Use of composite endpoints in thrombolysis trials of acute myocardial infarction

Although preventing early mortality following acute myocardial infarction (MI) is the most important goal of thrombolytic therapy, insistence on its use as the only or principal endpoint in trials of acute MI will limit the number of new thrombolytic-antithrombotic regimens that can be tested, and thus may inhibit future progress of this important area of cardiovascular therapeutics. Trials of thrombolytic therapy over the past decade, as discussed in this article, have demonstrated that: (1) thrombolytic therapy improves both mortality and intermediate endpoints, and (2) intermediate nonfatal endpoints are strongly linked to long-term mortality. Taken together, these facts provide strong evidence that intermediate nonfatal events can be used as valid endpoints in future trials of thrombolytic therapy. The unsatisfactory outcome composite endpoint, which incorporates mortality and important intermediate endpoints, will make it possible to compare innovative new regimens in much smaller trials. Ultimately, both of these approaches (i.e., megatrials using a mortality endpoint and smaller trials utilizing a composite unsatisfactory outcome endpoint) can be used in a complementary fashion. A new regimen could first be tested using the unsatisfactory outcome endpoint; if it showed particular promise, it could then become a candidate for testing in a megatrial. Conversely, if it did not prove better than standard regimens, futile research in tens of thousands of patients might be prevented. Thus, the use of composite endpoints will expand the number of new thrombolytic-antithrombotic regimens that can be tested and, it is hoped, accelerate progress in the treatment of acute MI.     

Direct coronary angioplasty versus thrombolysis in the acute phase of myocardial infarction--inpatient outcome

Both thrombolysis and percutaneous transluminal coronary angioplasty (PTCA) are effective methods for the treatment of acute myocardial infarction (AMI). In our centre we perform primary PTCA during the available schedule of the hemodynamics laboratory. In this article we compare the predischarge evolution of patients submitted to each therapeutic procedure. From January 1996 to June 1997, 298 patients were admitted with the diagnosis of AMI. Eighty-four patients (28%) were thrombolysed (TB group) and 30 patients (10%) underwent primary PTCA (PTCA group). There were no significant differences among the two groups concerning demographic characteristics: age (61 +/- 13--TB and 59 +/- 12 years--PTCA); sex (male 81%--TB; 83%--PTCA), risk factors and previous cardiac history. The mean time since the onset of symptoms until arrival at the hospital was 156 +/- 156 minutes for TB and 202 +/- 210 minutes for PTCA (p < 0.02). The delay since admission until the beginning of treatment was 100 +/- 88 minutes for TB and 119 +/- 142 minutes for PTCA. The primary success rate of PTCA was 94% and there were no complications during the procedure. During the hospital stay, 12 patients developed post-infarction angina in the TB group and two patients in the PTCA group; in 15 patients of the TB group a revascularization procedure was performed (surgery in 5 and PTCA in 10 patients); one patient suffered reinfarction in the TB group. Two patients of the TB group (2.4%) had intracranial hemorrhage; the in-hospital mortality was 9.5% in the TB group and 3.3% in the PTCA (p < 0.001). The mean in-hospital stay was 11 +/- 5.6 in the TB group and 7.8 +/- 2.5 days in the PTCA group (p = 0.055). In our experience, primary PTCA in AMI appeared to be a safe procedure with lower occurrence of coronary events and hemorrhagic complication, with an earlier hospital discharge when compared to thrombolysis.     

Analysis of reperfusion by thrombolysis of the artery responsible for acute myocardial infarction

