Werf, F.J.J. van de

Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years (Article)

2012-02-16T00:00:00Z

Background: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15 years. Methods: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. Results: Over time, in-hospital and discharge use of thienopyridines (p = 0.001), statins (p < 0.0001), and angiotensin-converting enzyme inhibitors (p < 0.0001) increased, and hospital length-of-stay decreased (p = 0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p = 0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p = 0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p = 0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p = 0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p = 0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p = 0.539). Conclusions: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15 years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events (from the BRAVO Trial) (Article)

2008-11-15T00:00:00Z

Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (<162 mg vs ≥162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was employed because propensity analysis was not feasible. Compared with lower aspirin doses, higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%, respectively; log rank chi-square 8.6, p = 0.0034). Higher aspirin dose remained independently predictive of lower all-cause mortality in a multivariable Cox proportional hazards model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p = 0.037). However, there was no significant difference in the incidence of the composite endpoint death, nonfatal myocardial infarction, or nonfatal stroke (6.1% vs 6.2%, p = 0.74). Higher aspirin dose was a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12 to 1.55, p = 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin doses of ≥162 mg/day may be more beneficial than those <162 mg/day at preventing death.

Creatine kinase-MB elevation after coronary artery bypass grafting surgery in patients with non-ST-segment elevation acute coronary syndromes predict worse outcomes: Results from four large clinical trials (Article)

2007-02-01T00:00:00Z

Aims: To assess the significance of creatine kinase (CK)-MB elevations in outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who have undergone coronary artery bypass grafting (CABG) surgery. Methods and results: This analysis includes data from 26 465 patients with NSTE ACS enrolled in four major trials. In total, 4626 (17.5%) of patients had CABG within 30 days. Patients were excluded if CK-MB was elevated within 24 h before surgery and there was no CK-MB measured after surgery. Overall, 4401 patients were included in these analyses. The incidence of mortality increased with peak CK-MB ratios of 0-1, > 1-3, > 3-5, > 5-10, and > 10 x the upper limit of normal measured at the local lab (P < 0.001 across categories): 1.1, 2.8, 2.4, 3.1, and 10.8% in hospital; 1.1, 3.0, 2.9, 3.5, and 10.2% at 30 days; and 1.6, 4.4, 4.7, 6.0, and 10.9% at 180 days. Multivariable predictors of 6-month mortality included age, heart rate and randomization, peak CK-MB ratio, time to CABG, prior angina, signs of congestive heart failure and randomization, three- and two-vessel coronary disease, enrolment infarction, ST-segment depression at enrolment, female sex, experimental treatment, and systolic blood pressure. Conclusion: CK-MB elevations after CABG are independently associated with increased risk of mortality in patients with NSTE ACS.

Outcomes of patients with acute coronary syndromes and prior percutaneous coronary intervention: a pooled analysis of three randomized clinical trials. (Article)

2005-01-01T00:00:00Z

AIMS: We sought to characterize the outcomes of patients with a prior percutaneous coronary intervention (PCI) who presented with a non-ST-segment elevation acute coronary syndrome (ACS). METHODS AND RESULTS: We analysed the 30 and 180 day outcomes of 3012 patients with prior PCI and 21 154 patients without prior PCI enrolled in three randomized ACS trials (GUSTO IIb, PURSUIT, and PARAGON-B). The median (25th, 75th percentile) interval between the prior PCI and randomization was 647 (123, 1585) days. Patients with prior PCI had significantly more adverse baseline clinical characteristics, left ventricular dysfunction, and multi-vessel coronary artery disease. After adjusting for baseline characteristics and treatment, we found that patients with prior PCI had a significantly lower mortality rate at 30 days [hazard ratio (HR), 0.60; 95% confidence interval (CI), 0.45-0.80; P=0.0006] and 180 days (HR, 0.81; 95% CI, 0.66-0.98; P=0.029). However, no difference was observed in the composite of death or myocardial infarction (MI) at 30 days (HR, 0.95; 95% CI, 0.83-1.08; P=0.42) or 180 days (HR, 1.01; 95% CI, 0.90-1.13; P=0.90). Patients with prior PCI had a higher rate of MI at 180 days (13.3 vs. 12.0%; P=0.045). Prior-PCI patients had lower incidences of in-hospital cardiogenic shock, congestive heart failure (CHF), and atrial fibrillation. CONCLUSION: Patients with prior PCI who present with non-ST-segment elevation ACS have a lower mortality rate than those without prior PCI.

