R. W. Brower

RANDOMISED TRIAL OF INTRAVENOUS RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR VERSUS INTRAVENOUS STREPTOKINASE IN ACUTE MYOCARDIAL INFARCTION: Report from the European Cooperative Study Group for Recombinant Tissue-type Plasminogen Activator

In a single-blind randomised trial in patients with acute myocardial infarction of less than 6 h duration, the frequency of coronary patency was found to be higher after intravenous administration of recombinant human tissue-type plasminogen activator (rt-PA) than after intravenous streptokinase. 64 patients were allocated to 0.75 mg rt-PA/kg over 90 min, and the infarct-related coronary artery was patent in 70% of 61 assessable coronary angiograms taken 75-90 min after the start of infusion; 65 patients were allocated to 1 500 000 IU streptokinase over 60 min, and the infarct-related vessel was patent in 55% of 62 assessable angiograms. The 95% confidence interval of the differences ranges from +/- 30 to -2% (p = 0.054). Bleeding episodes and other complications were less common in the rt-PA patients than in the streptokinase group. Hospital mortality was identical in the 2 treatment groups. At the end of the rt-PA infusion the circulating fibrinogen level was 61 +/- 35% of the starting value, as measured by a coagulation-rate assay, and 69 +/- 25% as measured by sodium sulphite precipitation. After streptokinase infusion, corresponding fibrinogen levels were 12 +/- 18% and 20 +/- 11%. In the rt-PA group only 4.5% of the fibrinogen was measured as incoagulable fibrinogen degradation products, compared with 30% in the streptokinase group. Activation of the systemic fibrinolytic system was far less pronounced with rt-PA than with streptokinase.

Left ventricular performance, regional blood flow, wall motion, and lactate metabolism during transluminal angioplasty.

The response of left ventricular function, coronary blood flow, and myocardial lactate metabolism during percutaneous transluminal coronary angioplasty (PTCA) was studied in a series of patients undergoing the procedure. From four to six balloon inflation procedures per patient were performed with an average duration per occlusion of 51 +/- 12 sec (mean +/- SD) and a total occlusion time of 252 +/- 140 sec. Analysis of left ventricular hemodynamics in 19 patients showed that the relaxation parameters, peak negative rate of change in pressure, and early time constants of relaxation, responded earliest to short-term coronary occlusion (peak effect at 17 +/- 7 sec) while other parameters, such as peak pressure, left ventricular end-diastolic pressure, and peak positive rate of change in pressure, responded more gradually, suggesting a progressive depression of myocardial mechanics throughout the procedure. Left ventricular angiograms, available for 14 patients, indicated an early onset of asynchronous relaxation concurrent with the early response in peak negative dP/dt and the time constant of early relaxation. All hemodynamic functions fully recovered within minutes after the end of PTCA. Mean blood flow in the great cardiac vein and proximal coronary sinus and the hyperemic response were measured in 20 patients. Before PTCA mean flow in the great cardiac vein was 69 +/- 17 ml/min and in the coronary sinus it was 129 +/- 34 ml/min. Reactive hyperemia (great cardiac vein) was 55% after the first PTCA and 91% after the third. A more pronounced reaction was observed when the residual functional coronary stenosis was reduced in subsequent dilatations. Arteriovenous lactate difference appeared constant during the first two occlusions (control +0.11 mmol/liter, first PTCA -0.87 mmol/liter, and second PTCA -0.82 mmol/liter) and did not increase during subsequent occlusions. Within minutes after the procedure lactate balance was again positive, demonstrating the reversibility of the metabolic disturbances after repeated ischemia. The results of this study indicate that there is no permanent dysfunction of global or regional myocardial mechanics, myocardial blood flow, or lactate metabolism after PTCA with four to six coronary occlusions of 40 to 60 sec.

DOUBLE-BLIND RANDOMISED TRIAL OF INTRAVENOUS TISSUE-TYPE PLASMINOGEN ACTIVATOR VERSUS PLACEBO IN ACUTE MYOCARDIAL INFARCTION

In a double-blind randomised trial 129 patients with first myocardial infarction of less than 6 h duration were allocated to treatment with human recombinant tissue-type plasminogen activator (rt-PA) given intravenously over 90 min, or to placebo infusion. Coronary angiography at the end of this infusion showed that the infarct-related vessel was patent in 61% of 62 assessable coronary angiograms in the rt-PA-treated group compared with 21% in the control group. Treatment with rt-PA was not accompanied by any major complications. In the rt-PA group the circulating fibrinogen level at the end of the catheterisation was 52 +/- 29% (mean +/- SD) of the starting value.

