Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial.

BACKGROUND: Intracranial haemorrhage is an important limitation to pharmacologic reperfusion therapy for acute myocardial infarction. The combination of a glycoprotein IIb/IIIa inhibitor, half-dose plasminogen activator and reduced-dose heparin has been evaluated as an alternative to standard fibrinolytic therapy in this setting. METHODS AND RESULTS: We evaluated the relation between univariate and multivariate predictors of intracranial haemorrhage and the effect of treatment with either reteplase alone (10 U bolus twice, 30 min apart) with standard-dose heparin (5000 U bolus followed by an infusion of 1000 Uh(-1)for patients > or =80 kg and 800 Uh(-1)for those <80 kg) or combination therapy with abciximab (0.25mg/kg bolus and 0.125 microg/kg/min for 12h) and half-dose reteplase (two boluses of 5U 30 min apart) with reduced-dose heparin (60 Ukg(-1)bolus, maximum 5000 U, followed by an infusion of 7 Ukg(-1)h(-1)) in the 16 588 patients randomized in the GUSTO V trial. Overall, the incidence of intracranial haemorrhage was similar in the two groups (0.6% vs 0.6%; OR 1.05, 95% CI 0.71, 1.56). The median (25th-75th) time from drug administration to intracranial haemorrhage was 5.5 (3.4-11) hours with combination therapy and 9.2 (5.9-22) hours with reteplase (P=0.048). Among the multivariable predictors of intracranial haemorrhage, only age showed a significant interaction with treatment effect (age per treatment interaction chi-square 4.60, P=0.032) with a lower risk of combination therapy for younger patients and a higher risk for the elderly. CONCLUSIONS: Although no additional risk of intracranial haemorrhage has been observed with combination therapy in the whole population, a significant age pertreatment interaction exists, with a lower risk with combination therapy in younger patients, and a higher risk in the elderly.

Exercise cardiovascular responses to gallopamil in ischemic heart disease.

UNLABELLED: In a single-blind, placebo-controlled, crossover trial versus diltiazem, we evaluated the influence of gallopamil on cardiovascular responses evoked by bicycle exercise. Twelve patients with chronic stable angina were enrolled. After a 5 days placebo run-in period, patients were randomly assigned either to gallopamil (50 mg thrice daily) or diltiazem (60 mg thrice daily) for 10 days. Then, patients were changed to the alternative drug. After placebo, and at the end of each subsequent period, all subjects underwent right heart catheterization by means of a Swan-Ganz thermodilution catheter. Hemodynamics were determined in 3 ways: supine, standing and during a multistage exercise test. RESULTS: anginal attacks were reduced to a similar degree by gallopamil (2.1 +/- 1/week versus 5.8 +/- 2.8/week during placebo, p less than 0.01) and diltiazem (2.0 +/- 0.8/week versus 5.8 +/- 2.8/week during placebo, P less than 0.01). At rest, gallopamil caused a significant decrease in heart rate and a slight fall in systemic vascular resistance. Cardiac index rose during exercise and was higher with respect to placebo at peak exercise (6.7 vs 5.6 l/min/m2, P less than 0.05). As a consequence, stroke volume index and stroke work index both increased at maximum workload (P less than 0.05). Compared to placebo, exercise time was significantly improved by gallopamil (+50%, P less than 0.02) and diltiazem (+38%, P less than 0.05). Likewise, time to onset of ST-segment depression was prolonged by 70% with gallopamil (P less than 0.01) and by 64% with diltiazem (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

[Urokinase in the therapy of spontaneous angina]. / L'urochinasi nella terapia dell'angina spontanea.

UNLABELLED: In an open non-comparative clinical study, 19 patients with spontaneous angina pectoris admitted to hospital with attacks lasting greater than 10 minutes, unresponsive to nitrate and/or calcium antagonist treatment, at least 2 ECG readings of raised (greater than or equal to 1.5 mm) or lowered (greater than or equal to 1 mm) ST segment not attributable to earlier AMI in the same area, were treated after the interruption of conventional treatment (mean 47 +/- 34.2 min) with 2 million IU endovenous UK in 15 mins followed by 1 million IU endovenous UK in 60 mins. Sixty minutes after UK administration was terminated, they were given a bolus of 5000 IU calcium heparin, followed by 1000 IU per hour for 2 days. Coronary angiography (Judkins technique) was performed before the start of UK treatment and 15, 30, 45, 60 and 75 minutes into it. RESULTS: Basal coronarography showed only "multiple organic stenosis" in 5 out of the 19 patients, a more complex situation suggestive of thrombi in the coronary arteries in 14. Subsequent angiographies (mean 30 mins later) revealed coronarographic improvement in 11 out of the 19 (58%), or 11 out of 14 (78.5%) if we exclude those with simple stenosis. Angina attacks were significantly lower in the 8 days after UK treatment than in the week before it in terms of number (4 v. 1; p less than 0.01), global severity (7 v. 1.5; p less than 0.01) and global duration (45 v. 4.25 min; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiographic correlate of post-reperfusion abnormal Q waves.