A dose-finding study of Fondaparinux in patients with non-ST segment elevation acute coronary syndromes (Article)

2004-06-16T00:00:00Z

OBJECTIVES: In this dose-finding study, we sought to compare fondaparinux with enoxaparin in patients with acute coronary syndromes (ACS). BACKGROUND: Fondaparinux is a synthetic pentasaccharide that selectively inhibits activated clotting factor X. It has been demonstrated as effective in preventing thromboembolic complications in orthopedic surgery. METHODS: Four doses fondaparinux (2.5, 4, 8, or 12 mg once daily) and enoxaparin (1 mg/kg twice daily) were compared, both given for three to seven days, in patients with ACS without persistent ST-segment elevation. RESULTS: The rates of the combined primary end point of death, myocardial infarction, or recurrent ischemia after nine days were 27.9%, 35.9%, 34.7%, 30.3%, and 35.7% in patients allocated to fondaparinux doses of 2.5, 4, 8, and 12 mg and enoxaparin, respectively (p = NS). In the per-protocol analysis (929 patients who received adequate study drug and had adequate ST-segment monitoring), these figures were 30.0%, 43.5%, 41.0%, 34.8%, and 40.2%. Again, no dose response was observed. The lowest event rates were observed in the 2.5-mg fondaparinux group, which had significantly lower rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per-protocol analysis (p < 0.05). Bleeding rates were low and not different among the patient groups. No differences were observed in fondaparinux concentrations in patients with or without death, myocardial infarction, recurrent ischemia, or bleeding events. CONCLUSIONS: This dose-finding study revealed no dose response for different fondaparinux doses ranging from 2.5 to 12 mg subcutaneously and suggests that the efficacy and safety of fondaparinux may be similar to that of enoxaparin. Further studies with fondaparinux in ACS might include the lowest dose (2.5 mg) investigated in this study.

Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes. (Article)

2004-02-01T00:00:00Z

AIM: To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). METHODS AND RESULTS: Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017). CONCLUSIONS: Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.

Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease (Article)

2003-07-01T00:00:00Z

BACKGROUND: This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients. METHODS AND RESULTS: Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban. CONCLUSIONS: Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Oral glycoprotein IIb/IIIa receptor inhibitors in patients with cardiovascular disease: why were the results so unfavourable. (Article)

2002-03-01T00:00:00Z

Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major ranodmised clinical trials (Article)