Coronary artery atherosclerosis: severity of the disease, severity of angina pectoris and compromised left ventricular function

To determine if the severity of angina pectoris and the degree of altered left ventricular function correlated with the severity and extent of the underlying coronary artery disease, a coronary scoring system was derived. The system was based on the severity of luminal diameter narrowing and weighted according to the usual flow to the left ventricle in each coronary vessel. Thus, the most weight was given to the left main coronary artery, followed by the left anterior descending, circumflex, and right coronary arteries. The resultant number was an indicator of the overall severity of the obstructive coronary artery disease. A coronary arterial system with no obstructive disease was scored as zero and the greater the degree of obstructive disease present, the higher the coronary score. From 202 subjects, four groups were evaluated: group 1—coronary score = 0.5–4.5 (n = 10); group 2—coronary score = 10.5–12.5 (n = 11); group 3—coronary score = 17.5–20.5 (n = 11); and group 4—coronary score = 25.0–36.0 (n = 11). All subjects had coronary artery bypass surgery and had preoperative and l-year postoperative cardiac catheterization, including atrial pacing to maximal heart rate. The groups could not be separated on the basis of angina frequency, resting heart rate, cardiac index, left ventricular end-diastolic pressure, peak paced left ventricular end-diastolic pressure, dP/dt, V max, left ventricular end-diastolic volume index, left ventricular end-systolic volume index, stroke volume index, ejection fraction or mean circumferential fiber shortening velocity. Thus, based on this study, the severity of coronary artery disease does not statistically correlate with the frequency of angina pectoris or produce a predictable degree of altered left ventricular function. The frequency of angina pectoris cannot be used to predict prognosis orthe adequacy of myocardial revascularization.

Interaction of left ventricular relaxation and filling during early diastole in human subjects

Seventeen patients with coronary artery disease were studied with cineangiography and simultaneous tip manometry at resting heart rate and maximal tachycardia induced by atrial pacing. During early diastole, defined as the interval from the opening of the mitral valve to the point of minimal left ventricular pressure, 20 percent of total ventricular filling took place at resting heart rate, but 62 percent occurred during tachycardia. Minimal pressure was significantly correlated with the time constant of pressure decay during the isovolumic phase (r = 0.75 at resting heart rate and r = 0.81 during tachycardia). The measured minimal pressure could be predictd by extrapolating the exponential decay of ventricular isovolumic pressure to the time of occurence of the minimal pressure, which occurred on average 2.7 time constants from the peak negative rate of change of pressure. At resting heart rate the time constant of relaxation was inversely correlated with ventricular inflow volume (r = -0.64) and inflow rate (r = -0.72). It is concluded that left ventricular relaxatin has a relevant role in early diastolic pressure-volume relations and increases during tachycardia.

Regional wall motion from radiopaque markers after intravenous and intracoronary injections of nifedipine.

In 11 patients, 1 mg of i.v. nifedipine was administered over 3 minutes and regional wall motion was studied during atrial pacing. The dominant effect of nifedipine at basal heart rate (HR) was a lowering of peak left ventricular pressure (152 to 128 mm Hg) with an increase in HR from 70 to 86 beats/min. During pacing, nifedipine produced (p < 0.02) a similar reduction in pressure at all rates, which is a mechanism reducing or sparing myocardial oxygen consumption. At the highest paced rate, the maximal velocity (Vmax) of the contractile element was significantly (p < 0.02) increased from 61 to 68 sec−1 and the regional shortening fractions were increased over the entire pacing range: basal HR, 13.7% to 14.6% (p < 0.025); HR 120 beats/min, 11.6% to 13.5% (p < 0.005); maximal HR, 10.9% to 11.8% (p < 0.05). No evidence of a negative inotropic effect after i.v. administration of nifedipine was observed, myocardial oxygen consumption was probably reduced and there was an increase in regional function.Nifedipine (0.1 mg within 10 seconds) was selectively injected into bypass grafts at a constant paced rate in 10 patients. Seventeen marker pair regions were directly supplied by bypasses selectively injected with nifedipine (group A), and nine were independently perfused (group B). The pressure-derived variables showed a direct negative inotropic effect and a slowed relaxation phase. Thirty seconds after injection, minimal marker separation in group A occurred 78 msec after end-systole (ES), whereas before injection, minimal marker separation occurred 39 msec before ES (p < 0.0001). At the same time, the relation between minimal marker separation and ES in group B was unaffected. In consequence, the regional shortening fraction in group A contributing to left ventricular ejection decreased significantly 30 seconds after injection (−32%, p < 0.01), while that calculated simply from minimal and maximal marker separation remained unchanged (−9%, NS). Active regional contraction starting after the beginning of ejection and ending after ES must be considered as asynchrony and can be considered responsible for the slowed isovolumic contraction and relaxation of the whole ventricle. The dominant effect of i.v. nifedipine at clinical dosage levels is a lowering of systemic blood pressure, possibly reducing oxygen demand. When regionally administered, nifedipine exerts a direct negative inotropic effect, but after i.v. injection, this effect is overridden by reflex increases in contractility and in heart rate as a result of lowered systemic arterial pressure.