OBJECTIVE: To analyze the role of the culprit coronary artery in myocardial infarction, its evolution and mortality. And to correlate with clinical criteria of reperfussion. MATERIALS AND METHODS: We included patients with clinical diagnosis of acute myocardial infarction (MI) treated with thrombolytic therapy, and coronariography. We used the TIMI study angiographic scale to evaluate the level of permeability of the culprit artery. RESULTS: Of 473 patients with of acute MI; coronariography was made in 377. The most frequent culprit vessel was anterior descending artery in 168 patients (45%) and right coronary artery in 139 patients (36%). In 276 patients the culprit vessel was permeable (73%). Of them in 30 patients, had TIMI 1 alterations, TIMI 2 in 97 patients, had TIMI 3 in 148 patients, only 102 patients had TIMI 0. In anterior MI the most frequent reperfussion arrhythmia was ventricular ectopic beats followed by slow ventricular tachycardia and ventricular tachycardia in 54%, ventricular fibrillation was observed only in six patients, of whom TIMI scale was 2 and 3 in five patients. In inferior MI, ventricular ectopic beats and slow ventricular tachycardia was seen in 25% of patients. In patients with permeable culprit artery we observed significant depression of ST segment, (159 patients, 42%), and significant increase in CK-MB levels, seen in 191 patients (51%). In the group of patients with total occlusion of the culprit artery, twenty-one (30%) had left ventricular disfuntion, and only six of them were in cardiogenic shock. In the group of patients with permeable culprit artery only two percent had cardiogenic shock. Therefore the analysis of the clinical evolution is the maia marker to take into consideration to send patients to early coronary arteriography with the objective to look for other therapeutic alternatives.     

Randomized trial of direct coronary angioplasty versus intravenous streptokinase in acute myocardial infarction

OBJECTIVES: The objective of this study was to obtain preliminary data on the relative clinical utility of direct coronary angioplasty compared with that of intravenous thrombolytic therapy for patients with acute myocardial infarction. BACKGROUND: The relative merits of intravenous thrombolytic therapy and direct coronary angioplasty as treatment for acute myocardial infarction are incompletely understood, and randomized trials of these treatments have been extremely limited. METHODS: One hundred patients with ST segment elevation presenting to a single high volume interventional center within 6 h of the onset of chest pain were randomized to receive either streptokinase (1.2 million U intravenously over 1 h) or immediate catheterization and direct coronary angioplasty. Patients were excluded for age > or = 75 years, prior bypass surgery, Q wave infarction in the region of ischemia or excessive risk of bleeding. All patients were then treated with aspirin (325 mg orally/day) and heparin (1,000 U intravenously/h) for 48 h until catheterization was performed to determine the primary study end point, namely, infarct-related artery patency at 48 h. Secondary end points were in-hospital death, left ventricular ejection fraction at 48 h and time to treatment. RESULTS: There was no difference in the baseline characteristics of the two treatment groups. Overall patient age was 56 +/- 10 years, 83% of patients were male, 11% had prior infarction, 40% had anterior infarction and 97% were in Killip class I or II. Although time to treatment was delayed in the angioplasty group (238 +/- 112 vs. 179 +/- 98 min, p = 0.005), there was no difference in 48-h infarct-related artery patency or left ventricular ejection fraction (patency 74% vs. 80%; ejection fraction 59 +/- 13% vs. 57 +/- 13%; angioplasty vs. streptokinase, p = NS for both). There were no major bleeding events, and the mortality rate with angioplasty (6%) and streptokinase (2%) did not differ (p = NS). CONCLUSIONS: These results suggest that intravenous thrombolytic therapy might be preferred over coronary angioplasty for most patients because of the often shorter time to treatment.     

Intravascular ultrasound assessment of direct percutaneous transluminal coronary angioplasty in patients with acute myocardial infarction

BACKGROUND: Acute myocardial infarction is caused by sudden thrombotic occlusion of the coronary artery due to a previous rupture of atherosclerotic plaque. OBJECTIVE: To use intracoronary ultrasound measurements to evaluate lumen and plaque changes in patients with acute myocardial infarction. METHODS: Patients (n = 103) with acute myocardial infarction who had been scheduled to undergo primary percutaneous transluminal coronary angioplasty (PTCA) were selected. Both before and after successful coronary angioplasty, intracoronary 30 MHz ultrasound studies were performed using a 3.5F monorail catheter. The ultrasound catheter was successfully advanced into the occluded vessel segment without major complications prior to PTCA in 79 of 103 (76.7%) patients and after PTCA in 88 of 103 (85.3%) patients. RESULTS: The plaques were eccentric in 66 patients (83.5%). The plaque morphology was purely low echogenic in 14 (17.7%), highly echogenic in six (7.6%) and mixed in 59 (74.7%) patients. Partial (59 of 79, 74.7%) or ring-like calcification (3 of 79, 3.8%) was observed in 62 patients (78.5%). Plaque fissuring or dissection was detected prior to PTCA in 25 patients (31.7%). Coronary angioplasty successfully enlarged the inner luminal area from 2.1 +/- 0.7 to 7.4 +/- 1.9 mm2 (P < 0.01), whereas the plaque-thrombus area decreased significantly (13.8 +/- 1.7 mm2 before and 9.0 +/- 1.9 mm2 after PTCA; P < 0.01). The total vessel area remained virtually constant (15.9 +/- 1.9 mm2 before and 16.4 +/- 2.5 mm2 after PTCA, NS). PTCA-induced plaque rupture or dissection was observed in only 13 (16.5%) patients. CONCLUSION: Intracoronary ultrasound imaging can be performed safely and successfully prior and subsequent to PTCA in selected patients with acute myocardial infarction. Early reperfusion via PTCA seems to be attributable to a significant reduction in the amount of low-echogenic plaque and thrombus material, whereas factors like balloon-induced dissection and stretching of vessels play only a minor role.     

