Double-blind randomized trial of alteplase versus placebo in patients with chest pain at rest.

Patients who have chest pain occurring at rest are at a significant risk of myocardial infarction and or sudden death. Most trials enter patients with anginal rest pain after an initial screening period. Thus, the clinical efficacy of early thrombolytic treatment for patients with rest pain remains unproven. Eighty patients with chest pain at rest and with ECG changes of ST depression of at least 1 mm in any ECG lead, were randomized to alteplase 100 mg infused over 3 h, or placebo. Concomitantly, all patients received intravenous heparin and 300 mg of aspirin daily (unless contra-indicated). Seventy-four patients had coronary angiography (the majority within 72 h of admission) of which 73 were assessable. The patency of the ischaemia-related vessel was not significantly greater in the alteplase treated group (81% vs 78%, P = 0.82). The culprit lesion morphology tended to be more concentric in the alteplase treated group (84% vs 56%, P = 0.06) although alteplase treatment was not associated with a significant reduction in the severity of the culprit lesion stenosis. Intra-coronary thrombi were detected in 7% of patients (3% placebo, 11% alteplase, P = 0.35). The mean left ventricular ejection fraction or the alteplase-treated group was 49 +/- 3% and for the placebo-treated patients 56 +/- 3% (P = 0.05). There was no difference in the total in-hospital cardiac event rate i.e. cardiac death, myocardial infarction and coronary revascularization between patients receiving alteplase (10%, 63%, and 38%) and those receiving placebo (8%, 65%, and 30%) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of double bolus alteplase in the treatment of acute myocardial infarction.

Fifty-nine consecutive patients presenting within 6 hours of the onset of symptoms of an acute myocardial infarction were treated with 150 mg of soluble aspirin orally, and either 70 or 100 mg of alteplase divided into 2 intravenous bolus injections separated by 30 minutes. Dosage regimens were either 20 followed by 50 mg (group A), 50 followed by 20 mg (group B), or 50 followed by 50 mg (group C). Coronary angiography 60 minutes after the first bolus showed infarct-related coronary artery patency (Thrombolysis in Myocardial Infarction score 2 or 3) in 13 of 16 (81%) patients in group A, 12 of 17 (71%) in group B, and 10 of 11 (91%) in group C (overall patency rate at 60 minutes: 35 of 44 [80%] patients; 95% confidence interval 68 to 91%). At 90 minutes, patency rates were 15 of 20 (75%) patients in both groups A and B, and 18 of 19 (95%) in group C (overall patency rate 48 of 59 [81%] patients; 95% confidence interval 72 to 91%). Residual thrombus was identified with the 90-minute angiogram in 7 patients in group A, 5 in group B, and 3 in group C. Although there was no statistically significant difference in patency between the 3 dosage regimens at either 60 or 90 minutes there was a trend toward increased patency and more complete thrombolysis at 90 minutes in group C. No episodes of bradyarrhythmia, hypotension or cerebrovascular bleeding were observed after double bolus therapy. There were 7 episodes (12%) of reocclusion, and 3 deaths (5%) within 1-month follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombolytic therapy within one hour of the onset of acute myocardial infarction.

Between 1986 and 1988, 239 consecutive patients with acute myocardial infarction received thrombolytic therapy up to 285 minutes after onset of symptoms; in 39 (17 with anterior infarction, 21 inferior, one lateral infarction) recombinant tissue plasminogen activator or anistreplase was administered a mean of 51 minutes (range 20-60 minutes) after the onset of symptoms. The patency rates (26 of 30; 87 per cent), rapid ST segment resolution (36 of 38; 95 per cent) and QRS score of less than or equal to 3 (28 of 38; 74 per cent) were statistically significantly higher for those seen and treated in the first hour in comparison with those seen and treated later. For those treated within the first hour mean peak creatine kinase was 1264 U/l for those with TIMI grade 2 or 3 (partial or complete perfusion) compared with 3005 U/l for those with TIMI grade 0 or 1 (no perfusion or penetration without perfusion) (p = 0.02): mean peak creatine kinase-MB for those with TIMI grade 2 or 3 perfusion was 115 U/l compared with 312 U/l for those with TIMI grade 0 or 1 (p = 0.01). Four of the 39 patients developed ventricular fibrillation following thrombolytic therapy, three within 24 hours of infarction and one following reinfarction on day 15. There were no significant bleeding complications. One patient died. Thrombolytic therapy within 1 hour of the onset of symptoms led to a very high angiographic patency rate, rapid ST segment resolution with preservation of left ventricular function. This therapy is without significant complications.