Relative value of clinical variables, bicycle ergometry, rest radionuclide ventriculography and 24 hour ambulatory electrocardiographic monitoring at discharge to predict 1 year survival after myocardial infarction

The relative value of predischarge clinical variables, bicycle ergometry, radionuclide ventriculography and 24 hour ambulatory electrocardiographic monitoring for predicting survival during the first year in 351 hospital survivors of acute myocardial infarction was assessed. Discriminant function analysis showed that in patients eligible for stress testing the extent of blood pressure increase during exercise slightly improved the predictive accuracy beyond that of simple clinical variables (history of previous myocardial infarction, persistent heart failure after the acute phase of infarction and use of digitalis at discharge), whereas radionuclide ventriculography and 24 hour electrocardiographic monitoring did not. The predictive value for mortality was 12% with clinical variables alone and 15% with the stress test added. Radionuclide ventriculography and 24 hour electrocardiographic monitoring were slightly additive to clinical information in the whole group of patients independent of the eligibility for stress testing (predictive value for mortality 24% with clinical variables alone and 26% with radionuclide ejection fraction and 24 hour electrocardiographic monitoring added). It is concluded that the appropriate use of simple clinical variables and stress testing is sufficient for risk stratification in postinfarction patients, whereas radionuclide ventriculography and 24 hour electrocardiographic monitoring should be limited to patients not eligible for stress testing.

Direct method for determining regional myocardial shortening after bypass surgery from radiopaque markers in man.

A new method is described for determining localized epicardial shortening in regions newly perfused after saphenous vein bypass grafting. Four to six radiopaque markers are sutured to the ventricular epicardium in pairs, 2 cm apart and 0 to 3 cm distal to the coronary anastomosis. Shortening fraction and time to onset of shortening are reported in 56 patients examined noninvasively with use of cinefluorography 1 week to 6 months after operation. The right coronary bypass region showed the greatest improvement in shortening fraction in 6 months (from 10.1 to 16.7 percent); the left anterior descending region showed the least (but still significant) improvement (from 8.6 to 11.5 percent). Paradoxical systolic expansion occurred predominantly in the region of the left anterior descending coronary bypass (95 percent of all such occurrences). Measurement error, observer variability and beat to beat variability were less important than the physiologic changes in the postoperative period. This technique is a direct method providing heretofore unavailable follow-up information on localized shortening in newly perfused myocardium after coronary bypass grafting.

Increased serum levels of fibrinogen degradation products due to treatment with recombinant tissue-type plasminogen activator for acute myocardial infarction are related to bleeding complications, but not to coronary patency

The association of increasing serum levels of fibrinogen degradation products after recombinant tissue-type plasminogen activator (rt-PA) therapy with bleeding and early coronary patency was assessed in 242 patients with acute myocardial infarction. After administration of 5,000 IU heparin, a median of 40 mg (range 35 to 60) of double chain rt-PA was given intravenously in 90 min. Bleeding occurred in 62 patients; in 73% of patients it was observed within the 1st 24 h and 84% of events consisted of hematoma or prolonged bleeding, or both, at puncture sites. Bleeding events occurred 2.12 times as often in patients with serum levels of fibrinogen degradation products greater than 85 mg/liter as in patients with serum levels less than 22 mg/liter (95% confidence interval 1.01 to 4.43). The infarct-related coronary vessel was patent in 65% of patients at 90 min after the start of rt-PA infusion. In patients with high serum levels of fibrin(ogen) degradation products, coronary patency at 90 min after the start of rt-PA infusion was not better (13% less, 95% confidence interval - 33%, 13%) than in patients with low serum levels. This uncoupling of thrombolytic effect in terms of coronary patency and systemic fibrinogenolysis confirms the experimentally demonstrated fibrin specificity of double chain rt-PA in human subjects. Because fibrin specificity of single chain rt-PA is at least similar to that of double chain rt-PA, the observations in this analysis most likely hold also for single chain rt-PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction of mortality in hospital survivors of myocardial infarction. Comparison of predischarge exercise testing and radionuclide ventriculography at rest.

The relative merits of resting ejection fraction measured by radionuclide angiography and predischarge exercise stress testing were compared for predicting prognosis in hospital survivors of myocardial infarction. Two hundred and fourteen survivors of myocardial infarction out of 338 consecutive patients with acute myocardial infarction were studied over a 14 month period. Hospital mortality was 13% (45 of 338) whereas 19 additional patients out of 214 died in the subsequent year (9%). High, intermediate, and low risk groups could be identified by left ventricular ejection fraction measurement. Mortality was 33% for nine patients with an ejection fraction less than 20%, 19% for 58 patients with an ejection fraction between 20% and 39%, and 3% for 147 patients with an ejection fraction greater than 40%. Mortality was high (23%) in 47 patients who were unable to perform the stress test because of heart failure (19) or other limitations (28). The patients could be stratified further into intermediate and low risk groups according to the increase in systolic blood pressure during exercise: six deaths occurred in 46 patients with a blood pressure increase of less than 30 mm Hg and two deaths occurred in 121 patients with an increase greater than or equal to 30 mm Hg. Maximum workload, angina, ST changes, and ventricular arrhythmias were less predictive than blood pressure changes. It is concluded that the prognostic value of radionuclide angiography at rest and of symptom limited exercise testing is similar. The latter investigation should be the method of choice since it provides more specific information for patient management.