To determine whether post-reperfusion acute Q waves are due to irreversible myocardial necrosis, we studied the relationship between abnormal Q waves and left ventricular regional wall motion in 74 patients who had coronary thrombolysis following acute myocardial infarction. In 48 cases, acute pathologic Q waves appeared on the ECG-recordings after coronary reperfusion (group A), whereas in 26 patients the QRS complex had no or only minimal changes (group B). A control group consisted of 27 patients with unsuccessful thrombolysis. Quantitative left ventricular angiography was performed after coronary thrombolysis and repeated before discharge from the hospital. Regional wall motion of the infarcted area was determined by a system of 48 radii traced from the centroid of the end-diastolic and end-systolic silhouettes. Myocardial akinesis was significantly more extensive in group A than in group B (18 +/- 9% vs. 10 +/- 6%, p less than 0.02). Regional wall motion of the infarcted area improved in both groups at predischarge study (mean radial shortening +5 +/- 6% in group A and +4 +/- 7% in group B). Moreover, regional wall motion was significantly better in group A with respect to the control group (angio score of hypo-akinesis 166 +/- 124 vs. 412 +/- 174, p less than 0.01). In conclusion, post-reperfusion abnormal Q waves 1) are associated with more extensive myocardial damage, 2) do not preclude late recovery of ischemic myocardium, and 3) do not necessarily indicate irreversible transmural necrosis.

Importance of early recanalization of the occluded coronary artery in acute myocardial infarction for preservation of left ventricular function.

Ninety-two patients with acute myocardial infarction, treated with intracoronary thrombolysis within 3 h from the onset of ischemic symptoms, were studied with coronary arteriography and left ventriculography. These examinations were repeated after 2 to 4 weeks to assess the importance of duration of ischemia on recovery of regional and global left ventricular pump function. Patency was achieved acutely and maintained at control angiography in 73 patients (87%), who were subdivided into three groups according to duration of ischemia before reperfusion: group 1 (29 patients): revascularized within 3 h; group 2 (22 patients): revascularized between 3 and 4 h; group 3 (22 patients): revascularized after 4 h. Patency was acutely achieved, but not maintained at control angiography in 11 patients (group 4), while thrombolysis was unsuccessful in eight patients (group 5). In group 1 there was a significant reduction in the number of hypokinetic segments (P less than 0.001) and a significant increase in mean percentual area change of hypokinetic segments (P less than 0.001) and in global ejection fraction (P less than 0.001). A still significant, but less evident improvement in these parameters was also seen in group 2 (P less than 0.05, P less than 0.01, P less than 0.01 respectively). Insignificant changes, with only occasional improvements were observed on group 3, while a tendency toward deterioration was found in group 4. A clear and significant (P less than 0.001) worsening of local and global ventricular function was detected in group 5. Our results indicate a significant inverse relationship between duration of ischemia and left ventricular functional improvement. Particularly, the first 3 to 4 h after onset of ischemic symptoms are critical for preservation of left ventricular function (group 1 and 2). Reperfusion after 4 h (group 3) is only rarely associated with improvement of ventricular motion. The importance of very early pharmacological thrombolysis and of maintenance of coronary patency is stressed.

[The course of residual stenosis after intracoronary thrombolysis]. / Evoluzione della stenosi residua dopo trombolisi intracoronarica.

UNLABELLED: Clinical outcome after coronary thrombolysis are strictly related to the residual stenosis. However, the natural history of this lesion is largely unknown. To assess this topic we evaluated 25 patients who had coronary recanalization by urokinase in acute myocardial infarction. Serial coronary angiograms were taken immediately after fibrinolytic therapy, before hospital discharge and 1 year later. Angiographically detected coronary reocclusion and/or new ischemic events were exclusion criteria. Angiographic analysis was performed at a five-fold magnification. The followings were specifically evaluated: a) vessel contours at the site of the residual stenosis; b) luminal diameter reduction; c) presence of intraluminal filling defects. RESULTS: the vessel narrowing progressively improved from the acute phase (percent of stenosis 92 +/- 7) to the hospital discharge (82 +/- 8%, p less than .01) and to 1 year follow-up (76 +/- 11%, p less than .001 vs hospital discharge). Moreover, the residual stenosis appears to be "complicated" in early period (irregular contours with superimposed thrombus), but become regular and "uncomplicated" at follow-up examination (smooth contours, hourglass configuration, no intraluminal filling defects). IN CONCLUSION: a) the residual coronary stenosis is a dynamic process and may improve at follow-up examination; b) a practical approach to the management of the residual stenosis must take in account the natural history of the lesion to give a correct indication for coronary surgery or PTCA.

