventions in the USA.

A pooled analysis of coronary arterial patency and left ventricular function after intravenous thrombolysis for acute myocardial infarction

Individual studies of patency rates and left ventricular (LV) function after thrombolysis have generally been limited by small numbers of observations, wide confidence intervals, and limited numbers of time points. To obtain a more reliable estimate of patterns of patency and LV ejection fraction, a systemic overview of angiographic studies was performed after intravenous thrombolytic therapy. A total of 14,124 angiographic observations from 58 studies evaluating patency after no thrombolytic agent, streptokinase, standard dose tissue-type plasminogen activator (t-PA), accelerated dose t-PA, or anistreplase (anisoylated plasminogen streptokinase activator complex [APSAC]) were included. At 60 and 90 minutes, streptokinase had the lowest patency rates of 48% and 51%, respectively, standard dose t-PA and APSAC had similar intermediate rates of approximately 60% and 70%, and accelerated t-PA had the highest patency rates of 74% and 84%. By 2 to 3 hours and longer, the patency rates were similar for the various regimens. Reocclusion rates in studies including 1,172 patients randomized to t-PA versus a nonfibrin-specific agent were higher after t-PA (13.4% vs 8.0%, p = 0.002). Ten studies enrolling 4,088 patients treated with thrombolytic therapy versus control demonstrated a modest improvement in mean LV ejection fraction in the thrombolytic group at each of the times after thrombolytic therapy: hour 4, day 1, day 4, day 7 to 10, and day 10 to 28 after thrombolysis. By 4 days, mean ejection fraction was 53% versus 47% (thrombolytic vs control therapy, p < 0.01); by 10 to 28 days it was 54.1% and 51.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

ST-Segment Recovery Adds to the Assessment of TIMI 2 and 3 Flow in Predicting Infarct Wall Motion After Thrombolytic Therapy

BACKGROUND Early resolution of ST-segment elevation (ST-segment recovery) is associated with an improved outcome after infarction. Whether this relation is present in patients with Thrombolysis In Myocardial Infarction (TIMI) grade 2 or 3 flow (ie, patent) infarct-related arteries is not known. METHODS AND RESULTS To examine the associations between time to achieve stable 50% ST-segment recovery assessed by continuous ECG monitoring, infarct artery flow, and infarct zone wall motion (at 48 hours), we studied 134 patients who underwent angiography at 99 (interquartile range 92 to 110) minutes after commencing streptokinase, initiated within 12 hours of onset of symptoms of myocardial infarction. Patients with TIMI 2 or 3 flow who failed to achieve early stable ST-segment recovery (50% ST-segment recovery sustained for > or 4 hours with <100 microV change in the peak lead) by 60 or 90 minutes had a higher fraction of chords in the infarct zone >2 SD below normal wall motion (TIMI 2: 55.5% vs 15.3%, P=0.006; and 56.5% vs 26.8%, P=0.01, respectively; and TIMI 3: 48.8% vs 28.3%, P=0.07; and 51.8% vs 29.9%, P=0.03, respectively). Time to stable ST-segment recovery was a multivariate predictor of infarct zone wall motion (P=0.04) independent of TIMI flow grade and the time from symptom onset to streptokinase therapy. CONCLUSIONS In patients with TIMI 2 or 3 flow in infarct-related artery, early stable ST-segment recovery is associated with improved infarct zone wall motion at 48 hours. ST-segment recovery may provide additional information about the degree of myocyte reperfusion achieved in patients with a patent epicardial infarct-related artery after thrombolytic therapy.