Withholding thrombolysis in patients with diabetes mellitus and acute myocardial infarction

The benefits of thrombolytic therapy in a patient with diabetes having a myocardial infarction are now well accepted but this treatment may be withheld inappropriately because of concerns about retinal haemorrhage. We therefore examined whether junior doctors alter their use of thrombolysis for the treatment of acute myocardial infarctions according to the type of diabetic retinopathy present. A questionnaire asking whether thrombolysis would be given to a 50-year-old male smoker with insulin-treated diabetes and an acute anterior MI was shown, with four unlabelled retinal photographs, to all doctors prescribing thrombolytic therapy in a south London teaching hospital and an affiliated district general hospital. In all, 24 medical SHOs, 16 medical registrars/specialist registrars, 3 medical senior registrars, and 23 casualty SHOs were interviewed. Of these 89% would thrombolyse such a patient with normal fundi, 55% with background diabetic retinopathy, 54 % if this also involved the macula, and 26% if they saw proliferative retinopathy. The more senior grades were more aggressive in their approach. As we believe that all patients with an acute anterior myocardial infarction and diabetes should be considered for thrombolysis irrespective of their retinal appearance these results suggest thrombolytic therapy is being withheld inappropriately.     

Danish multicenter randomized study of invasive versus conservative treatment in patients with inducible ischemia after thrombolysis in acute myocardial infarction (DANAMI). DANish trial in Acute Myocardial Infarction

BACKGROUND: The aim of the DANish trial in Acute Myocardial Infarction (DANAMI) study was to compare an invasive strategy of percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) with a conservative strategy in patients with inducible myocardial ischemia who received thrombolytic treatment for a first acute myocardial infarction (AMI). METHODS AND RESULTS: Of the 503 patients randomized to an invasive strategy, PTCA was performed in 266 (52.9%) and CABG in 147 (29.2%) from 2 to 10 weeks after the AMI. Of the 505 patients in the conservative treatment group, only 8 (1.6%) had been revascularized 2 months after the AMI. The patients were followed up from 1 to 4.5 years. The primary end points were mortality, reinfarction, and admission with unstable angina. At 2.4 years' follow-up (median), mortality was 3.6% in the invasive treatment group and 4.4% in the conservative treatment group (not significant). Invasive treatment was associated with a lower incidence of AMI (5.6% versus 10.5%; P=.0038) and a lower incidence of admission for unstable angina (17.9% versus 29.5%; P<.00001). The percentages of patients with a primary end point were 15.4% and 29.5% at 1 year, 23.5% and 36.6% at 2 years, and 31.7% versus 44.0% at 4 years (P=<.00001) in the invasive and conservative treatment groups, respectively. At 12 months, stable angina pectoris was present in 21% of patients in the invasive treatment group and 43% in the conservative treatment group. CONCLUSIONS: Invasive treatment in post-AMI patients with inducible ischemia results in a reduction in the incidence of reinfarction, fewer admissions due to unstable angina, and lower prevalence of stable angina. We conclude that patients with inducible ischemia before discharge who have received treatment with thrombolytic drugs for their first AMI should be referred to coronary arteriography and revascularized accordingly.     