2002-01-19T00:00:00Z

BACKGROUND: Platelet glycoprotein IIb/IIIa inhibitors have been shown to reduce cardiac complications in patients undergoing percutaneous coronary intervention. The clinical efficacy of these drugs in acute coronary syndromes, however, is still unclear. We did a meta-analysis of all large randomised trials designed to study the clinical efficacy and safety of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes who were not routinely scheduled to undergo early coronary revascularisation. METHODS: Inclusion criteria were: randomisation of patients with acute coronary syndromes but without persistent ST elevation; comparison of a glycoprotein IIb/IIIa inhibitor with placebo or control therapy; non-recommendation of early coronary revascularisation during study-drug infusion; and enrollment of at least 1000 patients. Data on individual patients were obtained from all participants in these trials. FINDINGS: Six trials, enrolling 31402 patients, fulfilled the inclusion criteria. 30 days after randomisation, 3530 (11.2%) patients died or developed a myocardial infarction. At 30 days, a 9% reduction in the odds of death or myocardial infarction was seen with glycoprotein IIb/IIIa inhibitors compared with placebo or control (10.8% [1980/18297] vs 11.8% [1550/13105] events; odds ratio 0.91 [95% CI 0.84-0.98]; p=0.015). The relative treatment benefit was similar in subgroups of patients according to important clinical baseline characteristics; hence, the absolute treatment benefit was largest in high-risk patients. An unexpected and significant interaction was seen between sex and allocated treatment, with a treatment benefit in men (0.81 [0.75-0.89] but not in women (1.15 [1.01-1.30]). However, once patients were stratified according to troponin concentration, there was no evidence of a sex difference in treatment response, and a risk reduction was seen in men and women with raised troponin concentrations. Major bleeding complications were increased by glycoprotein IIb/IIIa inhibitors (2.4% [445/18297] vs 1.4% [180/13105]; p<0.0001), but intracranial bleeding was not (16 [0.09%] vs 8 [0.06%]; p=0.40). INTERPRETATION: Glycoprotein IIb/IIIa inhibitors reduce the occurrence of death or myocardial infarction in patients with acute coronary syndromes not routinely scheduled for early revascularisation. The event reduction is greatest in patients at high risk of thrombotic complications. Treatment with a glycoprotein IIb/IIIa inhibitor might therefore be considered especially in such patients early after admission, and continued until a decision about early coronary revascularisation has been made.

Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation: incidence, predictors, and outcomes (Article)

2002-01-01T00:00:00Z

BACKGROUND: The prognosis of ventricular arrhythmias among patients with non-ST-elevation acute coronary syndromes is unknown. We studied the incidence, predictors, and outcomes of sustained ventricular arrhythmias in 4 large randomized trials of such patients. METHODS AND RESULTS: We pooled the datasets of the Global Use of Streptokinase and tPA for Occluded Arteries (GUSTO)-IIb, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON)-A, and PARAGON-B trials (n=26 416). We identified independent predictors of ventricular fibrillation (VF) and ventricular tachycardia (VT) and compared the 30-day and 6-month mortality rates of patients who did (n=552) and did not (n=25 864) develop these arrhythmias during the index hospitalization. Independent predictors of in-hospital VF included prior hypertension, chronic obstructive pulmonary disease, prior myocardial infarction, and ST-segment changes at presentation. Except for hypertension, these variables also independently predicted in-hospital VT. In Cox proportional-hazards modeling, in-hospital VF and VT were independently associated with 30-day mortality (hazard ratio [HR], 23.2 [95% CI, 18.1 to 29.8] for VF and HR, 7.6 [95% CI, 5.5 to 10.4] for VT) and 6-month mortality (HR, 14.8 [95% CI, 12.1 to 18.3] for VF and HR, 5.0 [95% CI, 3.8 to 6.5] for VT). These differences remained significant after excluding patients with heart failure or cardiogenic shock and those who died <24 hours after enrollment. CONCLUSIONS: Despite the use of effective therapies for non-ST-elevation acute coronary syndromes, ventricular arrhythmias in this setting are associated with increased 30-day and 6-month mortality. More effective therapies are needed to improve the survival of patients with these arrhythmias.

American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. (Article)

2001-12-17T00:00:00Z

Argatroban and alteplase in patients with acute myocardial infarction: the ARGAMI study (Article)

2000-01-01T00:00:00Z

ARGAMI was designed to assess safety and efficacy of argatroban compared with heparin as adjunctive treatment to alteplase in the treatment of patients with acute myocardial infarction. ARGAMI consisted of an open-dose finding study (35 patients) followed by a placebo-controlled study with double dummy technique and 2:1 (argatroban:heparin) randomization. An argatroban dosage of 100 microg/kg bolus plus 3 microg/kg/min infusion for 72 hours was selected for the randomized study in which 82 patients were allocated to argatroban and 45 to heparin (5000 U intravenous bolus, 1000 U/h infusion). Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) after 90 minutes was obtained in 62 patients (76%) allocated to argatroban versus 37 patients (82%) allocated to heparin (p=ns). Angiograms after 24 hours and 5 to 10 days showed low reocclusion rates in both groups. Bleeding complications were observed in 16 patients allocated to argatroban (19.5%) and in 9 patients allocated to heparin (20.0%). One patient allocated to heparin suffered from hemorrhage stroke. Argatroban, given as adjunctive treatment to alteplase, is tolerated well in patients with acute myocardial infarction. Safety and efficacy of the combination alteplase and argatroban (with this dose regimen) are similar to those of alteplase and heparin.