Prophylactic lidocaine use in acute myocardial infarction: Incidence and outcomes from two international trials☆☆☆★★★

BACKGROUND Early meta-analyses suggested that prophylactic lidocaine use reduces ventricular fibrillation but increases mortality rates after acute myocardial infarction. We determined the frequency and effect on clinical outcomes with its use in the thrombolytic era. METHODS AND RESULTS We studied 43,704 patients enrolled in GUSTO-I or GUSTO-IIb who had ST-segment elevation, underwent thrombolysis, and survived at least 1 hour after enrollment. Odds ratios (OR) and confidence intervals (CI) were calculated for the risk of asystole, atrioventricular block, ventricular fibrillation, and ventricular tachycardia during hospitalization; for 24-hour, in-hospital, and 30-day mortality rates; and for 24-hour and 30-day mortality rates after adjustment for baseline predictors of death. In GUSTO-I and GUSTO-IIb, 16% and 3.5% of patients, respectively, received prophylactic lidocaine. They had a lower risk of death at 24 hours (OR 0.81, 95% CI 0.67 to 0.97) and trends toward lower odds of in-hospital death (OR 0.90, 95% CI 0.81 to 1.01) and death at 30 days (OR 0.92, 95% CI 0.82 to 1. 02). After adjustment for baseline characteristics, however, the odds of death were similar with or without lidocaine (OR 0.90 and 0. 97, respectively). Outside the United States, lidocaine was associated with higher incidences of all serious arrhythmias, but in US patients it conferred a lower likelihood of ventricular fibrillation and no increase in asystole, atrioventricular block, or mortality rates. CONCLUSIONS Prophylactic lidocaine use has decreased with the advent of thrombolysis, although its use may not be associated with increased mortality rates.

A Model for Predicting Mortality in Acute ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention Results From the Assessment of Pexelizumab in Acute Myocardial Infarction Trial

Background—Accurate models to predict mortality are needed for risk stratification in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods and Results—We examined 5745 patients with STEMI undergoing primary PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction Trial within 6 hours of symptom onset. A Cox proportional hazards model incorporating regression splines to accommodate nonlinearity in the log hazard ratio (HR) scale was used to determine baseline independent predictors of 90-day mortality. At 90 days, 271 (4.7%) of 5745 patients died. Independent correlates of 90-day mortality were (in descending order of statistical significance) age (HR, 2.03/10-y increments; 95% CI, 1.80 to 2.29), systolic blood pressure (HR, 0.86/10-mm Hg increments; 95% CI, 0.82 to 0.90), Killip class (class 3 or 4 versus 1 or 2) (HR, 4.24; 95% CI, 2.97 to 6.08), heart rate (>70 beats per minute) (HR, 1.45/10-beat increments; 95% CI, 1.31 to 1.59), creatinine (HR, 1.23/10-&mgr;mol/L increments >90 &mgr;mol/L; 95% CI, 1.13 to 1.34), sum of ST-segment deviations (HR, 1.25/10-mm increments; 95% CI, 1.11 to 1.40), and anterior STEMI location (HR, 1.47; 95% CI, 1.12 to 1.93) (c-index, 0.82). Internal validation with bootstrapping confirmed minimal overoptimism (c-index, 0.81). Conclusions—Our study provides a practical method to assess intermediate-term prognosis of patients with STEMI undergoing primary PCI, using baseline clinical and ECG variables. This model identifies key factors affecting prognosis and enables quantitative risk stratification that may be helpful in guiding clinical care and for risk adjustment for observational analyses.

Smoking status and outcome after primary coronary angioplasty for acute myocardial infarction.

BACKGROUND Because of the increased propensity of intracoronary thrombi to form in cigarette smokers, percutaneous transluminal angioplasty (PTCA) for acute myocardial infarction (AMI) may be less effective in smokers. We sought to determine the impact of smoking status on outcome after PTCA for AMI. METHODS Patients enrolled in the GUSTO IIb Angioplasty Substudy were randomly assigned to receive PTCA or tissue-plasminogen activator (tPA) for AMI. The interaction of smoking status (nonsmokers = 344, former smokers = 294, current smokers = 490) and treatment strategy with the occurrence of death, nonfatal reinfarction, or nonfatal, disabling stroke at 30 days was analyzed. Procedural success (residual stenosis <50% and Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) was also analyzed for patients who underwent PTCA (n = 444). RESULTS Among patients who underwent PTCA, nonsmokers had worse percent stenosis of the culprit lesion before reperfusion (P =.03) and more often had TIMI flow grade 0 (P <.05). Procedural success was more common in smokers (65.6%) than in former smokers (53.3%) and nonsmokers (52. 4%; P =.02), reflecting a higher rate of postprocedure TIMI 3 flow. PTCA was associated with a better 30-day outcome than tPA for current smokers (odds ratio [95% confidence interval] = 0.41 [0.19 to 0.88]), with a similar trend for former smokers (0.73 [0.34 to 1. 58]) and nonsmokers (0.77 [0.42 to 1.40]). At 6 months, smokers randomly assigned to PTCA also had fewer deaths and reinfarction (0. 58 [0.31 to 1.07]). CONCLUSIONS Although smoking status affects angiographic variables before and after PTCA for AMI, PTCA is associated with a better 30-day outcome than tPA regardless of smoking status and should be considered when readily available.