Incidence of hibernating myocardium after acute myocardial infarction treated with thrombolysis

OBJECTIVE: To establish the incidence of hibernating myocardium after myocardial infarction treated with thrombolysis and to observe differences in the clinical outcome between patients with and without hibernating tissue. METHODS: 41 patients underwent gated positron emission tomography with 18-fluorodeoxyglucose and 13N-ammonia at a median of eight days after first myocardial infarction. RESULTS: All 41 subjects had a matched perfusion-metabolism deficit in the region of myocardium indicated as the site of infarction by an electrocardiograph; 32 patients (78%) had scans which also showed at least one area of reduced blood flow and contraction with a concomitant increase in glucose uptake, representing hibernating myocardium. Patients were followed up at a median of six months: all 41 were alive and none had sustained a further infarct or cardiac arrhythmia; 17 subjects with hibernating tissue (53.1%) and two without (25%) reported chest pain after myocardial infarction. CONCLUSIONS: Hibernating myocardium is relatively common shortly after myocardial infarction treated with thrombolysis. It does not influence mortality or the incidence of postinfarction chest pain.     

Fast track thrombolysis in acute myocardial infarction: a quality improvement project

To understand the clinical efficacy of traditional anti-rheumatic herbal medicines on acute and severe arthritis or immune diseases, four herbal formulas and one herb were tested in vitro to determine their effects on prostaglandin E2 (PGE2) and interleukin 2 (IL2). Peripheral blood mononuclear cells from healthy subjects were incubated with different concentrations of four herbal formulas including Shaur Yau Gan Tsao Tang (SYGTT), Shang Jong Shiah Tong Yong Tong Feng Wan (SJSTY), Shu Jin Lih An Saan (SJLAS), Ma Shing Yih Gan Tang (MSYGT) and one herb, Tripterygium wilfordii (T2) with and without mitogen stimulation. PGE2 and IL2 from culture supernatant were measured by enzyme immunoassay. The results showed that SYGTT, SJSTY, SJLAS at concentration of 100 microg and MSYGT at 500 microg/ml can significantly inhibit PGE2 release (P < 0.05) from mononuclear cells. However, T2 at 2 microg/ml expressed the same response. For the inhibition of IL2, the concentration of SYGTT, SJSTY and SJLAS must exceed 100 symbol microg/ml. MSYGT failed to inhibit IL2 at even concentrations of 500 microg/ml but T2 at a very low concentration (0.6 microg/ml) could strongly inhibit it. The findings suggest that the majority of traditional anti-rheumatic herbal formulas or herbs, except for T2, should not be used to treat acute and critical arthritis or immune diseases.     

Augmented platelet aggregation as predictor of reocclusion after thrombolysis in acute myocardial infarction

RATIONALE: Reocclusion after thrombolysis diminishes the benefits of early reperfusion after acute myocardial infarction (AMI). No clinical or laboratory variables have been identified as predictors for reocclusion yet. METHODS AND RESULTS: To evaluate hemostatic variables as potential risk determinants platelet aggregation (PA, representing platelet activity), thrombin/antithrombin complexes (TAT, representing thrombin generation), and plasminogen activator inhibitor type 1 (PAI-1, representing endogenous fibrinolysis) were determined in 31 patients with AMI at 0, 1, 2. and 12 h after the start of thrombolysis as well as at hospital discharge. Reocclusion (defined as reinfarction or angiographically confirmed, clinically silent coronary reocclusion) occurred in 5 patients within 5-14 days and in 8 patients within 1 year. TAT plasma concentrations were lower in patients with reocclusion than in those without (9.9+/-5.7 vs. 22.9+/-22.2 ng/ml at 2 h, 6.5+/-3.1 vs. 1 1.2+/-6.4 ng/ml at 12 h, means+/-SD, p <0.05 each). Neither concentration nor activity of PAI-1 in plasma differed between both patient groups. However, both slope and maximum of PA (induced by 2 micromol/l ADP) were augmented in patients with reocclusion (slope: 39.4+/-1.7 vs. 32.5+/-7.4 at 2 h, p <0.001; 42.6+/-2.6 vs. 36.6+/-8.9 at 12 h, p <0.01). Results were independent of the thrombolytic agent used (alteplase or reteplase). A PA slope at 2 h higher than the average slope before thrombolysis (37.2+/-5.7) could be identified as best predictor for early (within 5-14 d, p=0.017, sensitivity 1.00, specificity 0.69) and late reocclusion (within 1 y, p=0.009, 0.88 and 0.74, respectively). CONCLUSIONS: Increased PA following coronary thrombolysis appears to be associated with early and late reocclusion. This marker could be useful in identifying patients who may benefit from more aggressive antiplatelet (such as GP IIb/IIIa receptor antagonists), interventional, or both strategies.     