One-year follow-up after recombinant tissue plasminogen activator administered to patients with acute myocardial infarction.

Of 106 patients seen within 4 h of chest pain with 107 episodes of acute myocardial infarction, nine died before or during hospitalization mainly from cardiogenic shock, and four died during the next year, three were sudden deaths. The 93 survivors were reviewed at a mean of 53 (range 49-70) weeks after infarction. Of these 93, 18 had had attempted angioplasty (successful in 12) and 15 had had coronary artery bypass grafting (including one patient who had coronary artery bypass grafting performed after unsuccessful angioplasty). The remaining 61 patients continued on medical therapy only. During the one-year follow-up two patients suffered reinfarction and a further 22 had one or more cardiac admissions, mostly for chest pain. At review, 22 patients had angina (16 New York Heart Association Grade I or II) and five dyspnoea (all NYHA Grade II). Forty-three patients were taking oral nitrates, 53 were receiving calcium antagonists, 54 were using betablocking agents and 73 used anti-platelet agents. However, many of these patients continued on anti-anginal therapy prophylactically after their myocardial infarction, without continuing chest pain. Thus after recombinant tissue plasminogen activator therapy and following hospital discharge the mortality rate for patients with acute myocardial infarction was four out of 97 (4.1%) and reinfarction rate among survivors was two out of 93 (2.2%). Although the incidence of cardiac symptoms was low this may be partly due to the high incidence of angioplasty and coronary artery grafting, together with the use of anti-anginal agents.

Anistreplase in early acute myocardial infarction and the one-year follow-up.

Of consecutive patients seen with first myocardial infarction (88 of whom were treated out-of-hospital by mobile coronary care staff), 139 received 30 units of intravenous anistreplase at a mean of 101 minutes (range 35-180) from onset of symptoms. Thrombolysis in myocardial infarction patency grade 2 or 3 was found in 76/91 (83.5%) patients. At 3-4 months after hospital discharge, the mean global left ventricular ejection fraction and mean infarct-related regional third ejection fraction declined with increasing delay to anistreplase. For the first, second and third hour administrations, global ejection fraction was 54%, 50% and 45% (P = 0.002) and for regional third ejection fractions 49%, 43% and 41% (P = 0.02) respectively. Of the patients, 130 were reviewed at approximately 1 year: reinfarction had occurred in 9, 6 had undergone coronary angioplasty and 1 had coronary arterial bypass grafting performed since discharge. Mean global left ventricular ejection fraction was 52% and mean infarct-related regional third ejection fraction was 51%. Thus, intravenous anistreplase induces high rates of arterial patency. Global and regional third ejection fractions decline with increasing delay in the time of administration of anistreplase. Mortality and morbidity is low in the first year.

Transient release of lipid peroxides after coronary artery balloon angioplasty.

Free radical production may cause myocardial damage during reperfusion of ischaemic myocardial tissue; when free radicals interact with polyunsaturated fatty acids or their esters, lipid peroxides are produced. A product of lipid peroxidation, malondialdehyde, was measured in 10 subjects with stable angina who underwent angioplasty of a proximal high-grade stenosis (over 90%) of the left anterior descending coronary artery. In all subjects the duration of balloon occlusion was 60 s. Blood was withdrawn from the great cardiac vein immediately before balloon inflation (T0), immediately after balloon deflation (T60), 15 s after balloon deflation (T75), and 1 min after balloon deflation (T120). There was a significant increase in malondialdehyde at T60 compared with T0 for the first balloon inflation (mean increase 0.3 mumol/l [95% confidence limits 0.1, 0.5]), and at both T60 (0.31 mumol/l [0.15, 0.47]) and T75 (0.22 mumol/l [0.04, 0.40]) for the second balloon inflation. This model could be used to assess antioxidant effects of drugs.

A double blind placebo controlled study of early and late administration of recombinant tissue plasminogen activator in acute myocardial infarction.