Immediate effects of milrinone on metabolic and sympathetic responses to exercise in severe congestive heart failure

A randomized, double-blind, placebo-controlled protocol was used to determine whether milrinone exerts an immediate effect on exercise performance in patients with severe congestive heart failure. In each of 14 patients with New York Heart Association class III or IV congestive heart failure, intravenous milrinone (mean 57 +/- 5 micrograms/kg) and placebo were randomly administered just before maximal progressive upright cycle ergometry. The duration of exercise was significantly longer with milrinone than with placebo treatment (placebo 11.0 +/- 0.6 minutes, milrinone 12.5 +/- 0.9 minutes, p = 0.01). Compared with placebo, milrinone caused a higher peak oxygen uptake (placebo 10.8 +/- 0.6 ml/kg/min, milrinone 12.4 +/- 0.7 ml/kg/min, p = 0.001) and oxygen uptake at the anaerobic threshold (placebo 7.8 +/- 0.4 ml/kg/min, milrinone 9.2 +/- 0.4 ml/kg/min, p = 0.001). At peak exercise intensity, systolic blood pressure (placebo 119 +/- 5 mm Hg, milrinone 131 +/- 5 mm Hg, p = 0.001) and heart rate (placebo 114 +/- 5 beats/min, milrinone 126 +/- 6 beats/min, p = 0.001) were both increased with milrinone. Likewise, at matched submaximal exercise intensities, heart rate (placebo 111 +/- 19 beats/min, milrinone 117 +/- 20 beats/min, p less than 0.05) and systolic blood pressure (placebo 116 +/- 19 mm Hg, milrinone 121 +/- 19 mm Hg, p = 0.04) were higher with milrinone; plasma norepinephrine (placebo 1,692 +/- 208 ng/liter, milrinone 1,320 +/- 216 ng/liter, p = 0.05) and blood lactate concentrations (placebo 2.2 +/- 0.2 mM, milrinone 1.9 +/- 0.2 mM, p less than 0.05) were lower.(ABSTRACT TRUNCATED AT 250 WORDS)

Treating menstruating women with thrombolytic therapy: Insights from the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO-I) trial

OBJECTIVES The purpose of this study was to examine the clinical implications of administering thrombolytic therapy to menstruating women with acute myocardial infarction. BACKGROUND Although anecdotal case reports have suggested that thrombolytic therapy is safe during menstruation, the risk of increased bleeding in menstruating women receiving such therapy is poorly defined. METHODS We identified menstruating women who received thrombolytic therapy by soliciting information on all North American women enrolled in the GUSTO-I trial and then collected additional information about them with use of a one-page data form. We compared the characteristics and outcomes of these women with other GUSTO-I patient populations, including all North American women below the median age of menopause, all women and all patients. RESULTS The median age of the 12 menstruating women was 46 years; 75% were cigarette smokers. The median hospital stay was 7 days, 2 fewer than the overall stay in GUSTO-I. None of these women died or had a stroke or severe bleeding. Three patients (25%) had moderate bleeding (vaginal in two patients [66%]) that required transfusion compared with 11% of all GUSTO-I patients and all North American premenopausal women (p = 0.13) and 17% of all female GUSTO-I patients (p = 0.47). Because of the small sample size of 12 women, the power was low (0.37) to detect the observed difference in moderate bleeding. The median nadir hematocrit was 33% in the menstruating women compared with 34% in the premenopausal women and all women. The median time from symptom onset to treatment for the 12 women was 3.7 h, which was 0.9 h longer than the overall median in the trial (p = 0.09). CONCLUSIONS Although there was no statistically significant increase in bleeding risk during menstruation, this fact may be a result of low statistical power rather than a lack of effect. Thus, the results suggest that there may be a clinically significant increase in the risk of moderate bleeding. Nevertheless, the GUSTO-I experience is consistent with the concept that the lifesaving benefit of thrombolytic therapy for acute myocardial infarction should generally not be withheld because of active menstruation.