[Hemodynamic effects of diltiazem in the subacute stage of myocardial infarct treated by thrombolysis]. / Effetti emodinamici del diltiazem nella fase subacuta dell'infarto miocardico trattato con trombolisi.

Since Ca++-overloading is a major problem after myocardial reperfusion we studied the effects of Diltiazem on the left ventricular diastolic function in the early days following coronary thrombolysis. Twelve patients who had myocardial reperfusion by intracoronary urokinase in acute myocardial infarction were admitted to the study. Previous infarct, cardiogenic shock or late thrombolysis (greater than 4 h from symptoms onset) were exclusion criteria. All subjects were evaluated at control cardiac catheterization 5-8 days after the acute ischemia. Simultaneous left ventricular angiography and high-fidelity pressure recordings by means of a tip-micromanometer and angiographic catheter were performed at rest and after intravenous Diltiazem administration (16 mg over 2' + 0.008 mg/Kg/min). Indexes of myocardial relaxation and early ventricular filling were impaired at rest but improved significantly after Diltiazem (Tab. II). Isovolumic relaxation period fell from 92 +/- 8 msec to 77 +/- 12 msec (p less than .01), T constant of isovolumic pressure decay decreased from 61 +/- 7 msec to 55 +/- 7 msec (p = ns), first-third of filling rate increased from 64 +/- 7% to 79 +/- 6% (p less than .01). On the other hand, indexes of left ventricular compliance were altered after coronary reperfusion (left ventricular end-diastolic compliance 17 +/- 13 mmHg-1. 10(-3), modulus of chamber stiffness .045 +/- .008) but but did not change after calcium-blocker therapy. In conclusion, post-thrombolysis diastolic function is severely impaired at rest, probably because of raised intracellular Ca++ and delayed asynchronous relaxation. Diltiazem improves energy-dependent early diastole, but does not affect ventricular compliance.

Cardiovascular effects of a single high dose of dilazep by oral route.

The acute hemodynamic effects on the coronary and systemic arteries of a single high dose of dilazep given orally (200-400 mg; 3-5 mg/kg) were studied in 25 anginal patients who, for diagnostic reasons, underwent cardiac catheterization and coronary angiography. From 20 to 30 min after drug administration, systemic vascular resistance (1666 +/- 348 to 1367 +/- 312 dyn X sec X cm-5, P less than 0.05) and left ventricular end-diastolic pressure (16.5 +/- 5 to 12 +/- 4.4 mm Hg, P less than 0.01) decreased significantly. The heart rate rose from 74 +/- 10 to 84 +/- 12 beats/min (P less than 0.05), while the cardiac index, dp/dt max and pulmonary arteriolar resistance did not change significantly. Concomitantly, coronary blood flow significantly increased, coronary resistance was reduced by 42% (P less than 0.01) while myocardial oxygen consumption was unchanged. The increase in mean coronary arterial diameter was by 22-25%. It is concluded that dilazep has a prompt and potent vasodilating action even after oral administration. The drug is therefore useful in the chronic treatment of ischemic heart disease.

[Effects of propafenone on coronary and systemic hemodynamics]. / Effetti del propafenone sulla emodinamica coronarica e sistemica.

This study was undertaken to evaluate the effects of intravenous Propafenone (2 mg/kg over 5') on Left Ventricular (LV) function and coronary blood flow. Twelve patients with coronary artery disease and post-ischemic LV disfunction were examined during routine cardiac catheterization. Serial measurements of central hemodynamics, LV high-fidelity pressure and coronary blood flow were recorded at rest and every 10' after Propafenone administration. Heart rate was unchanged, suggesting that Propafenone did not affect sympathetic tone. Cardiac index slightly decreased (from 3.3 +/- 0.9 L/min/m2 to 3.1 +/- 0.6 L/min/m2 at 10', p = ns), LV end-diastolic pressure rose significantly (from 17.7 +/- 2.1 mmHg to 22.7 +/- 4.2 mmHg at 20', p less than 0.01) and dP/dt max fell from 1897 +/- 291 mmHg/sec to 1577 +/- 312 mmHg/sec (p less than 0.02). Systemic vascular resistances had only minimal changes. Concomitantly, coronary vascular resistances decreased (from 0.77 +/- 0.17 mmHg/ml/min to 0.61 +/- 0.12 mmHg/ml/min, p less than 0.02) and coronary blood flow increased (from 138 +/- 29 ml/min to 172 +/- 21 ml/min, p less than 0.01). No significant difference was noted in myocardial oxygen consumption. No symptoms related to LV failure were observed during the study. In conclusion hemodynamic effects of Propafenone are characterized by moderate LV depression and by coronary artery dilatation, probably due to a calcium blocker-like activity.