Within four hours of the onset of acute myocardial infarction 57 consecutive patients were randomised blindly to infusion of 150 mg recombinant tissue plasminogen activator (rt-PA) (group 1) over five hours or placebo (group 2) when they were first seen outside hospital or in the accident and emergency department. When they were admitted to the coronary care unit patients in group 1 also had placebo infused and those in group 2 were treated with rt-PA as well as placebo. Treatment with rt-PA started at a mean of 119 minutes (range 38-235) after the onset of pain in group 1 and 187 minutes (range 80-285) after the onset of pain in group. In 19 (79%) of 24 in group 1 and 16 of 25 (64%) in group 2 cardiac catheterisation 10-14 days after infarction showed thrombolysis in myocardial infarction grades 2 or 3. There was mean percentage shortening of the infarct related segments (Leighton method) of 16% in group 1 and 10.3% in group 2. For patients with anterior infarction mean percentage shortening was 20.5% in group 1 and 12.2% in group 2. Although there was no significant difference in global ejection fraction as assessed by contrast ventriculography or radionuclide ventriculography the infarct related regional third ejection fraction (a measure of the function of the territory of the affected coronary artery) was significantly improved by early treatment (41% group 1 and 28% group 2). Assessment of infarct size by the QRS scoring method of Palmeri showed QRS score less than or equal to 15/25 patients in group 1 and 8/27 in group 2. Nine patients developed 11 episodes of ventricular fibrillation; all patients in whom ventricular fibrillation developed during treatment with rt-PA were successfully resuscitated. There was no clinically significant bleeding. In seven (12%) patients clinical and electrocardiographic criteria suggested reocclusion. Five patients died from cardiac causes. Prehospital administration of rt-PA was feasible and significantly reduced the delay before thrombolysis was started. Earlier treatment improved myocardial function in the the infarct area and reduced the infarct size.

A randomised dose ranging study of recombinant tissue plasminogen activator in acute myocardial infarction.

To assess the thrombolytic efficacy and the effect on the systemic fibrinolytic system of recombinant tissue plasminogen activator doses of 20 mg, 50 mg, and 100 mg were compared in a randomised study. Tissue plasminogen activator was infused intravenously over 90 minutes in 50 consecutive patients with acute myocardial infarction of four hours' duration or less; on average the infusion was started 135 minutes (range 20 to 240) after the onset of pain. The affected artery was patent at the end of the 90 minute infusion in 14/17 (82%) of those who received 100 mg, 12/17 (71%) of those who received 50 mg, and 8/16 (50%) of those who received 20 mg. Regardless of dose, reperfusion rates were significantly better for patients treated within two hours of the onset of symptoms (81%) than for those treated in the third and fourth hours (54%). At the end of the infusion serum fibrinogen concentrations fell to 86% of the preinfusion value after 20 mg, 75% after 50 mg, and 63% after 100 mg, and similar dose dependent changes occurred in plasminogen, (alpha 2 anti-plasmin, and fibrinogen and fibrin degradation products. The mean infarct related regional third ejection fraction was 46% for patients with grade 2 or 3 reperfusion and 35% for those with grade 0 or 1. Ventricular fibrillation occurred in six (12%) patients during the infusion of tissue plasminogen activator, but no late ventricular fibrillation occurred. Bleeding was minimal, reocclusion occurred in three patients, and four patients died from cardiac causes. Recombinant tissue plasminogen activator is an effective thrombolytic agent which produces better reperfusion rates after a 50 or 100 mg dose than after a 20 mg dose. The effect on the systemic fibrinolytic system is dose dependent. Successful reperfusion results in improvement of left ventricular function.

Management of ventricular septal rupture in acute myocardial infarction.

Four patients with rupture of the interventricular septum after myocardial infarction are described. This condition carries a grave prognosis. Surgical repair of the septum is almost always urgently required if the left-to-right shunt is large (QP/WS > 3). Results are better if surgery can be deferred for six weeks to allow the infarcted area to heal and the tissues to be come firmer. This delay may be achieved by using a combination of agents to reduce afterload and to exert a positive inotropic effect. The timing of surgical intervention was an important factor in the survival of three of the four patients.

Observations on haemodynamic effects of mexiletine.

The haemodynamic effects of intravenous mexiletine have been studied in 16 patients with valvular heart disease without clinical evidence of heart failure. A bolus injection of 150 mg administered to 6 of the 16 patients resulted in a mean plasma concentration above the therapeutic range for at least 5 minutes after the drug was given. A small but significant rise in the mean pulmonary artery pressure occurred. In 10 patients, the effects of intravenous mexiletine were compared with those of intravenous saline in a double blind trial. No significant difference was found in the haemodynamic effects, though both saline and mexiletine produced a small rise in the mean pulmonary artery pressure. Mexiletine when administered to patients without heart failure in doses known to be clinically effective did not have important adverse haemodynamic effects.