Addition of nifedipine to maximal beta-blocker-nitrate therapy: Effects on exercise capacity and global left ventricular performance at rest and during exercise

Nifedipine is a potent coronary vasodilator in the resting state and an effective afterload-reducing agent. This study was undertaken because of the concern that the addition of nifedipine to beta-blocker therapy could produce serious untoward hemodynamic consequences. Although this combination is usually well tolerated, occasional reports suggest that the combination of nifedipine and beta-blocking agents may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina. Further, there is a need to know if the addition of nifedipine to therapy with maximally tolerated doses of long-acting nitrates and beta blockers would provide further symptomatic relief without excessive adverse effects. Finally, the effect of adjunctive nifedipine on global left ventricular performance at rest and during exercise was examined. Sixteen patients, all of whom had 3 or more episodes per week of angina pectoris despite therapy with long-acting nitrates and beta blockers, were selected. Radionuclide ventriculography was performed at rest and during exercise; global ejection fractions (EFs) were determined by manually tracing the left ventricular end-diastolic perimeter with an electronic cursor. In the first phase, beta blockers and nitrates were used; in the second phase nifedipine, 10 mg every 6 hours, was added and titrated to reduce systolic blood pressure at rest by at least 10 mm Hg or until intolerable adverse effects occurred. When nifedipine was added to therapy, the difference between global EF at rest and during exercise was reduced from - 0.15 to + 0.02 (p less than 0.00001); exercise duration was increased from 431 seconds to 532 (p less than 0.001), with only 8 patients limited by angina, compared with 16 during the initial therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise responses before and after long-term treatment with oral milrinone in patients with severe heart failure.

Administration of the positive inotropic vasodilator milrinone results in immediate improvement in the maximal and submaximal metabolic responses to exercise. To determine whether these effects persist during long-term therapy, nine patients with severe congestive heart failure were evaluated by upright maximal exercise testing before therapy (baseline), after 10 +/- 1 weeks of oral therapy, and during double-blind, placebo-controlled readministration of intravenous milrinone after withdrawal of oral drug for 24 hours. During long-term oral therapy, maximal oxygen uptake was unchanged (baseline 792 +/- 72 ml per minute, oral therapy 820 +/- 83 ml per minute), whereas the anaerobic threshold was increased significantly from 570 +/- 53 ml per minute to 681 +/- 61 ml per minute. After withdrawal of milrinone, maximal oxygen uptake and anaerobic threshold decreased significantly; subsequent intravenous administration caused significant increases in maximal oxygen uptake and anaerobic threshold, back to the values measured during oral therapy. After oral milrinone withdrawal, maximal oxygen uptake decreased below baseline values, suggesting progression of the underlying disease. The anaerobic threshold expressed as a percent of maximal oxygen uptake was significantly increased during oral therapy (baseline 73 +/- 2 percent, oral therapy 84 +/- 2 percent) and remained significantly increased after drug withdrawal, suggesting a peripheral circulatory effect. These results indicate that in selected patients with severe congestive heart failure, milrinone exerts persistent effects on the metabolic responses to both maximal and submaximal exercise. Because of progressive deterioration in exercise capacity during long-term oral therapy, the effects of milrinone may not be apparent unless it is withdrawn. The relation of milrinone therapy to disease progression is not known.