Extended Mortality Benefit of Early Postinfarction Reperfusion (Article)

1998-01-01T00:00:00Z

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.

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

1997-01-20T00:00:00Z

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.

Thrombolysis-induced coronary reperfusion causes acute and massive interstitial release of cardiac muscle cell proteins (Article)

1997-01-01T00:00:00Z

OBJECTIVE: Reperfusion of the infarct-related artery in patients with acute myocardial infarction limits infarct size, but also causes accelerated release into plasma of cardiac tissue proteins. The latter effect could reflect either enhanced protein washout from the heart or abrupt disruption of myocyte membranes. The present study indicates that the latter mechanism prevails. METHODS: In 26 patients, patency of the infarct-related artery was determined by coronary angiography 90 min and 5-7 days after thrombolytic treatment. Continuous electrocardiography was performed during the first 24 h after admission. Cumulative release of myoglobin (Mb) and creatine kinase (CK) into plasma was calculated from frequently sampled plasma concentrations. RESULTS: In patients with a patent infarct-related artery after 90 min, onset of a rapid (> 50%) decrease in ST-vector magnitude coincided with an equally rapid increase in QRS-vector magnitude, and with a sudden onset of release into plasma of Mb as well as CK. In these patients, a maximal initial release rate was observed and cumulative release conformed closely to a simple model for sudden interstitial liberation of proteins. In contrast, protein release started more gradually and could not be fitted to this model, in patients with persistent occlusion of the infarct-related artery at 90 min and absence of ST-vector normalisation. CONCLUSIONS: Previous studies have demonstrated significant myocardial salvage by timely reperfusion therapy. Nevertheless, this study indicates that the moment of recanalisation of the infarct-related artery coincides with sudden and massive disruption of myocyte membranes. Attenuation of this effect, if possible, could further improve the benefits of reperfusion therapy.

Perspectives on Large-Scale Cardiovascular Clinical Trials for the New Millenium (Article)

1997-01-01T00:00:00Z

Time From Symptom Onset to Treatment and Outcomes after Thrombolytic Therapy (Article)

1996-06-01T00:00:00Z

OBJECTIVES: This study sought to examine the relations among patient characteristics, time to thrombolysis and outcomes in the international GUSTO-I trial. BACKGROUND: Studies have shown better left ventricular function and decreased infarct size as well as increased survival with earlier thrombolysis, but the relative benefits of various thrombolytic agents with earlier administration are uncertain. METHODS: We evaluated the relations of baseline characteristics to three prospectively defined time variables: symptom onset to treatment, symptom onset to hospital arrival (presentation delay) and hospital arrival to treatment (treatment delay). We also examined the relations of delays to clinical outcomes and to the relative 30-day mortality benefit with accelerated tissue-type plasminogen activator (t-PA) versus streptokinase. RESULTS: Female, elderly, diabetic and hypertensive patients had longer delays at all stages. Previous infarction or bypass surgery was an additional risk factor for treatment delay. Early thrombolysis was associated with lower overall mortality rate (< 2 h, 5.5%; > 4 h, 9.0%), but no additional relative benefit resulted from earlier treatment with accelerated t-PA versus streptokinase (p = 0.38). Longer presentation and treatment delays were both associated with increased mortality rate (presentation delay < 1 h, 5.6% and > 4 h, 8.6%; treatment delay < 1 h, 5.4%, and > 90 min, 8.1%). As time to treatment increased, the incidence of recurrent ischemia or reinfarction decreased, but the rates of shock, heart failure and stroke increased. CONCLUSIONS: Earlier treatment resulted in better outcomes, regardless of thrombolytic strategy. Elderly, female and diabetic patients were treated later, adding to their already substantial risk.

