D.P. de Bono

THROMBOLYSIS WITH TISSUE PLASMINOGEN ACTIVATOR IN ACUTE MYOCARDIAL INFARCTION: NO ADDITIONAL BENEFIT FROM IMMEDIATE PERCUTANEOUS CORONARY ANGIOPLASTY

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.

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.

QT dispersion and mortality after myocardial infarction

QT dispersion may serve as a measure of variability in ventricular recovery time and may be a means of identifying patients at risk of arrhythmias and sudden death after acute myocardial infarction. We investigated this possibility on electrocardiograms (ECGs) recorded 2 or 3 days after infarction (early) and at least 4 weeks later (late). 163 patients who died between 1 day and 5 years after infarct were compared with an equal number of survivors matched for age and sex. 53 of the patients who died and 82 survivors also had late ECGs. There was no difference in early QT dispersion between the patients who died and the survivors (mean QTc dispersion 112.1 [SD 44.4] vs 109.9 [42.7] ms1/2). QTc dispersion fell significantly from early to late ECGs in survivors (110.9 [48.5] to 76.5 [28.8] ms1/2), but not in patients who died during follow-up (108.0 [51.0] to 98.9 [43.1] ms1/2). The difference between the groups in the mean change was significant (34.4 [55.2] vs 9.1 [60.8] ms1/2, p = 0.016). QT dispersion measured on an ECG recorded 2 or 3 days after acute myocardial infarction does not predict mortality during the next 5 years. Increased QT dispersion on ECGs recorded at least 4 weeks after infarct may be associated with subsequent mortality, but this finding must be confirmed in a prospective trial.

Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial.

OBJECTIVE--To determine whether concomitant treatment with intravenous heparin affects coronary patency and outcome in patients treated with alteplase thrombolysis for acute myocardial infarction. DESIGN--Double blind randomised trial. TREATMENT REGIMENS--Alteplase 100 mg (not weight adjusted) plus aspirin (250 mg intravenously followed by 75-125 mg on alternate days) plus heparin (5000 units intravenously followed by 1000 units hourly without dose adjustment) was compared with alteplase plus aspirin plus placebo for heparin. SETTING--19 cardiac centres in six European countries. SUBJECTS--652 patients aged 21-70 years with clinical and electrocardiographic features of infarcting myocardium in whom thrombolytic therapy could be started within six hours of the onset of major symptoms. MAIN OUTCOME MEASURE--Angiographic coronary patency 48-120 hours after randomisation. RESULTS--Coronary patency (TIMI grades 2 or 3) was 83.4% in the heparin group and 74.7% in the group given placebo for heparin. The relative risk of an occluded vessel in the heparin treated group was 0.66 (95% confidence interval 0.47 to 0.93). Mortality was the same in both groups. There were non-significant trends towards a smaller enzymatic infarct size and a higher incidence of bleeding complications in the group treated with heparin. CONCLUSIONS--Concomitant intravenous heparin improves coronary patency in patients with alteplase. Whether this can be translated into improved clinical benefit needs to be to be tested in a larger trial.

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.

Cardiac rehabilitation in the United Kingdom: guidelines and audit standards. National Institute for Nursing, the British Cardiac Society and the Royal College of Physicians of London.

This paper summarises a multidisciplinary workshop convened to prepare clinical guidelines and audit standards in cardiac rehabilitation in the United Kingdom. The workshop developed a three element model of the rehabilitation process and identified needs relating to medical and psychosocial care and the potential contributions of exercise, education, secondary prevention, and vocational advice. Draft clinical standards are proposed as a basis for locally developed guidelines and further research.

Complications of diagnostic cardiac catheterisation: results from 34,041 patients in the United Kingdom confidential enquiry into cardiac catheter complications. The Joint Audit Committee of the British Cardiac Society and Royal College of Physicians of London.