Angiographic features of the coronary arteries during intracoronary thrombolysis.

The angiographic appearance of the coronary arteries during successful thrombolysis with urokinase was determined in 35 patients with acute myocardial infarction. The lysing process passed through several phases: (a) total coronary occlusion with a convex or irregular distal margin (phase 0); (b) increasing patency of the lumen (phase 1); (c) re-establishment of flow but with intraluminal filling defects and delayed distal flow possibly due to microemboli (phase 2); (d) partial or complete disappearance of the filling defects (phase 3); and (e) further widening of the lumen which eventually attains a smooth regular outline (phase 4). The angiographic features which indicate the presence of coronary thrombosis are occlusion with an irregular or scalloped margin, staining with contrast medium, and progressive patency of the occluded vessel showing intraluminal filling defects.

[Beneficial effects of disopyramide on left ventricular outflow obstruction in a case of hypertrophic obstructive cardiomyopathy]. / Effetti favorevoli della disopiramide sull'ostruzione all'efflusso ventricolare sinistro in un caso di cardiomiopatia ipertrofica ostruttiva.

The Authors describe a patient with hypertrophic cardiomyopathy (HCM), severe left ventricular outflow tract obstruction and lack of response to beta-blockers or verapamil. Intravenous infusion of disopyramide resulted in a virtual disappearance of the LV pressure gradient, reduction of the systolic anterior motion of the mitral valve and slowing of the LV isovolumetric relaxation. One month after maintenance therapy with oral disopyramide a decrease of the anginal episodes and an improvement of the exercise tolerance were noted. Thus disopyramide, probably because of its negative inotropic action, is useful in the management of patients with HCM when LV outflow obstruction is the main cause of the clinical-hemodynamic findings.

[Intracoronary thrombolytic treatment with urokinase in myocardial infarct: clinical angiographic findings and effects on left ventricular function]. / Trattamento trombolitico intracoronarico con urochinasi nell'infarto miocardico: rilievi clinico-angiografici ed effetti sulla funzione ventricolare sinistra.

The effect of selective intracoronary thrombolysis was studied in 27 patients with evolving myocardial infarction. In the acute phase, angiography demonstrated complete occlusion in 22 cases (81,5%) (group A), and incomplete stenosis with diminished distal blood flow in 5 cases (18,5%) (group B). Urokinase was infused into the infarct-related coronary artery at a rate of 8000 u/min u/min until reperfusion was obtained and subsequently at a rate of 2-4000 u/min for 20-40 min. In group A, coronary recanalization was achieved in 18 of 22 patients (81,8%) (group A1), while in 4 patients (group A2) the procedure was unsuccessful. Group B patients showed no angiographic modifications following fibrinolytic therapy. Left ventricular function was studied during the acute phase (before and after therapy) in 9 patients; 22 patients were studied immediately after thrombolysis and before hospital discharge. Preliminary studies of patients in group A1 after reperfusion showed a decrease in telediastolic pressure from 18,9 to 24,4 mmHg and an increase in ejection fraction from 0,40 to 0,43 (p = ns). No modifications in these parameters were observed in group A2 or B. Follow-up examination of group A, revealed an increase in ejection fraction from 0,40 +/- 0,12 to 0,50 +/- 0,15 (p less than 0,05) and a decrease in the length of the akinetic segment from 6,49 +/- 2,4 to 4,40 +/- 1,35 (p less than 0.05). In group B, the ejection fraction increased from 0,41 +/- 0,06 to 0,50 +/- 0,04 (p less than 0.05) and the length of the akinetic segment decreased from 7,52 +/- 2,0 to 3,38 +/- 1,14 (p less than 0.05). On the contrary, in group A2, ejection fraction diminished from 0,39 +/- 0,06 to 0,34 +/- 0,07 and the length of the akinetic segment remained unchanged. Our results suggest that: A) coronary artery thrombosis is frequent in evolving myocardial infarction B) selective intracoronary thrombolysis and subsequent reperfusion of the infarcted area is readily obtainable with urokinase infusion C) no significant acute modifications of left ventricular function were observed D) 2-3 weeks after initial treatment, patients in which recanalization of an occluded vessel was achieved (group A1) and patients that presented with subocclusive stenosis and reduced blood flow (group B), showed an improvement in left ventricular function and a reduction in the akinetic area.