Predictors of 30-Day Mortality in the Era of Reperfusion for Acute Myocardial Infarction (Article)

1995-01-01T00:00:00Z

BACKGROUND: Despite remarkable advances in the treatment of acute myocardial infarction, substantial early patient mortality remains. Appropriate choices among alternative therapies and the use of clinical resources depend on an estimate of the patient's risk. Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk. Prior studies to define prognosis either were performed before widespread use of thrombolysis or were limited in sample size or spectrum of data. Using the large population of the GUSTO-I trial, we performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy. METHODS AND RESULTS: For the 41,021 patients enrolled in GUSTO-I, a randomized trial of four thrombolytic strategies, relations between clinical descriptors routinely collected at initial presentation, and death within 30 days (which occurred in 7% of the population) were examined with both univariable and multivariable analyses. Variables studied included demographics, history and risk factors, presenting characteristics, and treatment assignment. Risk modeling was performed with logistic multiple regression and validated with bootstrapping techniques. Multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile (< 45 years) and 20.5% in patients > 75 (adjusted chi 2 = 717, P < .0001). Other factors most significantly associated with increased mortality were lower systolic blood pressure (chi 2 = 550, P < .0001), higher Killip class (chi 2 = 350, P < .0001), elevated heart rate (chi 2 = 275, P < .0001), and anterior infarction (chi 2 = 143, P < .0001). Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data. Other significant though less important factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease. Combining prognostic variables through logistic regression, we produced a validated model that stratified patient risk and accurately estimated the likelihood of death. CONCLUSIONS: The clinical determinants of mortality in patients treated with thrombolytic therapy within 6 hours of symptom onset are multifactorial and the relations complex. Although a few variables contain most of the prognostic information, many others contribute additional independent prognostic information. Through consideration of multiple characteristics, including age, medical history, physiological significance of the infarction, and medical treatment, the prognosis of an individual patient can be accurately estimated.

Benefit of Thrombolytic Therapy is Sustained Throughout Five Years and Is Related to TIMI Perfusion Grade 3 But Not Grade 2 Flow at Discharge (Article)

1995-01-01T00:00:00Z

BACKGROUND: Long-term follow-up in patients treated with thrombolysis for acute myocardial infarction thus far has been reported in a few studies only, and no long-term follow-up is available for patients who underwent additional percutaneous transluminal coronary angioplasty (PTCA). This report describes 5-year survival as collected in patients who received placebo, recombinant tissue plasminogen activator (rTPA), or rTPA with additional immediate PTCA in two European Cooperative Study Group trials. Determinants for long-term survival were assessed in 1043 patients discharged alive. METHODS AND RESULTS: Five-year follow-up information on mortality was collected. Hospital mortality was lower after rTPA than placebo (2.5% versus 5.7%, P = .04) and higher after rTPA with immediate PTCA compared with rTPA without additional intervention (6.0% versus 2.2%, P = .07). Of the 1043 hospital survivors, data were available for 923 patients, of whom 109 died. In the placebo group, mortality after hospital discharge was 10.7% versus 11.0% in the comparative rTPA group. The patients treated with rTPA and immediate PTCA had a mortality rate of 10.5% versus 8.9% in the rTPA group without PTCA (all P = NS). Significant determinants of mortality in multivariate proportional hazards analysis were enzymatic infarct size, indicators of residual left ventricular function, number of diseased vessels and TIMI perfusion grade at discharge. Patients with TIMI grade 2 flow had mortality rates similar to those with TIMI flow grades 0 and 1, while prognosis was better in patients with TIMI flow grade 3. CONCLUSIONS: The initial in-hospital benefit of thrombolysis with intravenous rTPA is maintained throughout 5 years, with no early or late beneficial effect of systematic immediate PTCA. Enzymatic infarct size, left ventricular function, and extent of coronary artery disease are predictors for long-term survival. TIMI perfusion grade 2 at discharge should be considered as an inadequate result of therapy.