OBJECTIVES--To evaluate the frequency and nature of complications in patients undergoing diagnostic cardiac catheterisation and to assess the feasibility of a voluntary cooperative audit system. METHODS--27 centres enrolled patients over a two year period. Each centre voluntarily reported numbers of patients catheterised every month. Complications were reported as they occurred. Feedback was provided in the form of newsletters and reports. RESULTS--39,795 procedures were registered, of which 33,776 were diagnostic catheterisations in adults or adolescents, 1265 were paediatric catheter studies in patients under the age of 12 years, and 4754 were coronary angioplasties or balloon dilatation of valves. 83.3% of diagnostic catheter studies in adults were left heart studies with coronary arteriography. The overall complication rate for diagnostic studies was 0.80%, mortality rate 0.12%, emergency surgical intervention rate 0.08%. Complication rates varied between centres, but there was no correlation with case load. Different patterns of complication were associated with different technical approaches. CONCLUSIONS--Complication rates of diagnostic catheterisation are low but neither negligible nor irreducible. Voluntary audit of this kind has limitations, but it is useful and inexpensive.

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene and risk of restenosis after coronary angioplasty.

Early restenosis in over 30% of cases limits the benefits of percutaneous transluminal coronary angioplasty (PTCA). The mechanisms that underlie restenosis are uncertain, although experimental evidence suggests that the renin-angiotensin system is involved in the vascular response to angioplasty. An insertion(I)/deletion(D) polymorphism in the angiotensin-converting enzyme (ACE) gene, which influences plasma ACE level, has been associated with an increased risk of myocardial infarction in those with the DD genotype. To investigate whether this polymorphism influences the risk of restenosis after PTCA, 233 patients who underwent single-vessel angioplasty in the Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) study were genotyped for the I/D polymorphism and pre-PTCA, post-PTCA, and 4-month clinical and quantitative angiographic data were compared in the three genotype groups. The groups, (II 53, ID 117, and DD 63) were well matched for baseline clinical and both pre- and post-PTCA angiographic features. At 4-month follow-up there was no significant difference between the genotype groups with respect to any of the quantitative angiographic criteria of restenosis: minimal luminal diameter at the site of the angioplasty (DD 1.35 [SE 0.10] mm, ID/II 1.43 [0.05] mm, difference -0.08 [95% CI -0.30 to 0.14]), numbers of subjects with more than 50% diameter stenosis (DD 49%, ID/II 46%, relative risk 1.06 [0.79 to 1.43]), or the number of subjects with more than 50% loss of the acute diameter gain after PTCA (DD 54%, ID/II 43%, 1.26 [0.94 to 1.67]). Likewise, there was no difference in the number of subjects with angina or a positive exercise stress test. We conclude that, in patients undergoing elective PTCA, the I/D polymorphism in the ACE gene does not influence the extent of restenosis, and typing for the polymorphism will not be a useful predictor of risk before the procedure.

Clinical effects and kinetic properties of intravenous APSAC — anisoylated plasminogen-streptokinase activator complex (BRL 26921) in acute myocardial infarction

Fifty patients with a first myocardial infarction presenting within 4 hours of the onset of symptoms were treated with intravenous anisoylated plasminogen-streptokinase activator complex (APSAC-BRL 26921). Vessel patency with good flow was documented in 88%. The left ventricular ejection fraction declined with the duration of symptoms before treatment (r = -0.53, P less than 0.001). The correlation persisted for the group with anterior infarction (r = -0.46, P less than 0.05) where the mean left ventricular ejection fraction prior to discharge from hospital was 36 +/- 9% compared to 49 +/- 7% for the group with inferior infarction. Reinfarction developed in 12% and mortality at 6 months for the whole group was 6%. A degree of systemic fibrinolysis did occur with a fall in mean plasma fibrinogen from 3.20 g/l to 1.08 g/l. A pharmacokinetic study was performed in six patients demonstrating a clearance half-life of fibrinolytic activity of 87.5 +/- 5.0 min. APSAC is an effective intravenous thrombolytic agent with a relatively long half-life of fibrinolytic activity.

Coronary thrombolysis with intravenous anisoylated plasminogen-streptokinase complex BRL 26921.

BRL 26921 is a protected plasminogen-streptokinase complex with selective affinity for thrombus. When given intravenously within three hours of the onset of a first acute myocardial infarction angiographic patency of the infarct related vessel was seen in all 16 patients receiving the active drug compared with only two of 16 receiving a placebo. There was relative sparing of left ventricular function in the active treatment group with anterior infarction (mean left ventricular ejection fraction 37% compared with 23% for placebo), but no significant difference in left ventricular function between the active and placebo groups was seen in patients with inferior infarction. Intravenous BRL 26921 is highly effective in causing coronary reperfusion and may help to preserve left ventricular function when given early in the course of anterior infarction.