Increased levels of erythropoietin in the initial phase of acute myocardial infarction

BACKGROUND: It's know that cardiopulmonary function affects the kidney perfusion and that erythropoietin (EPO) release depends on it. We want to determine the plasma level of EPO in the acute phase of myocardial infarction (AMI). SUBJECTS AND METHODS: A transversal trial was carried out in 37 male patients with AMI aged between 31 and 84. We studied the following variables: cardiovascular risk factors, time lapse from beginning of symptoms until hospital arrival, transcutaneous oxygen saturation (ST02) and EPO plasma levels. 16 healthy males were used as control group. RESULTS: Patients with AMI have different EPO levels than control group (25/37 vs 0/16) (18.90 +/- 8.43 mUI/ml vs 9.70 +/- 3.48 mUI/ml respectively p < 0.001). Hyperintense patients have higher EPO levels than normotense ones (18.53 +/- 8.28 mUI/ml vs 12.88 +/- 7.29 mUI/ml p < 0.05). Hypercholesterolemic patients have higher EPO level than normocholesterolemic ones (19 +/- 8.88 mUI/ml vs 12.40 +/- 6.75 mUI/ml p < 0.01). There were no difference between smokers and no smokers. We didn't find correlation between time lapse and EPO levels. CONCLUSION: The trial remarks EPO levels increase during the initial phase of AMI and it is higher in hypertensive and hypercholesterolemic patients.     

Therapeutic strategies in acute myocardial infarction. Results of STIM 93 registry

A registry was set up by the national college of cardiologists practicing in general hospitals in February 1993. The data concerned mode of admission, demographic details, initial clinical and haemodynamic evaluation and hospital outcome. Special attention was given to the electrocardiographic changes before and, in patients receiving thrombolytic therapy, after treatment. An analysis of predictive factors for mortality was performed both in the group of patients "revascularised" and in the group treated conventionally. One thousand and twenty three cases from 327 centres were analysed. There were 1292 men and 531 women, with an average age of 67.9 years. The average time interval from onset of symptoms to hospital admission was 5 h 30 min, 56.8% of patients arriving within 6 hours. 36.4% of the population underwent thrombolysis or angioplasty, 75% of patients under 75 years of age admitted before the 5th hours underwent a procedure of myocardial revascularisation. The hospital mortality was 14%, 8.7% in those revascularised and 17% in patients treated conventionally. Factors predictive of mortality were age, female gender, Killip Classes III or IV, systolic blood pressure of less than 100 mmHg, heart rate of more than 100/min and contraindications of thrombolysis. The maximum ST depression, the sum of ST depression, the sum of ST elevation and depression, were also significant predictive factors of a fatal hospital outcome in the whole population group and in patients treated conventionally. In the reperfused group, only the initial sum of ST elevation and depression was predictive of mortality: 120 minutes after the beginning of thrombolysis, the sum of ST elevations and of elevations and depressions was predictive of twice the mortality when the values exceeded 0.6 mv and 1.4 mv respectively.     

Results of long-term administration of anticoagulants in patients with myocardial infarction and coronary heart disease without infarction

Long-term treatment with anticoagulants (Sintrom, Suncumar) was applied in 300 cases of myocardial infarction and 106 cases of coronary heart disease without infarction aged 31 to 70 years over periods ranging from one to six years. The control group comprised 347 patients with myocardial infarction and 195 patients with coronary heart disease without infarction in the same age range who were not treated with Syncumar because of contraindications. Treatment with Syncumar was started on the first day at hospital and was continued after discharge from the hospital on an outpatient basis. The level of prothrombin was kept within the range of 35-45%. In the Syncumar treated group the mortality in patients with myocardial infarction was 8.0% and in the control group it was 20.5%. In the Syncumar treated group the incidence of repeated infarctions was 12.7% and in the controls it was 33.1%. On the other hand, no effects of Syncumar on the mortality of patients with chronic coronary heart disease without infarction was observed.