An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction (Article)

1993-01-01T00:00:00Z

BACKGROUND: The relative efficacy of streptokinase and tissue plasminogen activator and the roles of intravenous as compared with subcutaneous heparin as adjunctive therapy in acute myocardial infarction are unresolved questions. The current trial was designed to compare new, aggressive thrombolytic strategies with standard thrombolytic regimens in the treatment of acute myocardial infarction. Our hypothesis was that newer thrombolytic strategies that produce earlier and sustained reperfusion would improve survival. METHODS: In 15 countries and 1081 hospitals, 41,021 patients with evolving myocardial infarction were randomly assigned to four different thrombolytic strategies, consisting of the use of streptokinase and subcutaneous heparin, streptokinase and intravenous heparin, accelerated tissue plasminogen activator (t-PA) and intravenous heparin, or a combination of streptokinase plus t-PA with intravenous heparin. ("Accelerated" refers to the administration of t-PA over a period of 1 1/2 hours--with two thirds of the dose given in the first 30 minutes--rather than the conventional period of 3 hours.) The primary end point was 30-day mortality. RESULTS: The mortality rates in the four treatment groups were as follows: streptokinase and subcutaneous heparin, 7.2 percent; streptokinase and intravenous heparin, 7.4 percent; accelerated t-PA and intravenous heparin, 6.3 percent, and the combination of both thrombolytic agents with intravenous heparin, 7.0 percent. This represented a 14 percent reduction (95 percent confidence interval, 5.9 to 21.3 percent) in mortality for accelerated t-PA as compared with the two streptokinase-only strategies (P = 0.001). The rates of hemorrhagic stroke were 0.49 percent, 0.54 percent, 0.72 percent, and 0.94 percent in the four groups, respectively, which represented a significant excess of hemorrhagic strokes for accelerated t-PA (P = 0.03) and for the combination strategy (P < 0.001), as compared with streptokinase only. A combined end point of death or disabling stroke was significantly lower in the accelerated-tPA group than in the streptokinase-only groups (6.9 percent vs. 7.8 percent, P = 0.006). CONCLUSIONS: The findings of this large-scale trial indicate that accelerated t-PA given with intravenous heparin provides a survival benefit over previous standard thrombolytic regimens

Confronting the issues of patient safety and investigator conflict of interest in an international clinical trial of myocardial reperfusion (Article)

1992-01-01T00:00:00Z

The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial is a large scale international trial of new myocardial reperfusion strategies. The primary hypothesis is that early and sustained coronary artery recanalization will be associated with a significant reduction in mortality. The four regimens that are being tested are 1) streptokinase with subcutaneous heparin; 2) streptokinase with intravenous heparin; 3) accelerated recombinant tissue-type plasminogen activator (rt-PA) with intravenous heparin; and 4) combination streptokinase, rt-PA and intravenous heparin. The planned recruitment of 41,600 patients in 1,500 sites from 15 countries is expected to be completed by December 1992 and will enable detection of a 15% reduction or 1% absolute difference in mortality compared with that associated with standard therapy (streptokinase and subcutaneous heparin). In designing the trial, two important issues were directly addressed. First, a strategy was developed to provide assurance of patient safety during large scale investigational use of an aggressive thrombolytic regimen. This includes fascimile transmission of a one-page safety summary form to the Data Coordinating Center within 24 h of death or discharge, acceptance of the concept of "net clinical benefit" and close surveillance of the trial's progress by the independent Data and Safety Monitoring Committee. Second, to avoid potential conflict of interest beyond elimination of any position of financial equity, the Steering Committee unanimously voted to prohibit any honoraria for speaking engagements, payment for consultancy or travel or reimbursement of any kind from any of the five corporate sponsors until 1 year after publication of the results. Incorporation of these approaches may facilitate the design of future large scale randomized trials in cardiovascular medicine.

Recombinant tissue-type plasminogen activator and immediate angioplasty in acute myocardial infarction. (Article)

1992-01-01T00:00:00Z

BACKGROUND. The European Cooperative Study Group conducted two randomized trials in patients with suspected myocardial infarction to assess the effect of 100 mg single-chain recombinant tissue-type plasminogen activator (rt-PA, alteplase) on enzymatic infarct size, left ventricular function, morbidity and mortality relative to placebo (alteplase/placebo trial) and to assess the effect of immediate percutaneous transluminal coronary angioplasty (PTCA) in addition to alteplase (alteplase/PTCA trial). One-year follow-up results are reported. METHODS AND RESULTS. In the alteplase/placebo trial, 721 patients with chest pain of less than 5 hours and extensive ST-segment elevation were allocated at random to 100 mg alteplase or placebo (double-blind) over 3 hours. In the alteplase/PTCA trial, 367 similar patients received alteplase and subsequently were allocated at random to immediate coronary angiography and angioplasty of the infarct-related vessel or control. All patients received aspirin and intravenous heparin. In the alteplase/placebo trial, mortality during the first year was reduced by 36% with alteplase (from 9.3% to 5.6%; difference, -3.7%; 95% confidence interval, -7.5% to 0.2%). Revascularization was performed more frequently after alteplase, and more patients in the alteplase group were in New York Heart Association functional class I or II. Reinfarction tended to occur more frequently after alteplase than after placebo. In the alteplase/PTCA trial, reinfarction was less common after immediate PTCA, and revascularization procedures were less frequent. However, this benefit was offset by a high rate of immediate reocclusion and early recurrent ischemia and by higher mortality at 1 year (9.3% versus 5.4%; difference, 3.9%; 95% confidence interval, -1.5% to 9.2%) in the invasive group. In a multivariate analysis of 1,043 hospital survivors, mortality after discharge was related to coronary anatomy, left ventricular function, age, and previous infarction but not to initial treatment allocation. Reinfarction after hospital discharge tended to be more common after alteplase and related to coronary anatomy. CONCLUSIONS. Benefit from treatment with alteplase, heparin, and aspirin is not diminished at 1 year. Routine immediate PTCA does not confer additional benefit. Prognosis after hospital discharge mainly is determined by coronary anatomy and residual left ventricular function and is unrelated to initial treatment assignment.

Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty (Article)

1988-01-30T00:00:00Z

A randomised trial of 367 patients with acute myocardial infarction was performed to determine whether an invasive strategy combining thrombolysis with recombinant tissue-type plasminogen activator (rTPA), heparin, and acetylsalicylic acid, and immediate percutaneous transluminal coronary angioplasty (PTCA) would be superior to a noninvasive strategy with the same medical treatment but without immediate angiography and PTCA. Intravenous infusion of 100 mg rTPA was started within 5 h after onset of symptoms (median 156 min). Angiography was performed 6-165 min later in 180 out of 183 patients allocated to the invasive strategy; 184 patients were allocated to the non-invasive strategy. Immediate PTCA reduced the percentage stenosis of the infarct-related segment, but this was offset by a high rate of transient (16%) and sustained (7%) reocclusion during the procedure and recurrent ischaemia during the first 24 h (17%). The clinical course was more favourable after non-invasive therapy, with a lower incidence of recurrent ischaemia within 24 h (3%), bleeding complications, hypotension, and ventricular fibrillation. Mortality at 14 days was lower in patients allocated to non-invasive treatment (3%) than in the group allocated to invasive treatment (7%). No difference between the treatment groups was observed in infarct size estimated from myocardial release of alpha-hydroxybutyrate dehydrogenase or in left ventricular ejection fraction after 10-22 days. Since immediate PTCA does not provide additional benefit there seems to be no need for immediate angiography and PTCA in patients with acute myocardial infarction treated with rTPA.

Thrombolysis with rt-PA in acute myocardial infarction: no additional benefit of immediate PTCA (Miscellaneous)

1988-01-30T00:00:00Z